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BACKGROUND: Mesenchymal stem cell (MSC)-based therapies offer potential for bone repair. MSC spheroid cultures may harbor enhanced therapeutic potential over MSC monolayers through increased secretion of trophic factors. However, the impact of spheroid size on trophic factor expression is unclear. OBJECTIVE: We investigated the effect of spheroid size on trophic factor-related gene expression. METHODS: KUM10, a murine MSC line was used. RNA-seq was used to screen the transcriptional profiles of MSC monolayer and spheroid cultures. Differentially expressed genes identified in RNA-seq were evaluated by q-PCR in cultures of 5 × 104 (S group), 5 × 105 (M group), 5 × 106 (L group) cells/well. RESULTS: Comparison of expression levels between KUM10 monolayer and spheroid cultures identified 2140 differentially expressed genes, of which 1047 were upregulated and 1093 were downregulated in KUM10 spheroids. Among these, 12 upregulated genes (Bmp2, Fgf9, Fgf18, Ngf, Pdgfa, Pdgfb, Tgfb1, Vegfa, Vegfc, Wnt4, Wnt5a, Wnt10a) were associated with secretory growth factors. Of these, expression of Fgf9, Fgf18, Vegfa and Vegfc was elevated in the L group, and Pdgfb and Tgfb1 was elevated in the S group. CONCLUSIONS: Spheroid size may impact trophic factor expression. Our results will be useful for future studies assessing the utility of MSC spheroids for treating bone injury. [ABSTRACT FROM AUTHOR]

BACKGROUND: A combination of synthetic porous materials and BMP-2 has been used to promote fracture healing. For bone healing to be successful, it is important to use growth factor delivery systems that enable continuous release of BMP-2 at the fracture site. We previously reported that in situ-formed gels (IFGs) consisting of hyaluronan (HyA)-tyramine (TA), horseradish peroxidase and hydrogen peroxide enhance the bone formation ability of hydroxyapatite (Hap)/BMP-2 composites in a posterior lumbar fusion model. OBJECTIVE: We examined the effectiveness of IFGs-HyA/Hap/BMP-2 composites for facilitating osteogenesis in refractory fracture model mice. METHODS: After establishing the refractory fracture model, animals were either treated at the site of fracture with Hap harboring BMP-2 (Hap/BMP-2) or IFGs-HyA with Hap harboring BMP-2 (IFGs-HyA/Hap/BMP-2) (n = 10 each). Animals that underwent the fracture surgery but did not receive any treatment were considered the control group (n = 10). We determined the extent of bone formation at the fracture site according to findings on micro-computed tomography and histological studies four weeks following treatment. RESULTS: Animals treated with IFGs-HyA/Hap/BMP-2 demonstrated significantly greater bone volume, bone mineral content and bone union than those treated with vehicle or IFG-HyA/Hap alone. CONCLUSIONS: IFGs-HyA/Hap/BMP-2 could be an effective treatment option for refractory fractures. [ABSTRACT FROM AUTHOR]

Using inverse radiative property value analysis, profiles of gray equivalent absorption coefficient are estimated with results similar to non-gray analysis when the coefficients are used in the corresponding gray analysis. For the inverse analysis, the results of non-gray analysis are used as the input. An approximate method is proposed for the estimation of the profiles of equivalent absorption coefficients without previously knowing the results of non-gray analysis. The profiles of the equivalent absorption coefficients obtained by the new method are compared with that estimated by the inverse analysis for two-dimensional model furnaces. The new method is shown to be useful in estimating the profile of absorption coefficients for gray analysis. [Copyright &y& Elsevier]

Sarcopenia is defined as decreasing in muscle strength and mass, and dynapenia is defined as decreasing in muscle strength and maintained muscle mass. This study elucidated the prevalence and characteristics of sarcopenia and dynapenia and evaluate in elderly spinal disorders patients. 1039 spinal disorders patients aged ≥ 65 years were included. We measured age, grip strength, muscle mass, spinal sagittal alignment parameters, low back pain (LBP) scores and health-related quality of life (HR-QoL) scores. Based on the previous reports, patients were categorised into normal group: NG, pre-sarcopenia group: PG, dynapenia group: DG, and sarcopenia group: SG. Pre-sarcopenia, dynapenia, and sarcopenia were found in 101 (9.7%), 249 (19.2%), and 91 (8.8%) patients, respectively. The spinal sagittal alignment parameters, trunk muscle mass, LBP, and HR-QoL scores were significantly worse in DG and SG compared with those in PG and NG. Spinal alignment, trunk muscle mass, and clinical outcomes, including LBP and HR-QoL scores, were maintained in the PG and poor in the DG and SG. Thus, intervention for muscle strength may be a treatment option for changes of spinal sagittal alignment and low back pain. [ABSTRACT FROM AUTHOR]

Background: Although guidelines recommend lipid injectable emulsions (ILEs) be used as a part of parenteral nutrition, many patients in Japan receive lipid-free parenteral nutrition. Furthermore, little is known about the effect of ILEs on clinical outcomes in medical inpatients managed with parenteral nutrition. The aim of this study was to investigate the clinical impact of ILEs on internal medicine inpatients receiving parenteral nutrition.Methods: A propensity score matching (PSM) analysis was performed using a medical claims database covering 451 hospitals in Japan. Participants included the following internal medicine inpatients, ages ≥ 18 years, fasting > 10 days, and receiving exclusively parenteral nutrition, between 2011 and 2020. Participants were divided into 2 groups: those who did and did not receive ILEs. The primary endpoint was in-hospital mortality. The secondary endpoints included intravenous catheter infection, activities of daily living (ADL), hospital length of stay (LOS), and total medical costs. To adjust for energy doses, logistic or multiple regression analyses were performed using energy dose as an additional explanatory variable.Results: After PSM, 19,602 matched pairs were formed out of 61,437 patients. The ILE group had significantly lower incidences than the non-ILE group of in-hospital mortality (20.3% vs. 26.9%; odds ratio [OR], 0.69; 95% confidence interval [CI], 0.66-0.72; p < 0.001), deteriorated ADL (10.8% vs. 12.5%; OR, 0.85; 95% CI, 0.79-0.92; p < 0.001), and shorter LOS (regression coefficient, - 0.8; 95% CI, - 1.6-0.0; p = 0.045). After adjusting for energy dose, these ORs or regression coefficients demonstrated the same tendencies and statistical significance. The mean total medical costs were $21,009 in the ILE group and $21,402 in the non-ILE group (p = 0.08), and the adjusted regression coefficient for the ILE vs. the non-ILE group was - $860 (95% CI, - $1252 to - $47).Conclusions: ILE use was associated with improved clinical outcomes, including lower in-hospital mortality, in internal medicine inpatients receiving parenteral nutrition. [ABSTRACT FROM AUTHOR]

Background: This study examined the association between parenteral energy/amino acid doses and in-hospital mortality among inpatients on long-term nil per os (NPO) status, using a medical claims database in Japan.Methods: Hospitalized patients with aspiration pneumonia, aged 65 and older, and on more than 7-day NPO status were identified in a medical claims database between January 2013 and December 2018. Using multivariate logistic regression and regression analyses, we examined the association between mean parenteral energy/amino acid doses and in-hospital mortality, and secondarily, the association between prognosis (in-hospital mortality, inability to receive full oral intake, readmission, and hospital stay length) and 4 groups of mean amino acid doses (no dose: 0 g/kg/day; very low dose: >0, ≤0.3 g/kg/day; low dose: >0.3, ≤0.6 g/kg/day; moderate dose: >0.6 g/kg/day).Results: The analysis population included 20 457 inpatients (≥80 years: 78.3%). In total, 5 920 mortalities were recorded. Increased amino acid doses were significantly associated with reduced in-hospital mortality (p < .001). With a no dose reference level, the odds ratios (95% confidence interval) of in-hospital mortality adjusted for potential confounders were 0.78 (0.72-0.85), 0.74 (0.67-0.82), and 0.69 (0.59-0.81) for very low, low, and moderate amino acid doses, respectively. Additionally, patients prescribed amino acid dose levels more than 0.6 g/kg/day had shorter hospitalization periods than those prescribed none.Conclusions: Increased amino acid doses were associated with reduced in-hospital mortality. Sufficient amino acid administration is recommended for patients with aspiration pneumonia requiring NPO status. [ABSTRACT FROM AUTHOR]

Animal studies suggest that pain-related-molecule upregulation in degenerated intervertebral discs (IVDs) potentially leads to low back pain (LBP). We hypothesized that IVD mechanical stress and axial loading contribute to discogenic LBP's pathomechanism. This study aimed to elucidate the relationships among the clinical findings, radiographical findings, and pain-related-molecule expression in human degenerated IVDs. We harvested degenerated-IVD samples from 35 patients during spinal interbody fusion surgery. Pain-related molecules including tumor necrosis factor alpha (TNF-alpha), interleukin (IL)-6, calcitonin gene-related peptide (CGRP), microsomal prostaglandin E synthase-1 (mPGES1), and nerve growth factor (NGF) were determined. We also recorded preoperative clinical findings including body mass index (BMI), Oswestry Disability Index (ODI), and radiographical findings including the vacuum phenomenon (VP) and spinal instability. Furthermore, we compared pain-related-molecule expression between the VP (−) and (+) groups. BMI was significantly correlated with the ODI, CGRP, and mPGES-1 levels. In the VP (+) group, mPGES-1 levels were significantly higher than in the VP (−) group. Additionally, CGRP and mPGES-1 were significantly correlated. Axial loading and mechanical stress correlated with CGRP and mPGES-1 expression and not with inflammatory cytokine or NGF expression. Therefore, axial loading and mechanical stress upregulate CGRP and mPGES-1 in human degenerated IVDs, potentially leading to chronic discogenic LBP. [ABSTRACT FROM AUTHOR]

BACKGROUND: Impaired fracture healing results in extensive and prolonged disability and long-term pain. Previous studies reported that nerve growth factor (NGF) was expressed during fracture healing and that anti-NGF antibody improves physical activity associate with facture pain. However, NGF expression levels in delayed or non-union are not fully understood. OBJECTIVE: We compared chronological changes in NGF in the callus of young mice after femur fracture with those in aged mice after femur fracture as a model of bone fracture in the elderly. METHODS: We used young (age 8 weeks) and aged (age 10 months) male C57BL/6J mice. A fracture was generated in the femur. At 5, 7, 10, 14, 17, and 21 days after creation of a fracture, mRNA expression levels of Col2a1, Col10a1, NGF were evaluated using quantitative PCR. We examined NGF protein expression levels and localization in the callus at day 14 using ELISA and immunohistochemistry, respectively. RESULTS: Expression of NGF in the callus after femur fracture in aged mice was significantly greater than that in young mice at days 5, 7, 10, 17, and 21 days. NGF protein levels in the callus of aged mice were also significantly higher than that in young mice. Immunohistochemical staining showed that NGF was heavily expressed in hypertrophic chondrocytes in the callus in aged mice. CONCLUSIONS: It is suggested that delayed Col2a1 and Col10a1 expression reflects delayed chondrocyte formation and delayed chondrocyte maturation in aged mice and that higher NGF expression in aged mice at day 14 may be associated with the presence of remaining hypertrophic chondrocytes in callus with delaying endochondral ossification. [ABSTRACT FROM AUTHOR]

Background: Recently, Oblique lumbar interbody fusion (OLIF) is commonly indicated to correct the sagittal and coronal alignment in adult spinal deformity (ASD). Endplate fracture during surgery is a major complication of OLIF, but the detailed location of fracture in vertebral endplate in ASD has not yet been determined. We sought to determine the incidence and location of endplate fracture and subsidence of the OLIF cage in ASD surgery, and its association with fusion status and alignment.Methods: We analyzed 75 levels in 27 patients were analyzed using multiplanar CT to detect the endplate fracture immediately after surgery and subsidence at 1 year postoperatively. The prevalence was compared between anterior and posterior, approach and non-approach sides, and concave and convex side. Their association with fusion status, local and global alignment, and complication was also investigated.Results: Endplate fracture was observed in 64 levels (85.3%) in all 27 patients, and the incidence was significantly higher in the posterior area compared with the anterior area (85.3 vs. 68.0%, p=0.02) of affected vertebra in the sagittal plane. In the coronal plane, there was no significant difference in incidence between left (approach) and right (non-approach) sides (77.3 and 81.3%, respectively), or concave and convex sides (69.4 and 79.6%) of wedged vertebra. By contrast, cage subsidence at 1 year postoperatively was noted in 14/75 levels (18.7%), but was not associated with endplate fracture. Fusion status, local and global alignment, and complications were not associated with endplate fracture or subsidence.Conclusion: Endplate fracture during OLIF procedure in ASD cases is barely avoidable, possibly induced by the corrective maneuver with ideal rod counter and cantilever force, but is less associated with subsequent cage subsidence, fusion status, and sustainment of corrected alignment in long fusion surgery performed even for elderly patients. [ABSTRACT FROM AUTHOR]

Age is a key factor in intervertebral disc (IVD) degeneration; however, the changes that occur in IVDs with age are not fully understood. Tissue-resident macrophages are critical for tissue homeostasis and are regulated by transforming growth factor- (TGF-) β. We examined changes in the proportion of resident macrophages in young versus aged mice and the role of TGF-β in regulating resident macrophages in IVDs. IVDs were harvested from 4-month (young) and 18-month-old (aged) C57BL/6J mice. The proportion of macrophages in IVDs was determined using flow cytometry (n = 5 for each time point) and the expression of Cd11b, Cd206, and Tgfb genes, which encode CD11b, CD206, and TGF-β protein, respectively, using real-time PCR. To study the role of TGF-β in the polarization of resident macrophages, resident macrophages isolated from IVDs from young and aged mice were treated with recombinant TGF-β with and without a TGF-β inhibitor (SB431542). Additionally, SB431542 was intraperitoneally injected into young and aged mice, and Cd206 expression was examined using real-time PCR (n = 10 for each time point). The proportion of CD11b+ and CD11b+ CD206+ cells was significantly reduced in aged versus young mice, as was Cd11b, Cd206, and Tgfb expression. TGF-β/IL10 stimulation significantly increased the expression of Cd206, an M2 macrophage marker, in disc macrophages from both young and aged mice. Meanwhile, administration of a TGF-β inhibitor significantly reduced Cd206 expression compared to vehicle control in both groups. Conclusion. Resident macrophages decrease with age in IVDs, which may be associated with the concomitant decrease in TGF-β. Our findings provide new insight into the mechanisms of age-related IVD pathology. [ABSTRACT FROM AUTHOR]

An enzymatic crosslinking strategy using hydrogen peroxide and horseradish peroxidase is receiving increasing attention for application with in situ-formed hydrogels (IFHGs). IFHGs may also be ideal carrier materials for bone repair, although their ability to carry bone morphogenetic protein-2 (BMP2) has yet to be examined.We examined the effectiveness of an IFHG made of hyaluronan (IFHG-HA) containing BMP2 for promoting bone formation in a mouse critical size bone defect model.C57/BL6J mice received a 2-mm femoral critical-sized bone defect before being randomly assigned to one of the following treatment groups (n = 6): control (no treatment), IFHG-HA only, PBS with BMP2, and IFHG-HA with BMP2. X-ray radiographs were utilized to track new bone formation, and micro-computed tomography and histological examination were performed on new bone formed at the bone defect site two weeks after surgery.Mice treated with PBS with BMP2 and IFHG-HA with BMP2 had greater bone volume (BV) and bone mineral content (BMC) than those receiving control, and successfully achieved consolidation. Mice treated with IFHG-HA with BMP2 had significantly higher BV and BMC than those treated with PBS with BMP2.IFHG-HA may be an effective carrier for BMP2 to enable delivery for bone defect repair. [ABSTRACT FROM AUTHOR]

In this paper, we address high performance extreme‐scale molecular dynamics (MD) algorithm in the GENESIS software to perform cellular‐scale molecular dynamics (MD) simulations with more than 100,000 CPU cores. It includes (1) the new algorithm of real‐space nonbonded interactions maximizing the performance on ARM CPU architecture, (2) reciprocal‐space nonbonded interactions minimizing communicational cost, (3) accurate temperature/pressure evaluations that allows a large time step, and (4) effective parallel file inputs/outputs (I/O) for MD simulations of extremely huge systems. The largest system that contains 1.6 billion atoms was simulated using MD with a performance of 8.30 ns/day on Fugaku supercomputer. It extends the available size and time of MD simulations to answer unresolved questions of biomacromolecules in a living cell. [ABSTRACT FROM AUTHOR]

Abstract: We have investigated, by the Monte Carlo simulation, spin systems which represent moments of arrayed magnetic nanoparticles interacting with each other only by the dipole–dipole interaction. In the present paper we aim the understanding of finite size effects on the magnetic nanoparticles arrayed in hexagonal columns cut out from the close-packing structures or from those with uniaxial compression. In columns with the genuine close-packing structures, we observe a single vortex state which is also observed previously in finite two-dimensional systems. On the other hand in the system with the inter-layer distance set times of the close-packing one, we found ground states which depend on the number of layers. The dependence is induced by a finite size effect and is related to a orientation transition in the corresponding bulk system. [Copyright &y& Elsevier]

Macrophages produce proinflammatory cytokines in injured intervertebral discs (IVDs). We recently showed that macrophage‐derived inflammatory cytokines contribute to the production of pain‐related factors. However, the mechanism by which macrophages are recruited to injured IVDs has not been fully clarified. Here, we examined the expression dynamics of the chemokine CCL2 in a mouse IVD injury model and the mechanisms of its regulation. The percentage of macrophages increased from day 1 after injury and persisted up until day 28. At 1 and 3 days after injury, the expression of both Ccl2 messenger RNA (mRNA) and CCL2 protein was elevated in the IVD injury group, after which expression decreased to basal levels. Consistent with the increase in CCL2 expression, Ccr2 and Tnfa expression and various types of macrophages were also immediately elevated following disc injury. Further, tumor necrosis factor‐α (TNF‐α) stimulated Ccl2 mRNA and CCL2 protein expression in IVD cells in vitro. The expressions of M1 (Cd86 and Nos2) and M2a (Ym1) macrophage markers were all significantly elevated from day 1 following injury in injured compared with control mice. Meanwhile, the expression of Cd206 (M2a and M2c marker) was significantly elevated on days 3, 7, 14, and 28 following injury. These results suggest that in IVD injury, TNF‐α stimulates CCL2, which, in turn, mediates the recruitment of macrophages with the recruited macrophages subsequently differentiating into M1 and M2 subtypes. CCL2 signaling may, therefore, play an important role in IVD pathology via macrophage recruitment. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:895‐901, 2020 [ABSTRACT FROM AUTHOR]

• Database study describing nutrition management for aspiration pneumonia in Japan • Approximately 35% of inpatients did not received oral nutrition by Day 7 • On NPO status parenteral energy, amino-acids, and fat doses lower than recommended • Co-administration of multiple solutions is recommended for aspiration pneumonia This study aimed to describe real-world nutrition management patterns among inpatients hospitalized for aspiration pneumonia, using a medical claims database in Japan. Patients aged ≥65 years hospitalized for aspiration pneumonia treatment were identified in a medical claims database between January 2013 and December 2018, to evaluate nutrition management initiation and adjustment timing, factors associated with >7-days nil per os (NPO) status, prescribed nutrition doses, and types of parenteral nutrition solutions. Patients who received oral intake or enteral nutrition on the day of admission (Day 1) were excluded. The analysis population included 72,315 inpatients. The median (first quartile, third quartile) initiation date of oral nutrition intake was Day 4 (3, 7) and 65.1% of patients received oral nutrition intake by Day 7. Factors associated with >7-day NPO included sex, BMI, treatment years, Barthel Index score, Japan Coma Scale score, and oxygen inhalation on the day of hospital admission. Amongst NPO patients on Day 7, only 5.3% were prescribed the recommended doses of ≥20 kcal/kg; 6.4% were prescribed ≥1.0 g/kg amino acids, and 5.7% were prescribed fat energy ratio at ≥15% of non-protein calories. Commonly prescribed parenteral nutrition solutions on Day 7 were carbohydrate/electrolyte solutions (52.8%) and peripheral parenteral nutrition solutions (49.0%). Prescribed parenteral energy, amino acids, and fat during the NPO period were lower than the recommended doses in the majority of patients. Prescribing recommended doses of each of these component nutrients may be beneficial when managing parenteral nutrition of patients during NPO. [ABSTRACT FROM AUTHOR]

Spinal sagittal malalignment due to vertebral fractures (VFs) induces low back pain (LBP) in patients with osteoporosis. This study aimed to elucidate spinal sagittal malalignment prevalence based on VF number and patient characteristics in individuals with osteoporosis and spinal sagittal malalignment. Spinal sagittal alignment, and VF number were measured in 259 patients with osteoporosis. Spinal sagittal malalignment was defined according to the SRS-Schwab classification of adult spinal deformity. Spinal sagittal malalignment prevalence was evaluated based on VF number. In patients without VFs, bone mineral density, bone turnover markers, LBP scores and health-related quality of life (HRQoL) scores of normal and sagittal malalignment groups were compared. In 205 of the 259 (79.2%) patients, spinal sagittal malalignment was detected. Sagittal malalignment prevalence in patients with 0, 1, or ≥2 VFs was 72.1%, 86.0%, and 86.3%, respectively. All LBP scores and some subscale of HRQoL scores in patients without VFs were significantly worse for the sagittal malalignment group than the normal alignment group (p < 0.05). The majority of patients with osteoporosis had spinal sagittal malalignment, including ≥70% of patients without VFs. Patients with spinal sagittal malalignment reported worse LBP and HRQoL. These findings suggest that spinal sagittal malalignment is a risk factor for LBP and poor HRQoL in patients with osteoporosis. [ABSTRACT FROM AUTHOR]