Anti­inflammatory effects of methanol extract from Peperomia dindygulensis Miq. mediated by HO­1 in LPS­induced RAW 264.7 cells.

Inflammation serves as a multifaceted defense mechanism activated by pathogens, cellular damage and irritants, aiming to eliminate primary causes of injury and promote tissue repair. Peperomia dindygulensis Miq. (P. dindygulensis), prevalent in Vietnam and southern China, has a history of traditional use for treating cough, fever and asthma. Previous studies on its phytochemicals have shown their potential as anti-inflammatory agents, yet underlying mechanisms remain to be elucidated. The present study investigated the regulatory effects of P. dindygulensis on the anti-inflammatory pathways. The methanol extracts of P. dindygulensis (PDME) were found to inhibit nitric oxide (NO) production and induce heme oxygenase-1 (HO-1) expression in murine macrophages. While MAPKs inhibitors, such as SP600125, SB203580 and U0126 did not regulate HO-1 expression, the treatment of cycloheximide, a translation inhibitor, reduced HO-1. Furthermore, PDME inhibited lipopolysaccharide (LPS)-induced inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) and TNF-α expression at both the mRNA and protein levels. The activity of NOS and the expression of TNF-α, iNOS and COX-2 decreased in LPS-stimulated Raw 264.7 cells treated with PDME and this effect was regulated by inhibition of HO-1 activity. These findings suggested that PDME functions as an HO-1 inducer and serves as an effective natural anti-inflammatory agent in LPS-induced inflammation.

Parathyroid hormone therapy improves MRSA-infected fracture healing in a murine diabetic model.

Introduction: Diabetes mellitus (DM) impairs fracture healing and is associated with susceptibility to infection, which further inhibits fracture healing. While intermittent parathyroid hormone (1-34) (iPTH) effectively improves fracture healing, it is unknown whether infection-associated impaired fracture healing can be rescued with PTH (teriparatide). Methods: A chronic diet-induced type 2 diabetic mouse model was used to yield mice with decreased glucose tolerance and increased blood glucose levels compared to lean-fed controls. Methicillin-resistant Staphylococcus aureus (MRSA) was inoculated in a surgical tibia fracture model to simulate infected fracture, after which mice were treated with a combination of antibiotics and adjunctive teriparatide treatment. Fracture healing was assessed by Radiographic Union Scale in Tibial Fractures (RUST), micro-computed tomography (µCT), biomechanical testing, and histology. Results: RUST score was significantly poorer in diabetic mice compared to their lean nondiabetic counterparts. There were concomitant reductions in micro-computed tomography (µCT) parameters of callus architecture including bone volume/total volume, trabecular thickness, and total mineral density in type 2 diabetes mellitus (T2DM) mice. Biomechanicaltesting of fractured femora demonstrated diminished torsional rigidity, stiffness, and toughness to max torque. Adjuvant teriparatide treatment with systemic antibiotic therapy improved numerous parameters of bone microarchitecture bone volume, increased connectivity density, and increased trabecular number in both the lean and T2DM group. Despite the observation that poor fracture healing in T2DM mice was further impaired by MRSA infection, adjuvant iPTH treatment significantly improved fracture healing compared to antibiotic treatment alone in infected T2DM fractures. Discussion: Our results suggest that teriparatide may constitute a viable adjuvant therapeutic agent to improve bony union and bone microarchitecture to prevent the development of septic nonunion under diabetic conditions.

Transcriptomic identification of genes expressed in invasive S. aureus diabetic foot ulcer infection.

Introduction: Infection in diabetic foot ulcers (DFUs) is one of the major complications associated with patients with diabetes. Staphylococcus aureus is the most common offending pathogen in patients with infected DFU. Previous studies have suggested the application of species-specific antibodies against S. aureus for diagnosis and monitoring treatment response. Early and accurate identification of the main pathogen is critical for management of DFU infection. Understanding the host immune response against species-specific infection may facilitate diagnosis and may suggest potential intervention options to promote healing infected DFUs. We sought to investigate evolving host transcriptome associated with surgical treatment of S. aureus- infected DFU. Methods: This study compared the transcriptome profile of 21 patients with S. aureus- infected DFU who underwent initial foot salvage therapy with irrigation and debridement followed by intravenous antibiotic therapy. Blood samples were collected at the recruitment (0 weeks) and 8 weeks after therapy to isolate peripheral blood mononuclear cells (PBMCs). We analyzed the PBMC expression of transcriptomes at two different time points (0 versus 8 weeks). Subjects were further divided into two groups at 8 weeks: healed (n = 17, 80.95%) versus non-healed (n = 4, 19.05%) based on the wound healing status. DESeq2 differential gene analysis was performed. Results and discussion: An increased expression of IGHG1, IGHG2, IGHG3, IGLV3-21, and IGLV6-57 was noted during active infection at 0 weeks compared with that at 8 weeks. Lysine- and arginine-rich histones (HIST1H2AJ, HIST1H2AL, HIST1H2BM, HIST1H3B, and HIST1H3G) were upregulated at the initial phase of active infection at 0 weeks. CD177 and RRM2 were also upregulated at the initial phase of active infection (0 weeks) compared with that at 8 weeks of follow-up. Genes of heat shock protein members (HSPA1A, HSPE1, and HSP90B1) were high in not healed patients compared with that in healed patients 8 weeks after therapy. The outcome of our study suggests that the identification of genes evolution based on a transcriptomic profiling could be a useful tool for diagnosing infection and assessing severity and host immune response to therapies.

Construction and evaluation of a clinically relevant model of septic arthritis.

Despite the creation of several experimental animal models for the study of septic arthritis, a protocol detailing the development of a reliable and easily reproducible animal model has not yet been reported. The experimental protocol described herein for the development of a clinically relevant mouse model of septic arthritis includes two main study stages: the first stage consisting of the preparation of the mice and of the methicillin-resistant Staphylococcus aureus (MRSA) cultures, followed by direct inoculation of MRSA into the knee joints of C57BL/6J mice (25-40 min); and a second study stage consisting of multiple sample collection and data analysis (1-3 days). This protocol may be carried out by researchers skilled in mouse care and trained to work with biosafety-level-2 agents such as MRSA. The model of septic arthritis described here has demonstrated clinical relevance in developing intra-articular inflammation and cartilage destruction akin to that of human patients. Moreover, we describe methods for serum, synovial fluid and knee joint tissue analysis that were used to confirm the development of septic arthritis in this model, and to test potential treatments. This protocol confers the advantages of enabling granular evaluation of the pathophysiology of MRSA infection and of the efficacy of therapeutic medications; it may also be employed to study a range of native joint diseases beyond inflammatory pathologies alone.

VISTA (PD-1H) Is a Crucial Immune Regulator to Limit Pulmonary Fibrosis.

VISTA (V domain immunoglobulin suppressor of T cell activation, also called PD-1H [programmed death-1 homolog]), a novel immune regulator expressed on myeloid and T lymphocyte lineages, is upregulated in mouse and human idiopathic pulmonary fibrosis (IPF). However, the significance of VISTA and its therapeutic potential in regulating IPF has yet to be defined. To determine the role of VISTA and its therapeutic potential in IPF, the expression profile of VISTA was evaluated from human single-cell RNA sequencing data (IPF Cell Atlas). Inflammatory response and lung fibrosis were assessed in bleomycin-induced experimental pulmonary fibrosis models in VISTA-deficient mice compared with wild-type littermates. In addition, these outcomes were evaluated after VISTA agonistic antibody treatment in the wild-type pulmonary fibrosis mice. VISTA expression was increased in lung tissue-infiltrating monocytes of patients with IPF. VISTA was induced in the myeloid population, mainly circulating monocyte-derived macrophages, during bleomycin-induced pulmonary fibrosis. Genetic ablation of VISTA drastically promoted pulmonary fibrosis, and bleomycin-induced fibroblast activation was dependent on the interaction between VISTA-expressing myeloid cells and fibroblasts. Treatment with VISTA agonistic antibody reduced fibrotic phenotypes accompanied by the suppression of lung innate immune and fibrotic mediators. In conclusion, these results suggest that VISTA upregulation in pulmonary fibrosis may be a compensatory mechanism to limit inflammation and fibrosis, and stimulation of VISTA signaling using VISTA agonists effectively limits the fibrotic innate immune landscape and consequent tissue fibrosis. Further studies are warranted to test VISTA as a novel therapeutic target for the IPF treatment.

Concurrent targeting of glycolysis in bacteria and host cell inflammation in septic arthritis.

Intracellular infiltration of bacteria into host cells complicates medical and surgical treatment of bacterial joint infections. Unlike soft tissue infections, septic arthritis and infection-associated inflammation destroy cartilage that does not regenerate once damaged. Herein, we show that glycolytic pathways are shared by methicillin-resistant Staphylococcus aureus (MRSA) proliferation and host inflammatory machinery in septic arthritis. MRSA readily penetrates host cells and induces proinflammatory cascades that persist after conventional antibiotic treatment. The glycolysis-targeting drug dimethyl fumarate (DMF) showed both bacteriostatic and anti-inflammatory effects by hindering the proliferation of intracellular MRSA and dampening excessive intraarticular inflammation. Combinatorial treatment with DMF and vancomycin further reduced the proliferation and re-emergence of intracellular MRSA. Combinatorial adjuvant administration of DMF with antibiotics alleviated clinical symptoms of septic arthritis by suppressing bacterial burden and curbing inflammation to protect cartilage and bone. Our results provide mechanistic insight into the regulation of glycolysis in the context of infection and host inflammation toward development of a novel therapeutic paradigm to ameliorate joint bioburden and destruction in septic arthritis.

Treating 'Septic' With Enhanced Antibiotics and 'Arthritis' by Mitigation of Excessive Inflammation.

Bacterial infection within the synovial joint, commonly known as septic arthritis, remains a clinical challenge as it presents two concurrent therapeutic goals of reducing bacterial burden and preservation of articular cartilage from destructive host inflammation. We hypothesized that mitigation of MRSA-induced inflammatory signaling could diminish destruction of articular cartilage in the setting of septic arthritis when used in conjunction with antibiotics. Herein, we provide evidence which supports a new therapeutic notion that concurrent antimicrobial therapy to address the 'septic' component of the disease with inflammation mitigation to manage the destructive 'arthritis' component. We established a murine model to mimic septic knee arthritis, as well as a variety of other inflammatory joint conditions. This murine septic arthritis model, in conjunction with in vitro and ex-vivo models, was utilized to characterize the inflammatory profile seen in active septic arthritis, as well as post-antibiotic treatment, via transcriptomic and histologic studies. Finally, we provided the clinical rationale for a novel therapeutic strategy combining enhanced antibiotic treatment with rifampin and adjuvant immunomodulation to inhibit post-infectious, excess chondrolysis and osteolysis. We identified that septic arthritis secondary to MRSA infection in our murine model led to increased articular cartilage damage compared to various types of inflammatory arthritis. The activation of the pERK1/2 signaling pathway, which is implicated with the mounting of an immune response and generation of inflammation, was increased in intracellular MRSA-infected synovial tissue and persisted despite antibiotic treatment. Trametinib, an inhibitor of ERK signaling through suppression of MEK1/2, alleviated the inflammation produced by the addition of intra-articular, heat-killed MRSA. Further, when combined with vancomycin and rifampin, mitigation of inflammation by pERK1/2 targeting improved outcomes for MRSA septic arthritis by conferring chondroprotection to articular cartilage and diminishing inflammatory osteolysis within bone. Our results support a new therapeutic notion that cell/biofilm-penetrating antibiotics alongside adjuvant mitigation of excessive intra-articular inflammation accomplish distinct therapeutic goals: reduction of bacterial burden and preservation of articular cartilage integrity.

Enhancement of Impaired MRSA-Infected Fracture Healing by Combinatorial Antibiotics and Modulation of Sustained Inflammation.

Fracture healing is impaired in the setting of infection, which begets protracted inflammation. The most problematic causative agent of musculoskeletal infection is methicillin-resistant Staphylococcus aureus (MRSA). We hypothesized that modulation of excessive inflammation combined with cell-penetrating antibiotic treatments facilitates fracture healing in a murine MRSA-infected femoral fracture model. Sterile and MRSA-contaminated open transverse femoral osteotomies were induced in 10-week-old male C57BL/6 mice and fixed via intramedullary nailing. In the initial therapeutic cohort, empty, vancomycin (V), rifampin (R), vancomycin-rifampin (VR), or vancomycin-rifampin-trametinib (VRT) hydrogels were applied to the fracture site intraoperatively. Rifampin was included because of its ability to penetrate eukaryotic cells to target intracellular bacteria. Unbiased screening demonstrated ERK activation was upregulated in the setting of MRSA infection. As such, the FDA-approved mitogen-activated protein kinase kinase (MEK)1-pERK1/2 inhibitor trametinib was evaluated as an adjunctive therapeutic agent to selectively mitigate excessive inflammation after infected fracture. Two additional cohorts were created mimicking immediate and delayed postoperative antibiotic administration. Systemic vancomycin or VR was administered for 2 weeks, followed by 2 weeks of VRT hydrogel or oral trametinib therapy. Hematologic, histological, and cytokine analyses were performed using serum and tissue isolates obtained at distinct postoperative intervals. Radiography and micro-computed tomography (µCT) were employed to assess fracture healing. Pro-inflammatory cytokine levels remained elevated in MRSA-infected mice with antibiotic treatment alone, but increasingly normalized with trametinib therapy. Impaired callus formation and malunion were consistently observed in the MRSA-infected groups and was partially salvaged with systemic antibiotic treatment alone. Mice that received VR alongside adjuvant MEK1-pERK1/2 inhibition displayed the greatest restoration of bone and osseous union. A combinatorial approach involving adjuvant cell-penetrating antibiotic treatments alongside mitigation of excessive inflammation enhanced healing of infected fractures. © 2022 American Society for Bone and Mineral Research (ASBMR).

Molecular Design Strategy for Orange Red Thermally Activated Delayed Fluorescence Emitters in Organic Light-Emitting Diodes (OLEDs).

Pure organic molecules based thermally activated delayed fluorescence (TADF) emitters have been successfully developed in recent years for their propitious application in highly efficient organic light emitting diodes (OLEDs). In the case of orange red emitters, the non-radiative process is known to be a serious issue due to its lower lying singlet energy level. However, recent studies indicate that there are tremendous efforts put to develop efficient orange red TADF emitters. In addition, the external quantum efficiency (EQE) of heteroaromatic based orange red TADF OLEDs surpassed 30 %. Such heteroaromatic type emitters showed wide emission spectra; therefore, more attention is being paid to develop highly efficient orange red TADF emitters along with good color purity. Herein, the recent progress of orange red TADF emitters based on molecular structures, such as cyanobenzene, heteroaromatic, naphthalimide, and boron-based acceptors, are reviewed. Further, our insight on these acceptors has been provided by their photophysical studies and device performances. Future perspectives of orange red TADF emitters for real practical applications are discussed.

Preoperative Meniscus: Pitfalls and Traps to Avoid

To accurately interpret knee MRI, it is important not only to know the basic meniscal anatomy but also to distinguish it from that under pathological conditions. Thus, it would be helpful to know the normal meniscus variants (false positives) that could be mistaken for meniscal tears, and tears that could easily be missed and incorrectly diagnosed as normal (false negatives).False positives include synovial recesses, meniscal flounce, the relationship between the popliteus tendon and lateral meniscus, transverse ligament, the anterior root of the meniscus, and meniscofemoral ligament. False negatives include focal radial tears, flap tears, posterior root tears, meniscocapsular separation, and discoid meniscal tears. In this pictorial essay, we reviewed the imaging data obtained in the aforementioned cases.

Fine Needle Aspiration Cytology vs. Core Needle Biopsy for Thyroid Nodules:A Prospective, Experimental Study Using Surgical Specimen

Purpose@#To evaluate and compare the diagnostic outcomes of ultrasonography (US)-guided fine needle aspiration (FNA) and core needle biopsy (CNB) performed on the same thyroid nodule using a surgical specimen for direct comparison. @*Materials and Methods@#We included 89 thyroid nodules from 88 patients from February 2015 to January 2016. The inclusion criterion was thyroid nodules measuring ≥ 20 mm (mean size: 40.0 ± 15.3 mm). Immediately after surgical resection, FNA and subsequent CNB were performed on the surgical specimen under US guidance. FNA and CNB cytopathologic results on the specimen were compared with the surgical diagnosis. @*Results@#Among the 89 nodules, 30 were malignant and 59 were benign. Significantly higher inconclusive rates were seen in FNA for malignant than benign nodules (80.0% vs. 39.0%, p < 0.001). For CNB, conclusive and inconclusive rates did not differ between benign and malignant nodules (p = 0.796). Higher inconclusive rates were seen for FNA among cancers regardless of US features, and in the subgroup of size ≥ 40 mm (62.5% vs. 22.9%, p = 0.028). Eleven cancers were diagnosed with CNB (36.7%, 11/30), while none was diagnosed using FNA. @*Conclusion@#In this experimental study using surgical specimens, CNB showed a potential to provide improved diagnostic sensitivity for thyroid cancer, especially when a conclusive diagnosis is limited with FNA.

Emergency Cervical Carotid Artery Stenting After Intravenous Thrombolysis in Patients With Hyperacute Ischemic Stroke

Background@#Intravenous recombinant tissue plasminogen activator (IV rtPA) is the mainstay of treatment for acute ischemic stroke to recanalize thrombosed intracranial vessels within 4.5 hours. Emergency carotid artery stenting for the treatment of acute stroke due to stenoocclusion of the proximal internal carotid artery (ICA) can improve symptoms, prevent neurological deterioration, and reduce recurrent stroke risk. The feasibility and safety of the combination therapy of IV rtPA and urgent carotid artery stenting have not been established. @*Methods@#From November 2005 to October 2020, we retrospectively assessed patients who had undergone emergent carotid artery stenting after IV rtPA for hyperacute ischemic stroke due to steno-occlusive proximal ICA lesion. Hemorrhagic transformation, successful recanalization, modified Rankin Scale (mRS) score at 90 days, and stent patency at 3 and 12 months or longer were evaluated. Favorable outcome was defined as a 90-days mRS score of ≤ 2. @*Results@#Nineteen patients with hyperacute stroke had undergone emergent carotid artery stenting after IV rtPA therapy. Their median age was 70 (67.5–73.5) years (94.7% men).Among 15 patients with an additional intracranial occlusion after flow restoration in the proximal ICA, a modified TICI grade ≥ 2b was achieved in 11 patients (73.3%). Hemorrhagic transformation occurred in five patients (26.3%); mortality rate was 5.7%. Eleven patients (57.9%) had favorable outcomes at 90 days. Stent patients (94.1%) maintained stent patency for ≥ 12 months. @*Conclusion@#We showed that emergent carotid artery stenting after IV rtPA therapy for hyperacute stroke caused by atherosclerotic proximal ICA steno-occlusion was feasible and safe.

Inflammatory conversion of quiescent osteoblasts by metastatic breast cancer cells through pERK1/2 aggravates cancer-induced bone destruction.

Disruption of bone homeostasis caused by metastatic osteolytic breast cancer cells increases inflammatory osteolysis and decreases bone formation, thereby predisposing patients to pathological fracture and cancer growth. Alteration of osteoblast function induces skeletal diseases due to the disruption of bone homeostasis. We observed increased activation of pERK1/2 in osteolytic breast cancer cells and osteoblasts in human pathological specimens with aggressive osteolytic breast cancer metastases. We confirmed that osteolytic breast cancers with high expression of pERK1/2 disrupt bone homeostasis via osteoblastic ERK1/2 activation at the bone-breast cancer interface. The process of inflammatory osteolysis modulates ERK1/2 activation in osteoblasts and breast cancer cells through dominant-negative MEK1 expression and constitutively active MEK1 expression to promote cancer growth within bone. Trametinib, an FDA-approved MEK inhibitor, not only reduced breast cancer-induced bone destruction but also dramatically reduced cancer growth in bone by inhibiting the inflammatory skeletal microenvironment. Taken together, these findings suggest that ERK1/2 activation in both breast cancer cells and osteoblasts is required for osteolytic breast cancer-induced inflammatory osteolysis and that ERK1/2 pathway inhibitors may represent a promising adjuvant therapy for patients with aggressive osteolytic breast cancers by altering the shared cancer and bone microenvironment.

Dual therapeutic targeting of intra-articular inflammation and intracellular bacteria enhances chondroprotection in septic arthritis.

Bacterial infections involving joints and vital organs represent a challenging clinical problem because of the two concurrent therapeutic goals of bacterial eradication and tissue preservation. In the case of septic arthritis, permanent destruction of articular cartilage by intense host inflammation is commonly seen even after successful treatment of bacterial infection. Here, we provide scientific evidence of a novel treatment modality that can protect articular cartilage and enhanced eradication of causative bacteria in septic arthritis. Locally delivered cell-penetrating antibiotics such as rifampicin effectively eradicate intracellular reservoirs of methicillin-resistant Staphylococcus aureus within joint cells. Furthermore, mitigation of intra-articular inflammation by targeting the NLRP3 (nucleotide-binding oligomerization domain-, leucine-rich repeat- and pyrin domain-containing 3) inflammasome protects articular cartilage from damage in a murine model of knee septic arthritis. Together, concurrent mitigation of intra-articular inflammation and local adjuvant targeting of intracellular bacteria represents a promising new therapeutic strategy for septic arthritis.

Biocompatibility of platinum-based bulk metallic glass in orthopedic applications.

Bulk metallic glasses (BMGs) are a class of amorphous metals that exhibit high strength, ductility paired with wear and corrosion resistance. These properties suggest that they could serve as an alternative to conventional metallic implants that suffer wear and failure. In the present study, we investigated Platinum (Pt)-BMG biocompatibility in bone applications. Specifically, we investigated osteoclast formation on flat and nanopatterned Pt57.5Cu14.7Ni5.3P22.5(atomic percent) as well as titanium (control). Specifically, receptor activator of NF-κB (RANK) ligand-induced murine bone marrow derived mononuclear cell fusion was measured on multiple nanopatterns and was found to be reduced on nanorods (80 and 200 nm in diameter) and was associated with reduced tartrate-resistant acid phosphatase (TRAP) and matrix metalloproteinase (MMP9) expression. Evaluation of mesenchymal stem cell (MSC) to osteoblast differentiation on nanopatterned Pt-BMG showed significant reduction in comparison to flat, suggesting that further exploration of nanopatterns is required to have simultaneous induction of osteoblasts and inhibition of osteoclasts.Invivo studies were also pursued to evaluate the biocompatibility of Pt-BMG in comparison to titanium. Rods of each material were implanted in the femurs of mice and evaluated by x-ray, mechanical testing, micro-computed tomography (micro-CT), and histological analysis. Overall, Pt-BMG showed similar biocompatibility with titanium suggesting that it has the potential to improve outcomes by further processing at the nanoscale.

Locally delivered adjuvant biofilm-penetrating antibiotics rescue impaired endochondral fracture healing caused by MRSA infection.

Infection is a devastating complication following an open fracture. We investigated whether local rifampin-loaded hydrogel can combat infection and improve healing in a murine model of methicillin-resistant Staphylococcus aureus (MRSA) osteomyelitis. A transverse fracture was made at the tibia midshaft of C57BL/6J mice aged 10-12 weeks and stabilized with an intramedullary pin. A total of 1 × 106 colony-forming units (CFU) of MRSA was inoculated. A collagen-based hydrogel containing low-dose (60 µg) and high-dose (300 µg) rifampin was applied before closure. Postoperative treatment response was assessed through bacterial CFU counts from tissue and hardware, tibial radiographs and microcomputed tomography (µCT), immunohistochemistry, and histological analyses. All untreated MRSA-infected fractures progressed to nonunion by 28 days with profuse MRSA colonization. Infected fractures demonstrated decreased soft callus formation on safranin O stain compared to controls. Areas of dense interleukin-1ß stain were associated with poor callus formation. High-dose rifampin hydrogels reduced the average MRSA load in tissue (p < 0.0001) and implants (p = 0.041). Low-dose rifampin hydrogels reduced tissue bacterial load by 50% (p = 0.021). Among sterile models, 88% achieved union compared to 0% of those infected. Mean radiographic union scale in tibia scores improved from 6 to 8.7 with high-dose rifampin hydrogel (p = 0.024) and to 10 with combination local/systemic rifampin therapy (p < 0.0001). µCT demonstrated reactive bone formation in MRSA infection. Histology demonstrated restored fracture healing with bacterial elimination. Rifampin-loaded hydrogels suppressed osteomyelitis, prevented implant colonization, and improved healing. Systemic rifampin was more effective at eliminating infection and improving fracture healing. Further investigation into rifampin-loaded hydrogels is required to correlate these findings with clinical efficacy.

Smoking Alters Inflammation and Skeletal Stem and Progenitor Cell Activity During Fracture Healing in Different Murine Strains.

Smokers are at a higher risk of delayed union or nonunion after fracture repair. Few specific interventions are available for prevention because the molecular mechanisms that result in these negative sequelae are poorly understood. Murine models that mimic fracture healing in smokers are crucial in further understanding the local cellular and molecular alterations during fracture healing caused by smoking. We exposed three murine strains, C57BL/6J, 129X1/SvJ, and BALB/cJ, to cigarette smoke for 3 months before the induction of a midshaft transverse femoral osteotomy. We evaluated fracture healing 4 weeks after the osteotomy using radiography, micro-computed tomography (µCT), and biomechanical testing. Radiographic analysis demonstrated a significant decrease in the fracture healing capacity of smoking 129X1/SvJ mice. µCT results showed delayed remodeling of fracture calluses in all three strains after cigarette smoke exposure. Biomechanical testing indicated the most significant impairment in the functional properties of 129X1/SvJ in comparison with C57BL/6J and BALB/cJ mice after cigarette smoke exposure. Thus, the 129X1/SvJ strain is most suitable in simulating smoking-induced impaired fracture healing. Furthermore, in smoking 129X1/SvJ murine models, we investigated the molecular and cellular alterations in fracture healing caused by cigarette smoking using histology, flow cytometry, and multiplex cytokine/chemokine analysis. Histological analysis showed impaired chondrogenesis in cigarette smoking. In addition, the important reparative cell populations, including skeletal stem cells and their downstream progenitors, demonstrated decreased expansion after injury as a result of cigarette smoking. Moreover, significantly increased pro-inflammatory mediators and the recruitment of immune cells in fracture hematomas were demonstrated in smoking mice. Collectively, our findings demonstrate the significant cellular and molecular alterations during fracture healing impaired by smoking, including disrupted chondrogenesis, aberrant skeletal stem and progenitor cell activity, and a pronounced initial inflammatory response. © 2020 American Society for Bone and Mineral Research (ASBMR).

Role of the Korean Triage and Acuity Scale to predict resource utilization in pediatric emergency center

Objective@#Triage in the emergency department is important as mistriage leads to inefficient use of resources. The Korean Triage and Acuity Scale (KTAS) was developed in 2012 and has been implemented in emergency departments nationwide since January 2016. The purpose of this study was to determine whether KTAS can predict resource use in a pediatric emergency center. @*Methods@#From October to December 2019, a retrospective analysis was conducted by a review of medical records. Demographic data, KTAS grades, Emergency Severity Index (ESI) as an indicator of resource utilization and details of the use of each resource were collected. Patients were divided into non-trauma and trauma groups. KTAS grades 1 and 2 were defined as the severe group, grade 3 was the moderate group, and grades 4 and 5 were defined as the mild group. We investigated whether triage using KTAS is related to resource utilization. @*Results@#In the non-trauma group, ESI, length of stay in the emergency department, and hospitalization were significantly correlated with the KTAS groups. In the trauma group, there was no significant difference between the moderate and mild groups in the above variables except for hospitalization. This was because there was no significant difference in sedation, procedure, and intravenous injection, in the trauma group. @*Conclusion@#The KTAS triage helped predict resource utilization in the non-trauma group, but not in the trauma group especially between the moderate and mild groups. Additional research will be needed to predict resource utilization in children with trauma.

Role of the Korean Triage and Acuity Scale to predict resource utilization in pediatric emergency center

Objective@#Triage in the emergency department is important as mistriage leads to inefficient use of resources. The Korean Triage and Acuity Scale (KTAS) was developed in 2012 and has been implemented in emergency departments nationwide since January 2016. The purpose of this study was to determine whether KTAS can predict resource use in a pediatric emergency center. @*Methods@#From October to December 2019, a retrospective analysis was conducted by a review of medical records. Demographic data, KTAS grades, Emergency Severity Index (ESI) as an indicator of resource utilization and details of the use of each resource were collected. Patients were divided into non-trauma and trauma groups. KTAS grades 1 and 2 were defined as the severe group, grade 3 was the moderate group, and grades 4 and 5 were defined as the mild group. We investigated whether triage using KTAS is related to resource utilization. @*Results@#In the non-trauma group, ESI, length of stay in the emergency department, and hospitalization were significantly correlated with the KTAS groups. In the trauma group, there was no significant difference between the moderate and mild groups in the above variables except for hospitalization. This was because there was no significant difference in sedation, procedure, and intravenous injection, in the trauma group. @*Conclusion@#The KTAS triage helped predict resource utilization in the non-trauma group, but not in the trauma group especially between the moderate and mild groups. Additional research will be needed to predict resource utilization in children with trauma.

Re-appraising the potential of naringin for natural, novel orthopedic biotherapies.

Naringin is a naturally occurring flavonoid found in plants of the Citrus genus that has historically been used in traditional Chinese medical regimens for the treatment of osteoporosis. Naringin modulates signaling through numerous molecular pathways critical to musculoskeletal development, cellular differentiation, and inflammation. Administration of naringin increases in vitro expression of bone morphogenetic proteins (BMPs) and activation of the Wnt/ß-catenin and extracellular signal-related kinase (Erk) pathways, thereby promoting osteoblastic proliferation and differentiation from stem cell precursors for bone formation. Naringin also inhibits osteoclastogenesis by both modifying RANK/RANKL interactions and inducing apoptosis in osteoclasts in vitro. In addition, naringin acts on the estrogen receptor in bone to mimic the native bone-preserving effects of estrogen, with few systemic side effects on other estrogen-sensitive tissues. The efficacy of naringin therapy in reducing the osteolysis characteristic of common musculoskeletal pathologies such as osteoporosis, degenerative joint disease, and osteomyelitis, as well as inflammatory conditions affecting bone such as diabetes mellitus, has been extensively demonstrated in vitro and in animal models. Naringin thus represents a naturally abundant, cost-efficient agent whose potential for use in novel musculoskeletal biotherapies warrants re-visiting and further exploration through human studies. Here, we review the cellular mechanisms of action that have been elucidated regarding the action of naringin on bone resident cells and the bone microenvironment, in vivo evidence of naringin's osteostimulative and chondroprotective properties in the setting of osteolytic bone disease, and current limitations in the development of naringin-containing translational therapies for common musculoskeletal conditions.