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Periodontitis is an inflammatory disease caused by microorganisms that induce the destruction of periodontal tissue. Inflamed and damaged tissue produces various inflammatory cytokines, which activate osteoclasts and induce alveolar bone loss and, eventually, tooth loss. Sirt6 expression suppresses inflammation and bone resorption; however, its role in periodontitis remains unclear. We hypothesized that Sirt6 has a protective role in periodontitis. To understand the role of Sirt6 in periodontitis, we compared periodontitis with ligature placement around the maxillary left second molar in 8-week-old control (C57BL/6J) male mice to Sirt6-overexpressing Tg (Sirt6Tg) mice, and we observed the resulting phenotypes using micro-CT. MDL801, a Sirt6 activator, was used as a therapy for periodontitis through oral gavage. Pro-inflammatory cytokines and increased osteoclast numbers were observed in alveolar bone tissue under periodontitis surgery. In the same condition, interestingly, protein levels from Sirt6 were the most downregulated among sirtuins in alveolar bone tissue. Based on micro-CT and CEJ-ABC distance, Sirt6Tg was observed to resist bone loss against ligature-induced periodontitis. Furthermore, the number of osteoclasts was significantly reduced in Sirt6Tg-ligated mice compared with control-ligated mice, although systemic inflammatory cytokines did not change. Consistent with this observation, we confirmed that bone loss was significantly reduced when MDL801, a Sirt6 activator, was included in the ligation mouse model. Our findings demonstrate that Sirt6 activation prevents bone loss against ligature-induced periodontitis. Thus, a Sirt6 activator may provide a new therapeutic approach for periodontitis.

Malignant hyperthermia (MH), a rare autosomal dominant pharmacogenetic disorder of skeletal muscle calcium regulation, is triggered by sevoflurane in susceptible individuals. We report a Korean having MH with multi-minicore myopathy functionally supported by RYR1-mediated intracellular Casup2+/suprelease testing in B lymphocytes. A 14-year-old boy was admitted for the evaluation of progressive torticollis accompanied by cervicothoracic scoliosis. During the preoperative drape of the patient for the release of the sternocleidomastoid muscle under general anesthesia, his wrist and ankle were observed to have severe flexion contracture. The body temperature was 37.1 °C. To treat MH, the patient was administered a bolus of dantrolene intravenously (1.5 mg/kg) and sodium bicarbonate. After a few minutes, muscle rigidity, tachycardia, and EtCO2 all resolved. Next-generation panel sequencing for hereditary myopathy identified a noveliRYR1/iheterozygous missense variant (NM_000540.2: c.6898Tamp;gt; C; p.Ser2300Pro), which mapped to the MH2 domain of the protein, a hot spot for MH mutations. Ex vivo RYR1-mediated intracellular Casup2+/suprelease testing in B lymphocytes showed hypersensitive Casup2+/supresponses to isoflurane and caffeine, resulting in an abnormal Casup2+/suprelease only in the proband, not in his family members. Our findings expand the clinical and pathological spectra of information associated with MH with multi-minicore myopathy.

KMRC011 is a novel Toll‐like receptor 5 agonist under development as a treatment for acute radiation syndrome (ARS). The aim of this first‐in‐human study was to investigate the tolerability, pharmacokinetics, and pharmacodynamics of a single intramuscular dose of KMRC011 in healthy subjects. A randomized, single‐blind, placebo‐controlled, single dose‐escalation study was conducted with the starting dose of 5 μg. Eight (4 only for 5 μg cohort) subjects per cohort were randomly assigned to KMRC011 or placebo in a 3:1 ratio. Dose‐limiting toxicity (DLT) was assessed throughout the study. Serum concentrations of KMRC011, granulocyte colony‐stimulating factor (G‐CSF), and interleukin‐6 (IL‐6) were measured up to 48 h postdose. Based on safety review, the dose of KMRC011 escalated up to 20 μg, and consequently, a total of 4 dose levels (5, 10, 15, and 20 μg) were explored. The most common adverse event was injection site reaction, showing no dose‐related trend. Three DLTs (2 cases of hepatic enzyme increased and 1 of pyrexia) were observed; 1 in the 15 μg cohort and 2 in the 20 μg cohort. A developed method could not detect any KMRC011 in serum. KMRC011 15 μg and 20 μg showed significant increases of G‐CSF, IL‐6, and absolute neutrophil counts, compared with the placebo. A single intramuscular administration of KMRC011 ranging from 5 to 15 μg was tolerated in healthy subjects. Doses of KMRC011 equal to or greater than 15 μg exerted TLR5 agonist‐like activities by increasing serum G‐CSF and IL‐6. It suggests that KMRC011 has the potential for a treatment for ARS.

We evaluated the tolerability, pharmacokinetics (PK) and preliminary efficacy of KML001, an oral trivalent arsenical, as a monotherapy in patients with advanced solid tumors.With a standard 3 + 3 design for dose-escalation stage, the planned dose levels of KML001 were 5, 7.5, 10, 12.5, and 15 mg/day for 28 days. Once the maximum tolerated dose was determined, 22 subjects were additionally enrolled for dose-expansion stage. PK analysis was performed in the 5, 10, and 15 mg/day cohort at the dose-escalation stage and also at the dose-expansion stage. Moreover, response was assessed using the standard RECIST 1.1.A total of 45 Korean subjects were enrolled. No DLT was reported at the dose-escalation stage. Three DLTs, two cases of prolonged QTc interval and one of neutropenia, were reported in the 12.5 mg/day cohort at the dose-expansion stage. Higher total daily doses up to 12.5 mg/day of KML001 resulted in higher trough plasma concentrations. Among the 18 subjects who completed 2 cycles of therapy, 15 had progressive disease and 3 had stable disease.Doses equal to or greater than 10 mg/day KML001 alone were tolerable and produced plasma concentrations higher than biologically relevant targets.

Background The purpose of this study was to evaluate clinical and radiological outcomes at skeletal maturity after a calcaneo-cuboid-cuneiform osteotomy (triple C osteotomy) for symptomatic flatfoot deformity compared with healthy young adult controls. Methods Nineteen patients (30 feet) who undergone a triple C osteotomy for idiopathic symptomatic flatfeet from July 2006 to April 2013 were compared with 19 controls (38 feet). Radiographic measurements at preoperative examination, 1-year postoperative follow-up, and follow-up at skeletal maturity were evaluated. Functional outcomes were assessed by using the validated visual analog scale foot and ankle (VAS-FA) and the modified American Orthopaedic Foot and Ankle Surgery (AOFAS) score. Results In the triple C osteotomy group, 11 of 12 radiographic measurements were significantly improved at 1 year postoperatively and the last follow-up (p < 0.001). There was no recurrence at skeletal maturity (p > 0.05). There were no significant differences in nine of 12 radiographic measurements between the triple C osteotomy group at maturity and the control group (p > 0.05). Average VAS-FA and AOFAS scores were significantly improved at the time of skeletal maturity (p < 0.001). Conclusions Surgical correction of symptomatic flatfoot deformity in childhood resulted in favorable outcomes after the triple C osteotomy. Deformity correction was also maintained during follow-up at skeletal maturity.

In this study, we aimed to identify a candidate drug that can activate endogenous Angiopoietin 1 (Ang1) expression via drug repositioning as a pharmacological treatment for avascular osteonecrosis. After incubation with 821 drugs from the Food and Drug Administration (FDA)-approved drug library, Ang1 expression in U2OS cell culture media was examined by ELISA. Metformin, the first-line medication for treatment of type 2 diabetes, was selected as a candidate for in vitro and in vivo experimental evaluation. Ang1 was induced, and alkaline phosphatase activity was increased by metformin treatment in U2OS and MG63 cells. Wound healing and migration assay showed increased osteoblastic cell mobility by metformin treatment in U2OS and MG63 cells. Metformin upregulated expression of protein markers for osteoblastic differentiation in U2OS and MG63 cells but inhibited osteoclastic differentiation in Raw264.7 cells. Metformin (25 mg/kg) protected against ischemic necrosis in the epiphysis of the rat femoral head by maintaining osteoblast/osteocyte function and vascular density but inhibiting osteoclast activity in the necrotic femoral head. These findings provide novel insight into the specific biomarkers that are targeted and regulated by metformin in osteoblast differentiation and contribute to understanding the effects of these FDA-approved small-molecule drugs as novel therapeutics for ischemic osteonecrosis.

We herein report a simultaneous frequency stabilization of two 780-nm external cavity diode lasers using a precision wavelength meter (WLM). The laser lock performance is characterized by the Allan deviation measurement in which we find $\sigma_{y}=10^{-12}$ at an averaging time of 1000 s. We also obtain spectral profiles through a heterodyne spectroscopy, identifying the contribution of white and flicker noises to the laser linewidth. The frequency drift of the WLM is measured to be about 2.0(4) MHz over 36 hours. Utilizing the two lasers as a cooling and repumping field, we demonstrate a magneto-optical trap of $^{87}$Rb atoms near a high-finesse optical cavity. Our laser stabilization technique operates at broad wavelength range without a radio frequency element., Comment: 6 pages, 5 figures

BackgroundCK2α/CSNK2A1 is involved in cancer progression by phosphorylating various signaling molecules. Considering the role of CSNK2A1 in cancer progression and phosphorylation of SIRT6 and the role of SIRT6 in chemoresistance through the DNA damage repair pathway, CSNK2A1 and SIRT6 might be involved in resistance to the conventional anti-cancer therapies.MethodsWe evaluated the expression of CSNK2A1 in the 37 osteosarcoma patients and investigated the effects of CSNK2A1 and phosphorylation of SIRT6 on Ser338 on the resistance to the anti-cancer effects of doxorubicin. Results Higher expression of CSNK2A1 predicted shorter overall survival and relapse-free survival in both general osteosarcoma patients and sub-population of patients who received postoperative chemotherapies. U2OS and KHOS/NP osteosarcoma cells with induced overexpression of CSNK2A1 were resistant to cytotoxic effects of doxorubicin, and knock-down of CSNK2A1 potentiated the cytotoxic effects of doxorubicin. CSNK2A1 overexpression-mediated resistance to doxorubicin was associated with SIRT6 phosphorylation and induction of the DNA damage repair pathway molecules ATM and Chk2. CSNK2A1 and SIRT6 mediated resistance to doxorubicin in vivo was attenuated via mutation of SIRT6 at the Ser338 phosphorylation site. Emodin, a CSNK2A1 inhibitor, potentiated the cytotoxic effects of doxorubicin in osteosarcoma cells in vitro. ConclusionsThis study demonstrates that the expression of CSNK2A1 might be used as a prognostic indicator of osteosarcoma. In addition, it suggests that CSNK2A1 induces resistance to doxorubicin through phosphorylation of SIRT6-mediated activation of the DNA damage repair pathway. Therefore, blocking the CSNK2A1-SIRT6-DNA damage repair pathway might be a new therapeutic stratagem for the poor prognostic subgroup of osteosarcomas with high expression of CSNK2A1.

Celecoxib is a selective cyclooxygenase-2 inhibitor widely used in patients with osteoarthritis and rheumatoid arthritis. Recently, nonclinical data on the inhibition of human ether-à-go-go-related gene potassium channels by celecoxib were reported, but there is no compelling evidence for this finding in humans. The aim of this study was to assess the potential effects of celecoxib on cardiac repolarization by conducting a thorough QT study, which was designed in compliance with the related guidelines.This randomized, open-label, positive- and negative-controlled, crossover clinical study was conducted in healthy male and female subjects. Each subject received, in 1 of 4 randomly assigned sequences, all of the following 3 interventions: celecoxib 400 mg once daily for 6 days; a single dose of moxifloxacin 400 mg, which served as a positive control to assess the assay sensitivity; and water without any drug, which served as a negative control. Serial 12-lead ECG and blood samples for pharmacokinetic analysis were collected periodically over 24 h. Individually RR-corrected QT intervals (QTcI) and Fridericia method-corrected QT intervals (QTcF) were calculated and evaluated.Twenty-eight subjects were allocated to 1 of the 4 intervention sequences. The largest time-matched mean effects of celecoxib on the QTcI and QTcF were5 ms, and the upper bounds of the 1-sided 95% CIs of those values did not exceed 10 ms. Moreover, none of the subjects had an absolute QTcI value of450 ms or a change from baseline in QTcI of60 ms after multiple administrations of celecoxib. The QTcI did not show a positive correlation with celecoxib concentrations in the range up to ~2700 μg/L. The overall effects of moxifloxacin on the QTcI and QTcF were enough to establish assay sensitivity. No serious adverse events were reported, with a total of 11 AEs reported in 8 subjects.Celecoxib caused no clinically relevant increase in the QT/QTc interval at the maximum dose level used in current practice settings. ClinicalTrials.gov identifier: NCT03822520.

The objective of study was to compare the pharmacokinetic and safety profiles of a fixed‐dose combination (FDC) formulation of 5/160/20 mg amlodipine/valsartan/atorvastatin with those of separate formulations of a 5/160‐mg amlodipine/valsartan tablet and a 20‐mg atorvastatin tablet. This was a randomized, open‐label, single‐dose, 3‐sequence, 3‐period replicate crossover study with 42 subjects. Serial blood samples for pharmacokinetic assessment were collected up to 72 hours postdose. For establishing bioequivalence (BE) for amlodipine, valsartan, and atorvastatin, a reference‐scaled average BE approach was used if applicable, as well as the conventional limit of 0.80‐1.25. The 90% confidence intervals (CIs) for the geometric mean ratios (GMRs) for the maximum plasma concentration (Cmax) and the area under the curve to the last measurable concentration (AUCt) between the FDC and separate formulations were within the 0.80‐1.25 limit for all analytes but atorvastatin. The estimated within‐subject standard deviation of the log‐transformed values of the separate formulations, the reference intervention, was 0.3804 for the Cmax of atorvastatin, being set at 0.7489‐1.3352 for the BE acceptance limit. For both the Cmax and AUCt for atorvastatin, the GMRs lay within 0.80‐1.25, and the 90%CIs for the GMRs were within the BE acceptance limit. This 3‐period replicate crossover study demonstrated the BE of the FDC formulation of amlodipine, valsartan, and atorvastatin and the separate formulations of an amlodipine/valsartan tablet and an atorvastatin tablet. A similar incidence of treatment‐emergent adverse events (TEAEs) was observed in both interventions, and headache was the most common TEAE.

Recent vision technology allows traffic engineers to analyze traffic safety based on image processing applications. Vehicle trajectory data including vehicle position and speed are extracted and converted into traffic conflicts related variables. These variables are analyzed to find correlations with crash data and geometric design variables and included in the statistical analysis process to evaluate the safety of intersections. In this paper, signal timing information data is included in the analysis process to investigate if there are any correlations with traffic conflict data. For example, traffic conflicts happen more frequently in a certain movement at certain signal time phase. The goal of this paper is to develop a method for vision technology-based traffic safety analysis process using traffic signal data to identify crash prone movement and signal to time at a given intersection. The proposed technique is demonstrated in real-world video data collected in an intersection. This paper is expected to provide more insight and technique in traffic safety evaluation.

Purpose. We evaluated potential drug-drug interactions between cilostazol and simvastatin, both CYP3A substrates, in healthy subjects. Methods. An open-label, two-period, fixed-sequence clinical study was conducted. Seventeen subjects were given a single oral dose of simvastatin 40 mg on day 1 and multiple oral doses of cilostazol 100 mg twice daily on days 2 to 5 followed by a single dose of cilostazol and simvastatin on day 6. Plasma concentrations of simvastatin and its active metabolite, simvastatin acid, were measured using liquid chromatography-tandem mass spectrometry for pharmacokinetic assessment. Moreover, serum lipid profiles under fasting conditions were determined. Results. The geometric mean ratios of the area under the plasma concentration-time curve from time zero to time infinity of simvastatin combined with cilostazol to that of simvastatin alone were 1.64 (90% CI, 1.38-1.95) for simvastatin and 1.31 (1.04-1.66) for simvastatin acid. In addition, coadministration with cilostazol significantly increased the maximum concentration of simvastatin and simvastatin acid, up to 1.8-fold and 1.6-fold, respectively. However, the effects of a single dose of simvastatin on serum lipid profiles were not affected notably when simvastatin was coadministered with cilostazol. Conclusions. Multiple doses of cilostazol increased the systemic exposure of simvastatin and simvastatin acid following a single dose of simvastatin.

Background IL4Rα and IL13Rα1 are constituents of the type II IL4 receptor. Recently, IL4Rα and IL13Rα1 were reported to have roles in cancer progression and suggested as potential prognostic markers. However, studies on IL4Rα and IL13Rα1 in soft-tissue sarcomas have been limited. Methods This study investigated the immunohistochemical expression of IL4Rα and IL13Rα1 in 89 soft-tissue sarcomas of the extremities, superficial trunk, and retroperitoneum. Immunohistochemical staining for IL4Rα and IL13Rα1 were scored according to a combination of staining intensity and staining area in tissue microarray samples. Positivity for the immunohistochemical expression of IL4Rα and IL13Rα1 were determined using receiver operating curve analysis. Statistical analysis was performed using regression analysis and a chi-square test. Results In human soft-tissue sarcomas, immunohistochemical expression of IL4Rα was significantly associated with IL13Rα1 expression. Nuclear and cytoplasmic expression of IL4Rα and IL13Rα1 were significantly associated with shorter survival of soft-tissue sarcoma patients in univariate analysis. Multivariate analysis indicated that nuclear expression of IL4Rα and IL13Rα1 were independent indicators of shorter overall survival (IL4Rα; p = 0.002, IL13Rα1; p = 0.016) and relapse-free survival (IL4Rα; p = 0.022, IL13Rα1; p p p Conclusions This study suggests IL4Rα and IL13Rα1 are associated with the progression of soft-tissue sarcoma, and the expression of IL4Rα and IL13Rα1 might be novel prognostic indicators of soft-tissue sarcoma patients.

BackgroundIL4Rα and IL13Rα1 are constituents of the type II IL4 receptor. Recently, IL4Rα and IL13Rα1 were reported to have roles in cancer progression and suggested as potential prognostic markers. However, studies on IL4Rα and IL13Rα1 in soft-tissue sarcomas have been limited. MethodsThis study investigated the expression of IL4Rα and IL13Rα1 in 89 soft-tissue sarcomas of the extremities, superficial trunk, and retroperitoneum. ResultsIn human soft-tissue sarcomas, immunohistochemical expression of IL4Rα was significantly associated with IL13Rα1 expression. Nuclear and cytoplasmic expression of IL4Rα and IL13Rα1 were significantly associated with shorter survival of soft-tissue sarcoma patients in univariate analysis. Multivariate analysis indicated that nuclear expression of IL4Rα and IL13Rα1 were independent indicators of shorter overall survival (IL4Rα; p = 0.002, IL13Rα1; p = 0.016) and relapse-free survival (IL4Rα; p = 0.022, IL13Rα1; p < 0.001) of soft-tissue sarcoma patients. Moreover, the co-expression pattern of nuclear IL4Rα and IL13Rα1 was an independent indicator of shorter survival of soft-tissue sarcoma patients (overall survival; overall p < 0.001, relapse-free survival; overall p < 0.001). ConclusionsThis study suggests IL4Rα and IL13Rα1 are associated with the progression of soft-tissue sarcoma, and the expression of IL4Rα and IL13Rα1 might be novel prognostic indicators of soft-tissue sarcoma patients.

Intrarenal robust inflammatory response following ischemia-reperfusion injury (IRI) is a major factor in the pathogenesis of renal injury in ischemic acute kidney injury (AKI). Although numerous studies have investigated various agents of immune modulation or suppression for ischemic AKI, few showed reproducible effects. We hypothesized that poly (ADP-ribose) polymerase (PARP) inhibitor may favorably change post-ischemic intrarenal immunologic micromilieu by reducing damage-associated molecular pattern (DAMP) signals and improve renal outcome in ischemic AKI. The effects of JPI-289 (a PARP inhibitor) on early renal injury in a murine IRI model and hypoxic HK-2 cell model were investigated. Bilateral IRI surgery was performed in three groups of 9-week-old male C57BL/6 mice (control, JPI-289 50 mg/kg, and JPI-289 100 mg/kg; n = 9-10 in each group). Saline or JPI-289 was intraperitoneally injected. Renal function deterioration was significantly attenuated in the JPI-289 treatment groups in a dose-dependent manner. Inflammatory cell infiltration and proinflammatory cytokine/chemokine expressions in the post-ischemic kidneys were also attenuated by JPI-289 treatment. JPI-289 treatment at 0.5 and 0.75 μg/ml facilitated the proliferation of hypoxic HK-2 cells. PARP inhibition with JPI-289 treatment showed favorable effects in ischemic AKI by attenuating intrarenal inflammatory cascade in a murine model and facilitating proliferation of hypoxic HK-2 cells.

Background SIRT6 has diverse roles in cells, and the role of SIRT6 in tumorigenesis is controversial. Considering the role of SIRT6 as an inducer of DNA damage repair, it might be involved in resistance to anti-cancer therapy. Methods We evaluated the prognostic significance of SIRT6 in 37 osteosarcomas and investigated the therapeutic efficacy of SIRT6 on the anticancer effects of doxorubicin, olaparib, and ATM inhibitor. Results Immunohistochemical expression of SIRT6 was significantly associated with shorter overall survival and relapse-free survival of osteosarcoma patients, especially in patients who received adjuvant chemotherapy. In U2OS and KHOS/NP osteosarcoma cells, knock-down of SIRT6 significantly potentiated apoptotic effects of doxorubicin and SIRT6 overexpression induced resistance to doxorubicin. Moreover, SIRT6 induced the DNA damage repair pathway and SIRT6-mediated resistance to doxorubicin was attenuated by blocking the DNA damage repair pathway with olaparib and ATM inhibitor. Conclusions This study suggests that suppression of SIRT6 in combination with doxorubicin might be an effective modality in the treatment of osteosarcoma patients, especially for osteosarcomas with shorter survival with high expression of SIRT6.

BackgroundCubitus varus is a complex three-dimensional deformity. Various osteotomies have been introduced to correct this complex deformity. The objective of the present study was to evaluate clinical and functional outcomes of adult cubitus varus deformity treated with translation step-cut osteotomy.MethodsSeventeen consecutive patients with a mean age of 25 years (range, 19–50 years) who underwent translation step-cut osteotomy were enrolled in this study. Their average follow-up period was 28.2 months. Radiographic measurements preoperatively, 3-month postoperatively, and at the last follow-up were compared. Functional outcomes were assessed using Disabilities of the Arm, Shoulder and Hand (DASH), Mayo Elbow Performance Score (MEPS), and Oppenheim criteria.ResultsThe mean humerus–elbow–wrist angle improved from 14.7° ± 6.4° (range, 6°–23°) varus preoperatively to 12.1° ± 6.6° (range, 5°–20°) valgus postoperatively (p p > 0.05) different from that at the initial presentation. Based on Oppenheim criteria, results were excellent for 7, good for 8, and poor for 2 patients. Mean final DASH value and MEPS were 2.5 ± 3.8 points (range, 0–15 points) and 97.0 ± 5.8 points (range, 85–100 points), respectively. With regard to complications, one case had delayed union and one case had transient radial nerve injury.ConclusionTranslation step-cut osteotomy using Y plate is an efficient procedure to correct varus alignment and flexion-extension deformities so that they are within normal limits of adults with post-traumatic cubitus varus deformity.Trial registrationInstitutional Review Board of Jeonbuk National University Hospital (IRB No.2020–01-020).

Ischemic osteonecrosis (ION) can produce permanent deformity and osteoarthritis in the femoral head and other joints. No biologic treatment has been established, and the molecular mechanisms involved in the pathogenesis of ION have not been elucidated. In this work, we found that treatment with sirtuin6 (Sirt6) suppressed inflammatory cytokines, bone resorption, progression of osteoarthritis, and reduced bone deformity in an ION mouse model. We used a deacetylase mutant adenovirus to confirm that those effects were caused by the deacetylase function of Sirt6. Among the osteoclastogenic factors of osteoblasts, only the receptor activator of NF-κb ligand (RANKL) level changed in response to Sirt6 knockout in primary osteoblasts. In particular, the vitamin D receptor physically interacted with Sirt6 and induced recruitment of Sirt6 around RANKL promoters. Finally, Tg mice overexpressing Sirt6 resisted osteocyte death, bone resorption, and progression of osteoarthritis after ischemic surgery, whereas osteoblast/osteocyte-specific Sirt6 knockout mice showed aggravated bone loss and severe deformity. Our findings demonstrate that administration of Sirt6 prevents bone loss and osteoarthritis in ischemic conditions. Activation of Sirt6 in osteoblasts/osteocytes could be a new therapeutic approach to treating ION of the femoral head and other bone regions. © 2020 American Society for Bone and Mineral Research (ASBMR).

일반적으로, 선박 축계는 프로펠러 중량의 영향으로 선미관 후부베어링의 국부적인 지지하중 증가가 현격하게 나타나 잠재적인 축계 베어링 손상의 위험성을 가진다. 이를 방지하기 위한 추진축계 정렬연구는 대부분 준정적 상태(quasi-static condition)에서 프로펠러축과 선미관 후부베어링간의 상대적 경사각을 감소시키는데 중점을 두어 진행되어 왔다. 그러나 보다 완전한 축계 안정성 평가를 위해서는 동적상태에 대한 고려가 필요하다. 본 연구에서는 동적 상태에서 선박 좌현 전타시 과도적으로 변동되는 프로펠러 편심추력이 선미관 내에서 유체 유도 불안정 상태와 스톨(stall)현상을 발생시키는 것을 확인하였다. 따라서 향후 추진축계 정렬 관련 연구에는 축계 안정성 확보를 위하여 과도상태시 편심추력에 의해 발생하는 불평형 진동 특성을 추가적으로 고려해야 할 필요가 있음을 확인하였다.

Objective: There is limited literature concerning the outcomes and role of THA as a surgical option for amputee patients. The aim of this study is to determine the mid-to long-term survival and complication rates of cementless total hip arthroplasty (THA) in patients with contralateral below knee amputations. Methods: A retrospective review of 54 patients with below knee amputation were perfomed who underwent THA for osteoarthritis of the contralateral hip over a 5-year period between 1999 and 2014. Patients were monitored for at least 5 years and assessed with the Harris Hip Score and activities of daily living scale and by evaluating migration or osteolysis around the acetabular cup and femoral stems (amputee group). The amputee group was compared with a control group (non-amputee group) with the same number of patients. Results: Differences in the Harris Hip Score (p = 0.021) and activities of daily living scale (p = 0.043) between the two groups were statistically significant lower in the amputee group at 3 months after surgery. However, no differences were found between the groups from 6 months postoperatively to the last follow-up (Harris Hip Score p = 0.812, activities of daily living scale p = 0.885). Radiologically, any cups or stems showed no signs of migration or osteolysis. In the amputee group, dislocation was found in 1 patient 2 months after arthroplasty (p = 0.315) and long stem revision surgery were performed on two patients due to periprosthetic fracture (p = 0.153). Conclusions: THA performed on the contralateral side of patients with below knee amputation is considered to be an effective treatment with good clinical and radiological results at mid-to long-term follow-up. Level of evidence: Level IV, therapeutic study. Keywords: Below knee amputation, Lower extremity amputation, Osteoarthritis, Total hip arthroplasty, Functional recovery

Synovitis of the affected joint is a common in avascular osteonecrosis (AVN). Increased levels of pro-inflammatory cytokine interleukin-6 (IL-6) have been reported in AVN, but the mechanism of this increase remains unclear. Silent information regulator transcript-1 (SIRT1), an NAD-dependent deacetylase, inhibits the release of inflammatory cytokines. Interferon β (IFN-β) has clear anti-inflammatory properties. We sought to investigate the effects of IFN-β treatment on AVN and to evaluate the specific signal pathway relating to IL-6 and SIRT1 affected during AVN. Using a dissection microscope, AVN was surgically induced in the distal femurs of mice. Exogenous IFN-β was administered to the model mice. The effects of exogenous IFN-β on AVN model mice were assessed using hematoxylin eosin and safranin-O staining, and bone resorption activity was measured using tartrate-resistant acid phosphatase (TRAP) and CD68 staining. Western blots, real-time RT-PCR, and immunohistochemical staining were performed to evaluate the production of SIRT1 and IL-6 in tissues. The RAW 264.7 cell line and bone marrow derived osteoclasts treated with exogenous IFN-β. Histological findings indicated well preserved trabecular bone and decreased osteoclast bone resorption activity in IFN-β treated mice compared with mice in the AVN group. Treatment with IFN-β increased SIRT1 expression and inhibited secretion of IL-6 in this AVN mouse model. IFN-β decreased IL-6 secretion by activating SIRT1 in the RAW 264.7 cell and bone marrow derived osteoclasts. Our work suggests that IFN-β could be used to treat AVN and that both SIRT1 and IL-6 are useful targets for treating patients with AVN.

Posttraumatic pediatric distal tibiofibular synostosis is a rare complication following fracture. This is a retrospective, multicenter case series of synostosis of distal tibiofibular fractures in children. The purpose was to evaluate the incidence and pattern of posttraumatic distal tibiofibular synostosis in children. Of the 604 pediatric distal tibiofibular fractures, 20 patients (3.3%) with synostosis after treatment of distal tibiofibular fractures were identified at 3 tertiary referral centers. There were 12 boys and 8 girls, with a mean age of 8.4±2.0 years (range, 3.7 to 11.5 y) at the time of injury. Medical records were reviewed, and serial radiographs were analyzed to determine fracture configuration, pattern of synostosis, and changes in the relative positions of the proximal and distal tibial and fibular physes and in the alignment of the ankle. The time from the occurrence of fracture until the recognition of the synostosis ranged from 2 to 6 months (mean, 2.8 mo). The most common fracture configuration was oblique tibial fracture combined with comminuted fibular fracture. There were 12 focal types and 8 extensive types. The proximal tibiofibular distance was decreased in 13 patients. Proximal migration of the distal fibular physis developed in all cases. Five patients exhibited ankle valgus of 10 degrees or greater with moderate or severe distal fibular shortening. Eight patients were symptomatic after synostosis and 12 patients were asymptomatic. We identified 2 patterns of synostosis after the treatment of pediatric distal tibiofibular fracture: focal and extensive. The focal type was more prevalent than the extensive type, which was more likely to occur due to high-energy injury. When a tibiofibular cross-union develops, it creates growth abnormalities that warrant observation and potential treatment, as it may lead to progressive deformity or ankle pain. Level IV.

Although the proximal humerus is a common site of osteochondroma, osteochondroma arising from the lesser tuberosity of the proximal humerus is rare. Because of the anatomy of the shoulder, mechanical impingement can occur via direct contact of the protruding lesser tuberosity against the glenoid rim or coracoid. In younger patients, this may cause isolated tearing of the subscapularis. In this study, is presented a rare case of osteochondroma on the lesser tuberosity that caused a subscapularis tear after shoulder impingement in a 34-year-old male. This case was managed using an arthroscopic approach. One year after the surgery, the patient had recovered a normal range of motion, with the resolution of impingement symptoms and the tearing of the subscapularis. Level of evidence IV.

Hypoxic‑ischemic injury of the bone results in osteonecrosis. Nicotinamide adenosine dinucleotide (NAD)‑dependent deacetylase sirtuin‑1 (SIRT1), a type of NAD‑dependent deacetylase, is involved in multiple biological functions, particularly in anti‑apoptosis. However, the effects of SIRT1 in osteoblasts remain unclear and whether SIRT1 protects osteoblasts in hypoxic conditions remains to be elucidated. In the present study, the role of SIRT1 in the osteoblast cells under hypoxia and the underlying mechanism of the anti‑apoptotic activity of SIRT1 were investigated. MC3T3‑E1 osteoblast cells were used for the present study and oxygen‑absorbing packs were used to induce cell hypoxia and apoptosis. MC3T3‑E1 cells were overexpressed SIRT1 by transfection with a SIRT1 adenovirus. The small interfering RNA of SIRT1 to was used to transfect cells to decrease the protein level. An MTT assay was used to estimate cell viability. Apoptosis was examined with the APOPercentage apoptosis assay kit and the activity of caspases was measured by a caspase 3 and 7 activity kit. Co‑immunoprecipitation was used to investigate protein binding ability. The mRNA and protein expression levels were quantified with reverse transcription‑quantitative polymerase chain reaction and immunoblotting. It was demonstrated that the expression of SIRT1 mRNA and protein were elevated, and peaked at 12 h under hypoxic conditions. The data demonstrated that SIRT1 overexpression in cells significantly increased cell viability and markedly decreased the percentage of apoptosis compared with the control and knockdown groups. Furthermore, overexpression of SIRT1 significantly activated anti‑apoptotic effects by deacetylating lysine residue binding to protein kinase B and decreasing the activity of caspases 3, 9 and subsequent pathways. The results from the present study suggested that SIRT1 may serve a protective function in hypoxia‑induced apoptosis in MC3T3‑E1 cells, and that SIRT1 intervention may potentially aid in the treatment of ischemic bone disease.

It has been suggested that post-infectious inflammation in central nervous system is a cause of tic disorder including Tourette's disorder (TD). Since pro-inflammatory cytokines are important mediators inducing inflammation, the cytokine levels are regarded as one of the important indicators of inflammation. Several studies have investigated the relationship of autoimmunity and the pathogenesis of TD by measuring the inflammatory cytokine levels of blood. However, when using human samples, the experimental results can be affected by the factors like size of sample, comorbidity, medication that patients take and the severity of the diseases. Thus, it is important to exclude the possibility that comorbidity and medication affects the level of inflammatory cytokines in the serum of TD patients. In our experiment, we recruited 29 patients without obsessive compulsive disorder (OCD) comorbidity and the majority of these patients did not take medication. The six pro-inflammatory cytokine levels of blood between patient and healthy groups were compared, considering the factors above, to determine more accurate results. Of the cytokines we investigated, the interleukin 12 p70 (IL-12p70) and tumor necrosis factor α (TNFα) levels increased in patient group compared to healthy controls and the patient group which have anti-streptolysin O (ASO) score under the 200 or YTGSS score from 10 to 19 also showed higher IL-12p70 or TNFα levels. In addition, the patients who did not take medication showed higher TNFα levels compared to healthy controls. In conclusion, we suggest that inflammatory pathways that involve IL-12p70 or TNFα are important to the pathogenesis of TD.

Rationale: Although chronic pyelonephritis and urolithiasis are established risk factors for squamous cell carcinoma (SCC), only a minority of patients with chronic urolithiasis eventually develop SCC. It is believed that the chronic irritation leads to squamous cell metaplasia that may subsequently develop into SCC. Although studies show that SSC generally spreads locally with associated symptoms of lymphadenopathy, metastasis to the lungs and liver have also been reported. However, cases spreading to the flank have yet to be reported. Therefore, the use of reconstructive techniques for the repair of extensive soft tissue defects in the flank region after extended retroperitoneal resection, is unknown. Patient concerns: We report a 54-year-old man who presented with a 1-month history of an enlarged skin mass on the right flank. Diagnoses: The patient was subsequently diagnosed with metastatic SCC involving the patient's integumentary system near the flank region proximal to the right kidney following percutaneous nephrostomy. Interventions: The skin mass and the surrounding muscle tissue of the right flank were excised with a wide resection margin including radial nephrectomy. The soft tissue defect after resection was reconstructed using a unilateral gluteus maximus myocutaneous V-Y advancement flap. Outcomes: No recurrence of the SSC was found on follow-up CT performed 12 months postoperatively. Lessons: In patients with long-standing nephrolithiasis complicated by staghorn stone-related infections, biopsies from suspicious lesions detected during percutaneous nephrolithotomy may facilitate early diagnosis. The modified gluteus maximus V-Y advancement flap may be a useful technique for the reconstruction of extensive soft-tissue defects involving the flank region.

MATLAB® is widely used for numerical analysis, modeling, and simulation. One of MATLAB's tools, SimBiology®, is often used for pharmacokinetic, pharmacodynamic model and dynamic systems; however, SimBiology seems to be rarely used for non-compartmental analysis (NCA), and the published official documentation provides a poor description of the analysis algorithm for NCA. Therefore, we conducted NCAs with a hypothetical dataset and some scenarios and compared the results. According to the results of this study, SimBiology estimates parameters using the unweighted linear regression for the terminal slope and linear interpolation method. Moreover, although the documentation describing the actual analysis algorithm used to process non-numeric data is not easily accessible to users, users may introduce numeric data at time zero to perform NCA properly. Using the command window, users can perform analyses more quickly and effectively. If the NCA official documentation were improved, SimBiology might be more widely adopted to perform NCA in clinical pharmacology.

Background FAM83H was initially identified as a protein essential for dental enamel formation. Recent reports have shown that FAM83H is also involved in the progression of human cancers in conjunction with tumor-associated molecules, such as MYC and β-catenin. However, the role of FAM83H in sarcoma has not yet been investigated. Methods The expression and roles of FAM83H and β-catenin were evaluated in human osteosarcomas from 34 patients and osteosarcoma cells. Results The expression of nuclear FAM83H, cytoplasmic FAM83H, and β-catenin were significantly associated with each other and significantly associated with shorter survival of osteosarcoma patients by univariate analysis. In multivariate analysis, cytoplasmic expression of FAM83H was an independent indicator of shorter survival of osteosarcoma patients (overall survival; P

Background The gluteus medius muscle plays a very important role in the stability of the gait, especially in patients with amputation of the lower limbs. Therefore, choosing the appropriate type of approach for hip arthroplasty is very important. Hence, this study aimed to compare the outcomes and complications between the anterolateral approach (ALA) and posterior approach (PA) for hip arthroplasty in patients with contralateral below knee amputation. Methods From January 1999 to November 2014, 67 patients who underwent hip arthroplasty with contralateral below knee amputation were retrospectively analyzed. The study subjects were divided into two groups: the PA group (33 cases) and the ALA group (34 cases). The results of the clinical functional recovery with Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score, Harris Hip Score, and activity of daily living scale were compared between the two groups. During the follow-up period, complications related to gait such as fall, dislocation, and periprosthetic fractures (PPFs) were investigated. Results The Harris Hip Score (p = 0.024) and the activity of the daily living scale (p = 0.043) of the ALA group were significantly lower at 3 months compared to the PA group, but no significant difference was observed between the two groups from 6 months postoperatively to the last follow-up. The WOMAC score was not significantly different between the two groups. Within 3 months after surgery, falls occurred in 3 cases in the PA group and in 11 cases in the ALA group (p = 0.019) Dislocation and PPF were caused by prosthesis-related trauma. Two dislocations and 1 PPF occurred 8 years postoperatively in the PA group. PPF occurred in 3 patients in the ALA group, of which 2 occurred within 3 months after surgery. Conclusion Orthopedic surgeons should pay particular attention in patients with hip arthroplasty on the contralateral side hip who had below knee amputation because functional recovery is delayed until 3 months after ALA compared with PA.

Angiogenesis is closely associated with osteoblast differentiation. Previously, we demonstrated that bone formation can be accelerated by treatment with COMP-Angiopoietin1, a known angiogenic factor. Angiopoietin1 (Ang1) is a specific growth factor that generates stable and mature vasculature through the Tie2 receptor. In this study, we aimed to identify a novel drug that can activate endogenous Ang1 expression as a pharmacological treatment for bone formation. Therefore, Ang1 expression was examined in U2OS osteoblast-like cells treated with 770 drugs from a library of Food and Drug Administration (FDA)-approved drugs by using ELISA for Ang1. l-thyroxine was selected as a novel drug candidate. l-Thyroxine is a synthetic form of the hormone thyroxine, which is used to treat patients with hypothyroidism. Enzyme-linked immunosorbent assays (ELISAs) were performed to test whether Ang1 is induced in a dose-dependent manner in human osteoblast-like cell lines, U2OS and MG63. The effects of l-thyroxine on osteoblast differentiation and mineralization were evaluated by alkaline phosphatase (ALP) activity and Alizarin red s staining. To determine the molecular mechanism, the expression of proteins related to bone formation and differentiation, such as type I collagen (COL1A1), osteocalcin (OC), bone sialoprotein (BSP), distal-less homeobox 5 (Dlx5), Runt-related transcription factor 2 (Runx2), osterix (OSX), and ALP, was tested by Western blotting analysis. Consequently, l-thyroxine induced Ang1 expression in a dose-dependent manner in both U2OS and M63 cells, which was confirmed by ELISA and Western blotting. Also, l-thyroxine activated ALP activity in U2OS and MG63 cells as well as ALP expression. Furthermore, l-thyroxine enhanced the expression of COL1A1, Runx2, OC, BSP, Dlx5, and OSX mRNA and proteins. Taken together, we demonstrated that l-thyroxine increased Ang1 expression and induces bone formation, differentiation, and mineralization in U2OS and MG63 cell lines, which suggests that l-thyroxine could be a potential bone production agent.

Periosteum contains enriched pools of osteogenic progenitors and is highly proliferative, thus giving this tissue a pivotal role in maintaining the diameter of the diaphyseal cortex and in recovery from fractures. Although periosteal proliferation has not been detected in normal bone, intense periosteal proliferation has been observed in pathologic states such as fracture, inflammation, and bone tumors. However, the mechanism by which periosteal osteoprogenitor proliferation is regulated remains poorly understood. To investigate this regulation mechanism, osteoblast/osteocyte-specific conditional knockout mice were developed lacking Smad4 and Osx, two factors that are essential for osteoblast differentiation and matrix mineralization. In Smad4 (Col) and Osx (Col) mice, osteocalcin, Dmp-1, and sclerostin expression were significantly decreased in the cortical bone. Interestingly, although Cre activity was not observed in the periosteum, the proliferation of periosteal osteoprogenitors was enhanced in Smad4 (Col) and Osx (Col) mice, as assessed by 5'-bromo-2'deoxyuridine incorporation and proliferating cell nuclear antigen localization. Since Wnt signaling is a major factor affecting periosteal proliferation, we evaluated Wnt signaling in the periosteum. The expression levels of β-catenin and Lef-1 were increased in the periosteal osteoprogenitors. Moreover, the mRNA levels of β-catenin, cyclin D1, Lef-1, and Axin2, all of which are Wnt target genes, were significantly increased in the periosteum of both Smad4 (Col) and Osx (Col) mice. These results indicated that extracellular proteins secreted by mature osteoblasts and osteocytes suppress the proliferation of periosteal osteoprogenitors by blocking Wnt signaling in a paracrine manner. Our data suggest a new concept of periosteal bone healing and periosteal bone formation.

Rationale: Myositis ossificans (MO) is a benign condition characterized by heterotopic bone formation in the skeletal muscle of extremities. Marked variation can occur in the incidence and location of the bone formed as well as resulting complications. Femoral vessel obstruction caused by MO is an extremely rare but disabling complication. Arterial occlusion may aggravate ischemic conditions, resulting in necrosis in the lower extremity. Patient concerns: We report a 41-year-old female with progressive pain and swelling of the right thigh region for 1 year. Diagnoses: We diagnosed it as obstruction of the superficial femoral artery and vein caused by external compression of the MO between the sartorius and vastus medialis of the thigh. Interventions and outcomes: Adherent tissues and mass were excised with care without damaging the femoral artery or the vein. However, normal morphology did not recover due to loss of elasticity of femoral vessels. Therefore, after resection of the narrowed region of the femoral artery, a femoral-to-femoral graft interposition using the greater saphenous vein was performed. At 12 months after the surgery, vessel reconstruction computed tomography images confirmed normal continuous flow of the femoral artery. Lessons: Vascular compression and peripheral inflammatory response due to MO can cause loss of normal vascular morphology. Surgical excision of the mass and the involved femoral artery segment followed by femoral arterial reconstruction should be considered for lesions that do not spontaneously regress to prevent functional impairment and secondary complications in extremities.