The effect of Schizophyllan on the differentiation of osteoclasts and osteoblasts.

Schizophyllan (SPG), a ß-glucan from Schizophyllum commune, is recognized for its antioxidant, immunoregulatory, and anticancer activities. In this study, its effects on bone cells, particularly osteoclasts and osteoblasts, were examined. We demonstrated that SPG dose-dependently inhibited osteoclastogenesis and reduced gene expression associated with osteoclast differentiation. SPG also decreased bone resorption and F-actin ring formation. This inhibition could have been due to the downregulation of transcription factors c-Fos and nuclear factor of activated T cells 1 (NFATc1) via the MAPKs (JNK and p38), IκBα, and PGC1ß/PPARγ pathways. In coculture, SPG lowered osteoclastogenic activity in calvaria-derived osteoblasts by reducing macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor-κB ligand (RANKL) expression. In addition, SPG slightly enhanced osteoblast differentiation, as evidenced by increased differentiation marker gene expression and alizarin red staining. It also exhibited antiresorptive effects in a lipopolysaccharide-induced calvarial bone loss model. These results indicated a dual role of SPG in bone cell regulation by suppressing osteoclastogenesis and promoting osteoblast differentiation. Thus, SPG could be a therapeutic agent for bone resorption-related diseases such as osteoporosis, rheumatoid arthritis, and periodontitis.

Peripheral artery disease diagnosis based on deep learning-enabled analysis of non-invasive arterial pulse waveforms.

This paper intends to investigate the feasibility of peripheral artery disease (PAD) diagnosis based on the analysis of non-invasive arterial pulse waveforms. We generated realistic synthetic arterial blood pressure (BP) and pulse volume recording (PVR) waveform signals pertaining to PAD present at the abdominal aorta with a wide range of severity levels using a mathematical model that simulates arterial blood circulation and arterial BP-PVR relationships. We developed a deep learning (DL)-enabled algorithm that can diagnose PAD by analyzing brachial and tibial PVR waveforms, and evaluated its efficacy in comparison with the same DL-enabled algorithm based on brachial and tibial arterial BP waveforms as well as the ankle-brachial index (ABI). The results suggested that it is possible to detect PAD based on DL-enabled PVR waveform analysis with adequate accuracy, and its detection efficacy is close to when arterial BP is used (positive and negative predictive values at 40 % abdominal aorta occlusion: 0.78 vs 0.89 and 0.85 vs 0.94; area under the ROC curve (AUC): 0.90 vs 0.97). On the other hand, its efficacy in estimating PAD severity level is not as good as when arterial BP is used (r value: 0.77 vs 0.93; Bland-Altman limits of agreement: -32%-+32 % vs -20%-+19 %). In addition, DL-enabled PVR waveform analysis significantly outperformed ABI in both detection and severity estimation. In sum, the findings from this paper suggest the potential of DL-enabled non-invasive arterial pulse waveform analysis as an affordable and non-invasive means for PAD diagnosis.

Application of sequential multimodal analgesia before and after impacted mandibular third molar extraction: Protocol for a randomized controlled trial.

Background: Several analgesics have been applied under various protocols to control the moderate-to-severe postoperative pain caused by the surgical extraction of an impacted mandibular third molar. However, a consensus on optimal pain management while minimizing side effects is yet to be reached. Methods: This multi-center, prospective, double-blind, randomized controlled trial aims to evaluate the efficacy and safety of sequential multimodal analgesia combined with postoperative zaltoprofen along with multiple preemptive analgesics. A total of 80 participants with bilateral impacted mandibular third molar from two hospitals were randomized into two groups. Two surgical extractions were performed at one-month intervals, and in a crossover design, celecoxib or tramadol/acetaminophen was administered before one extraction and placebo before the other extraction. Following extraction, all subjects took zaltoprofen for 5 days. The outcome measures included pain at specific times, time and intensity of the first pain onset after extraction, need of rescue drugs, and occurrence and frequency of side effects. Conclusions: This ongoing clinical trial was designed to provide evidence regarding a new protocol for effective postoperative pain management of a commonly performed surgical extraction. The results of this study will provide guidance to clinicians regarding the timing and combination of oral analgesics in various oral surgeries performed under local anesthesia. Trial registration: KCT0005450, registered on October 7, 2020.

Risk of acute and chronic coronary syndrome in a population with periodontitis: A cohort study.

OBJECTIVE: To investigate the role of periodontitis in the risk of acute and chronic coronary syndrome with compounding factors, including sociodemographic factors and medication use. METHODS: This retrospective cohort study used nationwide, population-based data from the Korean National Health Insurance Service-Health Screening Cohort database (514,866 individuals, 40-79 years). Propensity score matching was used for analysis. Information of subjects for 12 years was included. Socioeconomic and clinical factors were recorded and analysed. RESULTS: The periodontitis group had a greater risk of overall acute coronary syndrome (hazard ratio [95% confidence interval] =1.25 [1.15, 1.35], p < .001) and non-fatal acute coronary syndrome (1.26 [1.16, 1.37], p < .001). The hazard ratio for chronic coronary syndrome was higher in patients with periodontitis (1.35 [1.25, 1.46], p < .001). The cumulative incidence of both acute and chronic coronary syndrome gradually increased, and the hazard ratios reached 1.25 and 1.35 at the 12-year follow-up, respectively. Subgroup analysis revealed that periodontitis had a significantly greater link with acute coronary syndrome incidence in males, younger adults, smokers and subjects without hypertension (p < .01) and with chronic coronary syndrome incidence in smokers, subjects without hypertension and subjects without dyslipidaemia (p < .05). CONCLUSIONS: Periodontitis is associated with an increased risk of acute and chronic coronary syndrome.

Deep Learning-Based Diagnosis of Peripheral Artery Disease via Continuous Property-Adversarial Regularization: Preliminary in Silico Study.

This paper presents a novel deep learning-based arterial pulse wave analysis (PWA) approach to diagnosis of peripheral artery occlusive disease (PAD). Naïve application of deep learning to PAD diagnosis can be hampered by the fact that securing a large amount of longitudinal dataset encompassing diverse PAD severity as well as anatomical and physiological variability presents formidable challenge. Training of a deep neural network (DNN) to a small training dataset raises the risk of overfitting the PAD diagnosis algorithm only to the individuals in the training dataset while deteriorating its ability to generalize also to other individuals who may exhibit a large variability in anatomical and physiological characteristics beyond the training dataset. To overcome these obstacles, we propose a continuous property-adversarial regularization (CPAR) approach to robust generalization of a DNN against scarce datasets. Our approach fosters the exploitation of latent features that can facilitate the intended task independently of confounding property-induced disturbances. by regularizing the extraction of disturbance-dependent latent features in the network's feature extraction layer. By training and testing a deep convolutional neural network (CNN) for PAD diagnosis using scarce virtual datasets, we illustrated that the CNN trained by our approach was superior to a conventionally trained CNN in detecting and assessing the severity of PAD against disturbances originating from diversity in the patients' height and arterial stiffness: when trained with one-time pulse wave signal measurement at ankle and brachial arteries in a small number of patients, our approach achieved detection accuracy of >90% and severity assessment of 0.83 in r2 value, which were >15% and >40% improvement over conventional approach without CPAR. In addition, we ascertained the advantage of our approach in efficient training and robust generalization of DNN by contrasting it to multi-task learning which promotes the exploitation (as opposed to regularization in CPAR) of disturbance-dependent latent features in fulfilling the intended tasks.

Effect of Decompression on Jaw Cystic Lesions Based on Three-Dimensional Volumetric Analysis.

Background and objectives: This study aimed to evaluate the effectiveness of decompression on jaw cysts according to various parameters by volumetric analysis using three-dimensional computed tomography. Materials and methods: Fifty patients who underwent surgical decompression of the jaw cystic lesion were selected, and their preoperative and postoperative computed tomography results between 3 and 27 months were collected. Volumetric analysis was performed to evaluate any differences in the rate of volumetric change according to the sex, age, initial volume of the lesion, duration, location of the lesion, tooth extraction, expansion of the cortical layer, and pathological diagnosis. Multiple linear regression and generalised linear mixed models were used for statistical analyses. Results: The mean reduction rate among all patients was 54.68%. Multiple linear regression analysis revealed that higher reduction rates were associated with a long decompression period, young patient age, and location of the cyst in the posterior maxilla. Generalised linear mixed models revealed that higher reduction rates were associated with a long decompression period and young patient age. Conclusions: Decompression was an effective treatment for reducing the cyst size in all patients. Its effectiveness increased with a long treatment duration, young patient age, and cyst location in the posterior maxilla three-dimensionally.

Detection and Severity Assessment of Peripheral Occlusive Artery Disease via Deep Learning Analysis of Arterial Pulse Waveforms: Proof-of-Concept and Potential Challenges.

Toward the ultimate goal of affordable and non-invasive screening of peripheral occlusive artery disease (PAD), the objective of this work is to investigate the potential of deep learning-based arterial pulse waveform analysis in detecting and assessing the severity of PAD. Using an established transmission line model of arterial hemodynamics, a large number of virtual patients associated with PAD of a wide range of severity and the corresponding arterial pulse waveform data were created. A deep convolutional neural network capable of detecting and assessing the severity of PAD based on the analysis of brachial and ankle arterial pulse waveforms was constructed, evaluated for efficacy, and compared with the state-of-the-art ankle-brachial index (ABI) using the virtual patients. The results suggested that deep learning may diagnose PAD more accurately and robustly than ABI. In sum, this work demonstrates the initial proof-of-concept of deep learning-based arterial pulse waveform analysis for affordable and convenient PAD screening as well as presents challenges that must be addressed for real-world clinical applications.

Electrical and Self-Sensing Properties of Ultra-High-Performance Fiber-Reinforced Concrete with Carbon Nanotubes.

This study examined the electrical and self-sensing capacities of ultra-high-performance fiber-reinforced concrete (UHPFRC) with and without carbon nanotubes (CNTs). For this, the effects of steel fiber content, orientation, and pore water content on the electrical and piezoresistive properties of UHPFRC without CNTs were first evaluated. Then, the effect of CNT content on the self-sensing capacities of UHPFRC under compression and flexure was investigated. Test results indicated that higher steel fiber content, better fiber orientation, and higher amount of pore water led to higher electrical conductivity of UHPFRC. The effects of fiber orientation and drying condition on the electrical conductivity became minor as sufficiently high amount of steel fibers, 3% by volume, was added. Including only steel fibers did not impart UHPFRC with piezoresistive properties. Addition of CNTs substantially improved the electrical conductivity of UHPFRC. Under compression, UHPFRC with a CNT content of 0.3% or greater had a self-sensing ability that was activated by the formation of cracks, and better sensing capacity was achieved by including greater amount of CNTs. Furthermore, the pre-peak flexural behavior of UHPFRC was precisely simulated with a fractional change in resistivity when 0.3% CNTs were incorporated. The pre-cracking self-sensing capacity of UHPFRC with CNTs was more effective under tensile stress state than under compressive stress state.

BMP-9 enhances fibroblast growth factor 21 expression and suppresses obesity.

Although BMP-9 has been reported to induce browning of white adipose tissues (WATs) and suppress high fat diet-induced obesity, detailed molecular mechanism needs to be further elucidated. We report here that administration of MB109, a recombinant derivative of human BMP-9, into obese mice enhanced gene expression of fibroblast growth factor 21 (FGF21), a metabolic regulator, and alleviates a spectrum of pathological symptoms due to high fat diet-induced obesity. In addition, periodical injection of MB109 (500µg/kg/week) reduced an amount of lipid droplets in the liver, serum levels of alanine aminotransferase (ALT), and total cholesterol. These results indicate that MB109 is also effective to treat obesity-mediated non-alcoholic fatty liver disease (NAFLD).

Biphasic effects of FGF2 on adipogenesis.

Although stem cells from mice deficient of FGF2 have been reported to display enhanced capacity for adipogenesis, the literature using in vitro cell culture system has so far reported conflicting results on the role of FGF2 in adipogenesis. We here demonstrate that FGF2, depending on concentration, can function as either a positive or negative factor of in vitro adipogenesis by regulating activation of the ERK signaling pathway. FGF2 at concentrations lower than 2 ng/ml enhanced in vitro adipogenesis of human adipose-derived stem cells (hASCs). However, FGF2 at concentrations higher than 10 ng/ml was able to suppress adipogenesis by maintaining sustained phosphorylation of ERK and function as a dominant negative adipogenic factor toward BMP ligands. Expression levels of FGF2 in the fat tissues from high fat diet induced obese C57BL/6 mice were lower than those from normal chow diet mice, indicating that expression levels of FGF2 in the fat tissues might be in reverse correlation with the size of fat tissues. Our observation of concentration dependent biphasic effect as well as dominant negative effect of FGF2 on adipogenesis provides a mechanistic basis to understand roles of FGF2 in adipogenesis and development of fat tissues.

Lithium chloride suppresses LPS-mediated matrix metalloproteinase-9 expression in macrophages through phosphorylation of GSK-3ß.

Abnormal degradation of matrix components due to dysregulated expression of matrix metalloproteinase (MMP)-9 in macrophages has been linked to progression of acute cerebral ischemia and atherosclerosis. We report that lithium chloride (LiCl) or CHIR99021, inhibitors of Wnt signaling pathway, enhance phosphorylation of glycogen synthase kinase-3beta and suppress lipopolysaccharide-mediated upregulation of MMP-9 expression in murine macrophage RAW264.7 cells in a dose-dependent manner. Suppression of MMP-9 expression by LiCl or CHIR99021 did not result after inhibition of kinases involved in NFκB or AP-1 family proteins, but from changes in the activity of histone deacetylases. Beneficial effects on atherosclerosis or cerebral ischemia in animal studies caused by LiCl may be in part explained by the suppression of MMP-9 gene expression.

BMP-9 as a potent brown adipogenic inducer with anti-obesity capacity.

BMP-9, whose expression is highest in liver cells, has been demonstrated to regulate expression of enzymes involved in glucose homeostasis. However, the underlying mechanism of this effect has yet to be elucidated. We observed that MB109, a recombinant BMP-9 derivative, enhanced brown adipogenesis of human adipose tissue derived stem cells. With this observation of the cell culture system, we hypothesized that MB109 may be able to improve glucose metabolism by regulating expression of brown adipogenic genes. Systemic intraperitoneal injection of MB109 (200 µg/kg/wk) suppressed weight gaining of high fat diet-induced obese mice by reducing sizes of white adipocytes and decreased 16 h fasting blood glucose levels without changing food consumption or apparent behavioral performances. MB109 induced expression of brown adipogenic genes in the subcutaneous but not in the visceral fat tissues from the mice fed with high fat diet. In addition, systematic injection of MB109 enhanced fatty acid synthase expression in the liver of obese mice, which may help attenuate an obesity-associated increase of blood glucose levels. Our results demonstrate a role of BMP-9 in brown adipogenesis and suppressing pathophysiology of high fat diet-induced obesity, presumably through the activin receptor like kinase 1 signaling pathway.

Three-dimensional mandibular change after sagittal split ramus osteotomy with a semirigid sliding plate system for fixation of a mandibular setback surgery.

OBJECTIVE: This study proposes a new plate system, a sliding plate, after sagittal split ramus osteotomy (SSRO). The sliding plate was designed to adjust the spatial relationship between the proximal and distal segments during the postoperative period. This plate was used for mandibular setback surgery to minimize forward early relapse. STUDY DESIGN: Twenty-six Korean subjects who had undergone mandibular setback surgery by SSRO were included in this study. Skeletal stability was evaluated with lateral cephalograms and 3-dimensional cone-beam computerized tomography. RESULTS: Forward mandibular movement during the postoperative period was ~2 mm. The condyles rotated inward on the axial view after surgery. Postoperatively, the condyle rotated outward on the axial view, inward on the coronal view, and forward on the sagittal view by a statistically significant amount. CONCLUSIONS: The fixation method with sliding plates after SSRO was stable and convenient for the operators during surgery and postoperative care.

The fast skeletal muscle myosin light chain is differentially expressed in smooth muscle cells of OVA-challenged mouse trachea.

In a search for new molecular pathways associated with asthma, we performed an mRNA differential display analysis using total RNA extracted from the tracheal tissues of ovalbumin (OVA)-challenged mice and sham controls. cDNAs corresponding to mRNAs for which expression levels were altered by OVA-challenge were isolate and sequenced. Twenty-eight genes differentially expressed in sham and OVA challenged mice were identified. A GenBank BLAST homology search revealed that they were related to cytoskeleton remodeling, transcription, protein synthesis and modification, energy production, and cell growth and differentiation. Two were selected for further characterization. Up-regulation of both the perinatal skeletal myosin heavy chain (skMHC) and fast skeletal muscle myosin light chain (skMLC) genes was confirmed by RT-PCR of trachea tissue from OVA challenged mice. Overexpression of skMLC protein was observed in the smooth muscle layers of OVA-challenged mice by immunohistochemistry, and the surface areas stained with skMLC antibody increased in the OVA-challenged mice. The overexpression of skMLC in murine asthma may be associated with the changes of bronchial smooth muscle.

Production of bioactive human granulocyte-colony stimulating factor in transgenic rice cell suspension cultures.

Human granulocyte-colony stimulating factor (hG-CSF), a human cytokine, was expressed in transgenic rice cell suspension culture. The hG-CSF gene was cloned into the rice expression vector containing the promoter, signal peptide, and terminator derived from a rice alpha-amylase gene Amy3D. Using particle bombardment-mediated transformation, hG-CSF gene was introduced into the calli of rice (Oryza sativa) cultivar Dong-jin. Expression of the hG-CSF gene was confirmed by ELISA and Northern blot analysis. The amount of recombinant hG-CSF accumulated in culture medium from transgenic rice cell suspension culture on the sugar starvation was determined by time series ELISA. Biological activity of the plant derived hG-CSF was confirmed by measuring the proliferation of the AML-193 cells, and was similar to that of the commercial Escherichia coli-derived hG-CSF. In this paper, we discuss the attractive attributes of using rice cell suspension system for the expression of therapeutic recombinant hG-CSF.

Titanium dioxide particle-induced goblet cell hyperplasia: association with mast cells and IL-13.

BACKGROUND: Inhalation of particles aggravates respiratory symptoms including mucus hypersecretion in patients with chronic airway disease and induces goblet cell hyperplasia (GCH) in experimental animal models. However, the underlying mechanisms remain poorly understood. METHODS: To understand this, the numbers of goblet cells, Muc5ac (+) expressing epithelial cells and IL-13 expressing mast cells were measured in the trachea of sham or TiO2 particles-treated rats using periodic acid-Schiff, toluidine blue and immunohistochemical staining. RT-PCR for Muc-1, 2 and 5ac gene transcripts was done using RNA extracted from the trachea. Differential cell count and IL-13 levels were measured in bronchoalveolar lavage (BAL) fluid. In pretreatment groups, cyclophosphamide (CPA) or dexamethasone (DEX) was given before instillation of TiO2. TiO2 treatment markedly increased Muc5ac mRNA expression, and Muc5ac (+) or PAS (+) epithelial cells 48 h following treatment. RESULTS: The concentration of IL-13 in BAL fluids was higher in TiO2 treated-rats when compared to those in sham rats (p < 0.05). Pretreatment with cyclophosphamide (CPA) decreased the number of neutrophils and eosinophils in BAL fluid of TiO2 treated-rats (p < 0.05), but affected neither the percentage of PAS (+) cells, nor IL-13 levels in the BAL fluids (p > 0.05). In contrast, pretreatment with dexamethasone (DEX) diminished the percentage of PAS (+) cells and the levels of IL-13 (p < 0.05). TiO2 treatment increased the IL-13 (+) mast cells (p < 0.05) in the trachea, which was suppressed by DEX (p < 0.05), but not by CPA pretreatment (p > 0.05). In addition there were significant correlations of IL-13 (+) rate of mast cells in the trachea with IL-13 concentration in BAL fluid (p < 0.01) and with the percentage of Muc5ac (+) cells in the sham and TiO2 treated rats (p < 0.05). CONCLUSION: In conclusion, TiO2 instillation induces GCH and Muc5ac expression, and this process may be associated with increased production of IL-13 by mast cells.