Association between periodontal disease and malignant soft tissue sarcomas.

OBJECTIVE: Malignant soft tissue sarcoma (MSTS) is a rare disease, but is seen in patients undergoing orthopedic surgery. Although the association of periodontal disease with various cancers occurring in the oral cavity, gastrointestinal tract, lungs, and prostate, has been reported, the association between periodontal disease and MSTS remains unclear. This study investigated the association between periodontal disease and MSTS in patients undergoing orthopedic surgery. SUBJECTS AND METHODS: One hundred fifteen patients who underwent orthopedic surgery between 2017 and 2021 were retrospectively enrolled (mean age = 66.8 ± 10.7 years). The patient background was adjusted by the propensity score (PS). Subsequently, the association of periodontal disease with MSTS was analyzed using PS inverse probability of treatment weighting (IPTW). Periodontal status was determined by evaluating the periodontal inflamed surface area, which was calculated by measuring the periodontal probing pocket depth and detecting bleeding on probing. RESULTS: Multivariate logistic regression analysis after adjustment by the PS showed that severe periodontitis was significantly associated with MSTS (odds ratio 2.81, p = 0.04). Furthermore, IPTW showed that severe periodontitis was significantly associated with MSTS (odds ratio 3.21, p = 0.01). CONCLUSION: The results indicate an association between periodontal inflammation and MSTS.

Metabolic changes in adipose tissues in response to ß3 -adrenergic receptor activation in mice.

Brown and beige adipocytes dissipate energy as heat. Thus, the activation of brown adipocytes and the emergence of beige adipocytes in white adipose tissue (WAT) are suggested to be useful for preventing and treating obesity. Although ß3 -adrenergic receptor activation is known to stimulate lipolysis and activation of brown and beige adipocytes, fat depot-dependent changes in metabolite concentrations are not fully elucidated. The current study examined the effect of treatment with CL-316,243, a ß3 -adrenergic receptor agonist, on the relative abundance of metabolites in interscapular brown adipose tissue (iBAT), inguinal WAT (ingWAT), and epididymal WAT (epiWAT). Intraperitoneal injection of CL-316,243 (1 mg/kg) for 3 consecutive days increased the relative abundance of several glycolysis-related metabolites in all examined fat depots. The cellular concentrations of metabolites involved in the citric acid cycle and of free amino acids were also increased in epiWAT by CL-316,243. CL-316,243 increased the expression levels of several enzymes and transporters related to glucose metabolism and amino acid catabolism in ingWAT and iBAT but not in epiWAT. CL-316,243 also induced the emergence of more beige adipocytes in ingWAT than in epiWAT. Furthermore, adipocytes surrounded by macrophages were detected in the epiWAT of mice given CL-316,243. The current study reveals the fat depot-dependent modulation of cellular metabolites in CL-316,243-treated mice, presumably resulting from differential regulation of cell metabolism in different cell populations.

Prior Treatment with Anti-High Mobility Group Box-1 Antibody Boosts Human Neural Stem Cell Transplantation-Mediated Functional Recovery After Spinal Cord Injury.

Together with residual host neurons, transplanted neural stem cell (NSC)-derived neurons play a critical role in reconstructing disrupted neural circuits after spinal cord injury (SCI). Since a large number of tracts are disrupted and the majority of host neurons die around the lesion site as the damage spreads, minimizing this spreading and preserving the lesion site are important for attaining further improvements in reconstruction. High mobility group box-1 (HMGB1) is a damage-associated molecular pattern protein that triggers sterile inflammation after tissue injury. In the ischemic and injured brain, neutralization of HMGB1 with a specific antibody reportedly stabilizes the blood-brain barrier, suppresses inflammatory cytokine expression, and improves functional recovery. Using a SCI model mouse, we here developed a combinatorial treatment for SCI: administering anti-HMGB1 antibody prior to transplantation of NSCs derived from human induced pluripotent stem cells (hiPSC-NSCs) yielded a dramatic improvement in locomotion recovery after SCI. Even anti-HMGB1 antibody treatment alone alleviated blood-spinal cord barrier disruption and edema formation, and increased the number of neurites from spared axons and the survival of host neurons, resulting in functional recovery. However, this recovery was greatly enhanced by the subsequent hiPSC-NSC transplantation, reaching an extent that has never before been reported. We also found that this improved recovery was directly associated with connections established between surviving host neurons and transplant-derived neurons. Taken together, our results highlight combinatorial treatment with anti-HMGB1 antibody and hiPSC-NSC transplantation as a promising novel therapy for SCI. Stem Cells 2018;36:737-750.

GLI2 is a novel therapeutic target for metastasis of osteosarcoma.

Aberrant activation of the Hedgehog (Hh) pathway has been reported in several malignancies. We previously demonstrated that knockdown of GLI2 inhibited proliferation of osteosarcoma cells through regulation of the cell cycle. In this study, we analyzed the function of GLI2 in the pathogenesis of osteosarcoma metastasis. Immunohistochemical studies showed that GLI2 was overexpressed in patient osteosarcoma specimens. Knockdown of GLI2 inhibited migration and invasion of osteosarcoma cells. In contrast, the forced expression of constitutively active GLI2 in mesenchymal stem cells promoted invasion. In addition, xenograft models showed that knockdown of GLI2 decreased lung metastasis of osteosarcomas. To examine clinical applications, we evaluated the efficacy of arsenic trioxide (ATO), which is a Food and Drug Administration-approved antitumor drug, on osteosarcoma cells. ATO treatment suppressed the invasiveness of osteosarcoma cells by inhibiting the transcriptional activity of GLI2. In addition, the combination of Hh inhibitors including ATO, vismodegib and GANT61 prevented migration and metastasis of osteosarcoma cells. Consequently, our findings suggested that GLI2 regulated metastasis as well as the progression of osteosarcomas. Inhibition of the GLI2 transcription may be an effective therapeutic method for preventing osteosarcoma metastasis.

Impact of preoperative echocardiographic delay on timing of hip fracture surgery in elderly patients.

Objectives: Early surgery is recommended for hip fractures in elderly patients. This study was performed to evaluate factors contributing to delayed surgery and associated outcomes in a secondary hospital in Japan with a rehabilitation centre. Methods: We retrospectively reviewed the records of 895 patients aged >50 years [median age, 86 (81-91) years] treated for hip fractures at our institution from 2016 to 2020. We defined surgical delay as surgery performed >48 h after admission. We evaluated several risk factors for surgical delay and associated outcomes: mortality, length of hospital stay and walking status. Results: Binomial logistic regression analysis showed that several factors, including preoperative echocardiographic delay (odds ratio, 9.38; 95% confidence interval, 5.95-15.28), were risk factors for surgical delay. In the multiple regression analyses, surgical delay was a significant risk factor for a longer hospital stay (partial regression coefficient, 6.99; 95% confidence interval, 3.67-10.31). Conclusions: Our findings indicated that preoperative echocardiographic delay was one of the risk factors for surgical delay of hip fractures in elderly patients. Surgical delay was a risk factor for a longer hospital stay, including rehabilitation.

Time elapsed from definitive diagnosis to surgery for osteonecrosis of the femoral head: a nationwide observational study in Japan.

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

Treatment of a mouse model of spinal cord injury by transplantation of human induced pluripotent stem cell-derived long-term self-renewing neuroepithelial-like stem cells.

Because of their ability to self-renew, to differentiate into multiple lineages, and to migrate toward a damaged site, neural stem cells (NSCs), which can be derived from various sources such as fetal tissues and embryonic stem cells, are currently considered to be promising components of cell replacement strategies aimed at treating injuries of the central nervous system, including the spinal cord. Despite their efficiency in promoting functional recovery, these NSCs are not homogeneous and possess variable characteristics depending on their derivation protocols. The advent of induced pluripotent stem (iPS) cells has provided new prospects for regenerative medicine. We used a recently developed robust and stable protocol for the generation of long-term, self-renewing, neuroepithelial-like stem cells from human iPS cells (hiPS-lt-NES cells), which can provide a homogeneous and well-defined population of NSCs for standardized analysis. Here, we show that transplanted hiPS-lt-NES cells differentiate into neural lineages in the mouse model of spinal cord injury (SCI) and promote functional recovery of hind limb motor function. Furthermore, using two different neuronal tracers and ablation of the transplanted cells, we revealed that transplanted hiPS-lt-NES cell-derived neurons, together with the surviving endogenous neurons, contributed to restored motor function. Both types of neurons reconstructed the corticospinal tract by forming synaptic connections and integrating neuronal circuits. Our findings indicate that hiPS-lt-NES transplantation represents a promising avenue for effective cell-based treatment of SCI.

Low geriatric nutritional risk index is a risk factor for death within 1 year following hip fracture.

PURPOSE: Hip fracture is common in older patients and is associated with high mortality and functional impairment. The Geriatric Nutritional Risk Index (GNRI) evaluates the risk of malnutrition-related complications, and the Barthel Index (BI) evaluates older patients' functional status. The study aim was to determine the risk factors for both death and decreased BI within 1 year after hip fracture. METHODS: We retrospectively reviewed the records of 108 patients who were treated for hip fractures in 10 public or private hospitals from February to July 2007. Participating facilities comprised eight public or private hospitals with 200-499 beds, and two private or orthopedic hospitals with 20-199 beds. We evaluated several risk factors for death and lower BI within 1 year after hip fracture. RESULTS: The mortality rate within 1 year postoperatively for patients who survived inpatient stay was 6.5% (7/108). The proportion of patients with decreased postoperative BI was 43.6% (44/101). Binomial logistic regression analysis showed that several factors, including low GNRI (odds ratio [OR]: 0.80; 95% confidence interval [CI: 0.68-0.93]), were risk factors for death within 1 year. Postoperative delirium (OR: 8.84 [1.52-51.6]), postinjury dementia (OR: 34.8 [3.01-402]), preinjury BI (OR: 1.05 [1.02-1.08]), and preinjury dementia (OR: 6.22 [1.73-22.4]) were risk factors for decreased postoperative BI. CONCLUSIONS: Our findings indicated that lower GNRI was a risk factor for death within 1 year of hip surgery and that delirium and dementia were among the risk factors for decreased BI 1 year after hip fracture.

Revision total hip arthroplasty using a Kerboull-type acetabular reinforcement device and allogeneic structural bone graft.

PURPOSE: One of the major problems in revision total hip arthroplasty (THA) is severe acetabular bone loss. The aim of our study was to evaluate the clinical outcomes of revision THA using a Kerboull-type reinforcement device (KT plate) and allogeneic structural bone graft. METHODS: This retrospective study evaluated 48 hips that underwent revision THA using a KT plate and allogeneic structural bone graft between 2008 and 2016, with a median follow-up of 6.2 years (range 3-12.6 years). Functional outcome was assessed using the Japanese Orthopaedic Association (JOA) hip score. Postoperative and follow-up radiographs were compared to assess migration and breakage of the implant. RESULTS: The mean JOA hip score improved from 45.6 (±16.3) points before surgery to 72.1 (±11.9) points at the most recent follow-up examination (p < 0.001). Two hips (4.2%) underwent re-revision THA because of cup loosening due to breakage of the KT plate. A total of 13 hips (27.1%) were classified as radiological failures. Binomial logistic regression analysis showed that a Kawanabe classification of stage 4, which indicates massive bone defects in the weight-bearing area, was a risk factor for radiological failure (odds ratio: 4.57; 95% confidence interval: 1.01-26.35). CONCLUSIONS: A KT plate with an allogeneic structural bone graft is a useful method of acetabular reconstruction in revision THA that restores bone stock and improves hip function. Our findings indicated that a Kawanabe classification of stage 4 was a risk factor for radiological failure of the implant.

A scaling relation for the molecular cloud lifetime in Milky Way-like galaxies.

We study the time evolution of molecular clouds across three Milky Way-like isolated disc galaxy simulations at a temporal resolution of 1 Myr and at a range of spatial resolutions spanning two orders of magnitude in spatial scale from ∼10 pc up to ∼1 kpc. The cloud evolution networks generated at the highest spatial resolution contain a cumulative total of ∼80 000 separate molecular clouds in different galactic-dynamical environments. We find that clouds undergo mergers at a rate proportional to the crossing time between their centroids, but that their physical properties are largely insensitive to these interactions. Below the gas-disc scale height, the cloud lifetime τlife obeys a scaling relation of the form τlife∝ℓ-0.3 with the cloud size ℓ, consistent with over-densities that collapse, form stars, and are dispersed by stellar feedback. Above the disc scale height, these self-gravitating regions are no longer resolved, so the scaling relation flattens to a constant value of ∼13 Myr, consistent with the turbulent crossing time of the gas disc, as observed in nearby disc galaxies.

Development of in-house fully residual deep convolutional neural network-based segmentation software for the male pelvic CT.

BACKGROUND: This study aimed to (1) develop a fully residual deep convolutional neural network (CNN)-based segmentation software for computed tomography image segmentation of the male pelvic region and (2) demonstrate its efficiency in the male pelvic region. METHODS: A total of 470 prostate cancer patients who had undergone intensity-modulated radiotherapy or volumetric-modulated arc therapy were enrolled. Our model was based on FusionNet, a fully residual deep CNN developed to semantically segment biological images. To develop the CNN-based segmentation software, 450 patients were randomly selected and separated into the training, validation and testing groups (270, 90, and 90 patients, respectively). In Experiment 1, to determine the optimal model, we first assessed the segmentation accuracy according to the size of the training dataset (90, 180, and 270 patients). In Experiment 2, the effect of varying the number of training labels on segmentation accuracy was evaluated. After determining the optimal model, in Experiment 3, the developed software was used on the remaining 20 datasets to assess the segmentation accuracy. The volumetric dice similarity coefficient (DSC) and the 95th-percentile Hausdorff distance (95%HD) were calculated to evaluate the segmentation accuracy for each organ in Experiment 3. RESULTS: In Experiment 1, the median DSC for the prostate were 0.61 for dataset 1 (90 patients), 0.86 for dataset 2 (180 patients), and 0.86 for dataset 3 (270 patients), respectively. The median DSCs for all the organs increased significantly when the number of training cases increased from 90 to 180 but did not improve upon further increase from 180 to 270. The number of labels applied during training had a little effect on the DSCs in Experiment 2. The optimal model was built by 270 patients and four organs. In Experiment 3, the median of the DSC and the 95%HD values were 0.82 and 3.23 mm for prostate; 0.71 and 3.82 mm for seminal vesicles; 0.89 and 2.65 mm for the rectum; 0.95 and 4.18 mm for the bladder, respectively. CONCLUSIONS: We have developed a CNN-based segmentation software for the male pelvic region and demonstrated that the CNN-based segmentation software is efficient for the male pelvic region.

Recombinant human FGF-2 for the treatment of early-stage osteonecrosis of the femoral head: TRION, a single-arm, multicenter, Phase II trial.

Aim: This study aimed to evaluate the 2-year outcomes from a clinical trial of recombinant human FGF-2 (rhFGF-2) for osteonecrosis of the femoral head (ONFH). Patients & methods: Sixty-four patients with nontraumatic, precollapse and large ONFHs were percutaneously administered with 800 µg rhFGF-2 contained in gelatin hydrogel. Setting the end point of radiological collapse, we analyzed the joint preservation period of the historical control. Changes in two validated clinical scores, bone regeneration and safety were evaluated. Results: Radiological joint preservation time was significantly higher in the rhFGF-2 group than in the control group. The ONFHs tended to improve to smaller ONFHs. The postoperative clinical scores significantly improved. Thirteen serious adverse events showed recovery. Conclusion: rhFGF-2 treatment increases joint preservation time with clinical efficacy, radiological bone regeneration and safety.

Lay abstract Osteonecrosis of the femoral head is a disease that causes pain in the hip joint, making it impossible to walk. The causes of the disease are the use of corticosteroids and the drinking of alcohol. As the disease progresses, the hip joint needs to be replaced with an artificial joint. Risks with hip replacement surgery can include infection, implant dislocation, implant fracture and implant wear. The goal of this trial was to treat the disease with simple surgery using a drug called FGF. The surgical wound was 1 cm and the surgery took only 5 min. The results in 64 patients were better than in those without treatment. FGF treatment can be a therapeutic option for osteonecrosis of the femoral head.

Femoral head collapse rate among Japanese patients with pre-collapse osteonecrosis of the femoral head.

OBJECTIVE: In this study, we aimed to elucidate the relationship between the duration from diagnosis to femoral head collapse and the collapse rate among patients with pre-collapse osteonecrosis of the femoral head (ONFH). METHODS: In this retrospective, observational, multicenter study, we analyzed 268 patients diagnosed with ONFH and classified them using the Japanese Investigation Committee classification. The primary endpoint was duration from the time of diagnosis to femoral head collapse for each type of ONFH. RESULTS: The 12-, 24-, and 36-month collapse rates among participants were 0%, 0%, and 0% for type A, respectively; 0%, 2.0%, and 10.8% for type B, respectively; 25.5%, 40.8%, and 48.5% for type C-1, respectively; and 57.4%, 70.3%, and 76.7% for type C-2 ONFH, respectively. A comparison of unilateral and bilateral ONFH, using Kaplan-Meier survival curves demonstrated similar collapse rates. CONCLUSIONS: The lowest collapse rate was observed for ONFH type A, followed by types B, C-1, and C-2. Additionally, a direct association was observed between the collapse rate and location of the osteonecrotic lesion on the weight-bearing surface.

Distribution and kinematics of 26Al in the Galactic disc.

26Al is a short-lived radioactive isotope thought to be injected into the interstellar medium (ISM) by massive stellar winds and supernovae (SNe). However, all-sky maps of 26Al emission show a distribution with a much larger scale height and faster rotation speed than either massive stars or the cold ISM. We investigate the origin of this discrepancy using an N-body + hydrodynamics simulation of a Milky-Way-like galaxy, self-consistently including self-gravity, star formation, stellar feedback, and 26Al production. We find no evidence that the Milky Way's spiral structure explains the 26Al anomaly. Stars and the 26Al bubbles they produce form along spiral arms, but, because our simulation produces material arms that arise spontaneously rather than propagating arms forced by an external potential, star formation occurs at arm centres rather than leading edges. As a result, we find a scale height and rotation speed for 26Al similar to that of the cold ISM. However, we also show that a synthetic 26Al emission map produced for a possible Solar position at the edge of a large 26Al bubble recovers many of the major qualitative features of the observed 26Al sky. This suggests that the observed anomalous 26Al distribution is the product of foreground emission from the 26Al produced by a nearby, recent SN.

Development of an ion mobility spectrometer using radio-frequency electric field.

This paper describes the development of a new ion mobility spectrometer (IMS) using the radio-frequency (RF) electric field. The proposed IMS has high ion transmission efficiency. Seven connected IMS devices, in which the RF and DC electric fields are created by separate electrodes, are constructed. The ions are confined by the RF electric field and drifted by the DC electric field. The electrodes in each IMS device include short quadrupole electrodes and segmented vane electrodes. The uniform electric field in the IMS is verified by simulated results obtained using SIMION. To measure the exact value of reduced mobility K 0 at low Td (1 Td = 10-17 V cm2), two ion gates are installed in the IMS. By installing the ion gates at suitable positions for eliminating the effect of gas flow, the exact ion velocity through the IMS can be measured. The K 0 values of O2 + and C6H6 + ions are measured as a function of Td. In addition, the K 0 of CH3OCH2 + fragment ions is measured. These K 0 measurement results are consistent with previous results obtained using electrostatic drift tube apparatus. In summary, as our IMS can measure K 0 under low Td conditions, it can be used to better understand the structure of small molecular or fragment ions.