Research trends and perspective of low-intensity pulsed ultrasound in orthopedic rehabilitation treatment based on Web of Science: A bibliometric analysis.

BACKGROUND: Ultrasound has a long history as a diagnostic and therapeutic tool. Low-intensity pulsed ultrasound (LIPUS), whose intensity is below 300 mW/cm2, has been widely used in orthopedic rehabilitation treatment. However, the detailed bioeffects and underlying mechanisms of LIPUS treatment need to be explored. OBJECTIVE: To make a comprehensive view of the field, bibliometric and visualization analysis was used to reveal the global research trends of LIPUS in orthopedics and rehabilitation treatment between 1994 and 2023. METHODS: All literature data on LIPUS were retrieved from the Web of Science Core Collection database. VOSviewer and CiteSpace were applied for the bibliometric and visualization analysis. RESULTS: A total of 760 publications were included. The distribution of publications generally showed an unstable rising trend. China had the highest number of publications (28.0%), and Chong Qing Medical University was the organization with the highest number of publications (5.8%). Ultrasound in Medicine and Biology had the highest number of publications (8.8%), while BMJ-British Medical Journal had the highest impact factor among the retrieved journals. Ling Qin from the Chinese University of Hong Kong was the most active researcher. Our overlay visualization map showed that the keywords such as pain, knee osteoarthritis, apoptosis, chondrocytes, cartilage, and autophagy, which link to osteoarthritis, have becoming the new research trends and hotspots. CONCLUSION: LIPUS is a popular and increasingly important area of orthopedic rehabilitation, and collaboration of authors from different countries should be further strengthened. Predictably, clinical application of LIPUS on chronic inflammation-related diseases and regenerative medicine, and in-depth biological mechanisms are the orientations of LIPUS in orthopedic rehabilitation treatment.

An Hsp70 promoter-based mouse for heat shock-induced gene modulation.

Physical therapy is extensively employed in clinical settings. Nevertheless, the absence of suitable animal models has resulted in an incomplete understanding of the in vivo mechanisms and cellular distribution that respond to physical stimuli. The objective of this research was to create a mouse model capable of indicating the cells affected by physical stimuli. In this study, we successfully established a mouse line based on the heat shock protein 70 (Hsp70) promoter, wherein the expression of CreERT2 can be induced by physical stimuli. Following stimulation of the mouse tail, ear, or cultured calvarias with heat shock (generated by heating, ultrasound, or laser), a distinct Cre-mediated excision was observed in cells stimulated by these physical factors with minimal occurrence of leaky reporter expression. The application of heat shock to Hsp70-CreERT2; FGFR2-P253R double transgenic mice or Hsp70-CreERT2 mice infected with AAV-BMP4 at calvarias induced the activation of Cre-dependent mutant FGFR2-P253R or BMP4 respectively, thereby facilitating the premature closure of cranial sutures or the repair of calvarial defects. This novel mouse line holds significant potential for investigating the underlying mechanisms of physical therapy, tissue repair and regeneration, lineage tracing, and targeted modulation of gene expression of cells in local tissue stimulated by physical factor at the interested time points. KEY MESSAGES: In the study, an Hsp70-CreERT2 transgenic mouse was generated for heat shock-induced gene modulation. Heat shock, ultrasound, and laser stimulation effectively activated Cre expression in Hsp70-CreERT2; reporter mice, which leads to deletion of floxed DNA sequence in the tail, ear, and cultured calvaria tissues of mice. Local laser stimuli on cultured calvarias effectively induce Fgfr2-P253R expression in Hsp70-mTmG-Fgfr2-P253R mice and result in accelerated premature closure of cranial suture. Heat shock activated AAV9-FLEX-BMP4 expression and subsequently promoted the repair of calvarial defect of Hsp70-CreERT2; Rosa26-mTmG mice.

Total body water percentage and 3rd space water are novel risk factors for training-related lower extremity muscle injuries in young males.

PURPOSE: To identify the risk factors for training-related lower extremity muscle injuries in young males by a non-invasive method of body composition analysis. METHODS: A total of 282 healthy young male volunteers aged 18 - 20 years participated in this cohort study. Injury location, degree, and injury rate were adjusted by a questionnaire based on the overuse injury assessment methods used in epidemiological studies of sports injuries. The occurrence of training injuries is monitored and diagnosed by physicians and treated accordingly. The body composition was measured using the BodyStat QuadScan 4000 multifrequency Bio-impedance system at 5, 50, 100 and 200 kHz to obtain 4 impedance values. The Shapiro-Wilk test was used to check whether the data conformed to a normal distribution. Data of normal distribution were shown as mean ± SD and analyzed by t-test, while those of non-normal distribution were shown as median (Q1, Q3) and analyzed by Wilcoxon rank sum test. The receiver operator characteristic curve and logistic regression analysis were performed to investigate risk factors for developing training-related lower extremity injuries and accuracy. RESULTS: Among the 282 subjects, 78 (27.7%) developed training injuries. Lower extremity training injuries revealed the highest incidence, accounting for 23.4% (66 cases). These patients showed higher percentages of lean body mass (p = 0.001), total body water (TBW, p = 0.006), extracellular water (p = 0.020) and intracellular water (p = 0.010) as well as a larger ratio of basal metabolic rate/total weight (p = 0.006), compared with those without lower extremity muscle injuries. On the contrary, the percentage of body fat (p = 0.001) and body fat mass index (p = 0.002) were lower. Logistic regression analysis showed that TBW percentage > 65.35% (p = 0.050, odds ratio = 3.114) and 3rd space water > 0.95% (p = 0.045, odds ratio = 2.342) were independent risk factors for lower extremity muscle injuries. CONCLUSION: TBW percentage and 3rd space water measured with bio-impedance method are potential risk factors for predicting the incidence of lower extremity muscle injuries in young males following training.

Lymphatic vessels: roles and potential therapeutic intervention in rheumatoid arthritis and osteoarthritis.

Lymphatic vessel networks are a main part of the vertebrate cardiovascular system, which participate in various physiological and pathological processes via regulation of fluid transport and immunosurveillance. Targeting lymphatic vessels has become a potent strategy for treating various human diseases. The presence of varying degrees of inflammation in joints of rheumatoid arthritis (RA) and osteoarthritis (OA), characterized by heightened infiltration of inflammatory cells, increased levels of inflammatory factors, and activation of inflammatory signaling pathways, significantly contributes to the disruption of cartilage and bone homeostasis in arthritic conditions. Increasing evidence has demonstrated the pivotal role of lymphatic vessels in maintaining joint homeostasis, with their pathological alterations closely associated with the initiation and progression of inflammatory joint diseases. In this review, we provide a comprehensive overview of the evolving knowledge regarding the structural and functional aspects of lymphatic vessels in the pathogenesis of RA and OA. In addition, we summarized the potential regulatory mechanisms underlying the modulation of lymphatic function in maintaining joint homeostasis during inflammatory conditions, and further discuss the distinctions between RA and OA. Moreover, we describe therapeutic strategies for inflammatory arthritis based on lymphatic vessels, including the promotion of lymphangiogenesis, restoration of proper lymphatic vessel function through anti-inflammatory approaches, enhancement of lymphatic contractility and drainage, and alleviation of congestion within the lymphatic system through the elimination of inflammatory cells. At last, we envisage potential research perspectives and strategies to target lymphatic vessels in treating these inflammatory joint diseases.

The circUbqln1, regulated by XBP1s, interplays with 14-3-3ζ to inhibit collagen synthesis and promote osteoarthritis by controlling PRODH activity and proline metabolism.

INTRODUCTION: Osteoarthritis (OA) is a degenerative bone disease associated with ageing, characterized by joint pain, stiffness, swelling and deformation. Currently, pharmaceutical options for the clinical treatment of OA are very limited. Circular RNAs(cirRNAs) have garnered significant attention in OA and related drug development due to their unique RNA sequence characteristics.Therefore,exploring the role of cirRNAs in the occurrence and development of OA is of paramount importance for the development of effective medications for OA. OBJECTIVES: To identify a novel circRNA, circUbqln1, for treating osteoarthritis and elucidate its pathophysiological role and mechanisms in the treatment of OA. METHODS: The circUbqln1 expression and distribution were determined by qRT-PCR and FISH. XBP1 gene knockout(XBP1 cKO) spontaneous OA and DMM model and WT mouse CIOA model were used to explore the role of XBP1 and circUbqln1 in OA.Overexpression or knockdown of circUbqln1 lentivirus was used to observe the impacts of circUbqln1 on primary chondrocytes,C28/I2 and mice in vitro and in vivo.Chromatin immunoprecipitation,luciferase reporter assay,RNA pulldown,mass spectrometry,RNA immunoprecipitation,fluorescence in situ hybridization,and flow cytometry to explore the molecular mechanisms of circUbqln1. RESULTS: It was found that cartilage-specific XBP1 cKO mice exhibited a faster OA progression compared to normal's.Importantly,transcript factor XBP1s has the capacity to impede the biogenesis of circUbqln1,derived from Ubqln1. The circUbqln1 promotes cartilage catabolism and inhibits anabolism, therefore accelerates the occurrence of OA.Mechanismly,circUbqln1 can translocate to the chondrocyte nucleus with the assistance of phosphorylated 14-3-3ζ, upregulate the transcriptional activity of the proline dehydrogenase(Prodh) promoter and PRODH enzyme activity. Consequently, this leads to the promotion of proline degradation and the inhibition of collagen synthesis,ultimately culminating in the impairment of cartilage and its structural integrity. CONCLUSION: CircUbqln1 plays a crucial role in the occurrence and development of OA, indicating that the inhibition of circUbqln1 holds promise as a significant approach for treating OA in the future.

A Novel Cargo Delivery System-AnCar-ExoLaIMTS Ameliorates Arthritis via Specifically Targeting Pro-Inflammatory Macrophages.

Macrophages are heterogenic phagocytic cells that play distinct roles in physiological and pathological processes. Targeting different types of macrophages has shown potent therapeutic effects in many diseases. Although many approaches are developed to target anti-inflammatory macrophages, there are few researches on targeting pro-inflammatory macrophages, which is partially attributed to their non-s pecificity phagocytosis of extracellular substances. In this study, a novel recombinant protein is constructed that can be anchored on an exosome membrane with the purpose of targeting pro-inflammatory macrophages via antigen recognition, which is named AnCar-ExoLaIMTS . The data indicate that the phagocytosis efficiencies of pro-inflammatory macrophages for different AnCar-ExoLaIMTS show obvious differences. The AnCar-ExoLaIMTS3 has the best targeting ability for pro-inflammatory macrophages in vitro and in vivo. Mechanically, AnCar-ExoLaIMTS3 can specifically recognize the leucine-rich repeat domain of the TLR4 receptor, and then enter into pro-inflammatory macrophages via the TLR4-mediated receptor endocytosis pathway. Moreover, AnCar-ExoLaIMTS3 can efficiently deliver therapeutic cargo to pro-inflammatory macrophages and inhibit the synovial inflammatory response via downregulation of HIF-1α level, thus ameliorating the severity of arthritis in vivo. Collectively, the work established a novel gene/drug delivery system that can specifically target pro-inflammatory macrophages, which may be beneficial for the treatments of arthritis and other inflammatory diseases.

IRE1α protects against osteoarthritis by regulating progranulin-dependent XBP1 splicing and collagen homeostasis.

Osteoarthritis (OA) is a full-joint, multifactorial, degenerative and inflammatory disease that seriously affects the quality of life of patients due to its disabling and pain-causing properties. ER stress has been reported to be closely related to the progression of OA. The inositol-requiring enzyme 1α/X-box-binding protein-1 spliced (IRE1α/XBP1s) pathway, which is highly expressed in the chondrocytes of OA patients, promotes the degradation and refolding of abnormal proteins during ER stress and maintains the stability of the ER environment of chondrocytes, but its function and the underlying mechanisms of how it contributes to the progression of OA remain unclear. This study investigates the role of IRE1α/ERN1 in OA. Specific deficiency of ERN1 in chondrocytes spontaneously resulted in OA-like cartilage destruction and accelerated OA progression in a surgically induced arthritis model. Local delivery of AdERN1 relieved degradation of the cartilage matrix and prevented OA development in an ACLT-mediated model. Mechanistically, progranulin (PGRN), an intracellular chaperone, binds to IRE1α, promoting its phosphorylation and splicing of XBP1u to generate XBP1s. XBP1s protects articular cartilage through TNF-α/ERK1/2 signaling and further maintains collagen homeostasis by regulating type II collagen expression. The chondroprotective effect of IRE1α/ERN1 is dependent on PGRN and XBP1s splicing. ERN1 deficiency accelerated cartilage degeneration in OA by reducing PGRN expression and XBP1s splicing, subsequently decreasing collagen II expression and triggering collagen structural abnormalities and an imbalance in collagen homeostasis. This study provides new insights into OA pathogenesis and the UPR and suggests that IRE1α/ERN1 may serve as a potential target for the treatment of joint degenerative diseases, including OA.

Cir-DNA Sequencing Revealed the Landscape of Extrachromosomal Circular DNA in Articular Cartilage and the Potential Roles in Osteoarthritis.

OBJECTIVE: Extrachromosomal circular DNA (eccDNA) has been shown to be involved in several physiological and pathological processes including immunity, inflammation, aging, and tumor. However, the expression of eccDNA in cartilage has not been reported until now. In this study, we aimed to investigate the landscape of eccDNA in articular cartilage and analyze the potential roles in osteoarthritis (OA). METHODS: The samples of articular cartilage were obtained from total knee arthroplasty (TKA) donors with OA. The mitochondrial DNA (mtDNAs) and the linear DNAs from chondrocytes of articular cartilage were removed. Then the eccDNAs were enriched for cir-DNA sequencing. After quality control evaluation, we systematically revealed the identified eccDNA data including size distribution, the size range, and sequence pattern. Moreover, we explored and discussed the potential roles of eccDNA in OA via motif analysis and Gene Ontology (GO)/Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. RESULTS: The chondrocytes from OA cartilage contained an abundance of eccDNAs, which was termed as OC-eccDNAs (OA cartilage-derived eccDNA). The characteristics of OC-eccDNAs were tissue-specific, including the distribution, the size range, and sequence pattern. Moreover, the functional analysis indicated that eccDNA may be involved in the homeostasis maintenance of chondrocytes and participated in the process of OA. CONCLUSIONS: Our data first showed the landscape of eccDNA in articular cartilage and preliminarily indicated the potential roles of eccDNA in OA.

Ultraviolet light C in promoting rapid healing of delayed wound union: A case report.

INTRODUCTION AND IMPORTANCE: The purpose of this case is to present a useful phototherapy for rapid healing of recalcitrant postoperative wound disunion due to implantation of allogeneic bone and metal. CASE PRESENTATION: In this case, a middle-aged man was diagnosed as complex fracture of the left tibial plateau which caused movement loss, swelling and pain of the left knee. The patient's wound disunion was still present after been surgery for 26 days, with yellowish liquid persistently oozing out of the wound after several wound dressing. We treated the postoperative wound with ultraviolet light C (UVC) to promote wound healing. CLINICAL DISCUSSION: Incision disunion is a common complication of surgery, which increases patients' hospital days. Prevention and treatment of wound disunion is one of the key considerations for perioperative management. CONCLUSION: During 3-day consecutive UVC treatment, the yellowish wound exudate gradually reduced and disappeared. Subsequently, the non-healing postoperative wound scared over and healed rapidly. As a convenient, non-invasive, non-polluting and effectively physical therapy, UVC can promote rapid healing of recalcitrant wound disunion caused by implants in complex tibial plateau fracture.

Exogenous Indian hedgehog antagonist damages intervertebral discs homeostasis in adult mice.

Background: Vismodegib, as an exogenous Indian hedgehog (Ihh) antagonist, has been approved by the Food and Drug Administration (FDA) for the clinical treatment of patients with basal cell carcinoma, and previous observations implicate the potential therapeutic of vismodegib in osteoarthritis treatment. However, there is no direct evidence for the role of Ihh signaling in intervertebral discs (IVDs) homeostasis of adult mice. The aim of the present study is to assess the effect of systemic administration of Smoothened inhibitor (SMOi) - vismodegib on IVDs homeostasis during the adult stage. Methods: The expression of glioma-associated oncogene homolog 1 (Gli1), the downstream targeting gene of Ihh signaling, in IVDs of adult mice after receiving systemic administration of SMOi was examined by immunohistochemistry. The pathological changes of vertebral bodies after SMOi treatment were evaluated by X-ray and micro-CT. The effects of SMOi on homeostasis of IVDs including cartilaginous endplates (CEP), growth plates (GP) and annulus fibrous (AF) were evaluated by histological analysis. The expressions of Aggrecan, Matrix metalloproteinase 13 (MMP13) and Runt-related transcription factor 2 (Runx2), in IVDs were also investigated by immunohistochemistry. Changes in chondrocyte apoptosis and proliferation in IVDs were evaluated by terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay and analyzing the expression of the cell proliferation antigen Ki-67. Results: Systemic administration of SMOi significantly decreased the expression of Gli1 in IVDs that indicating effective inhibition of Ihh signaling. Bone mass of vertebral bodies was diminished after SMOi treatment. Moreover, IVDs degeneration (IDD) like defects including CEP sclerosis, degenerative nucleus pulposus (NP) and fissure within AF, as well as narrowed or fused GP and loss bone mass of vertebral bodies was observed in SMOi-treated mice. The severity of IDD was time-dependent with the administration of SMOi treatment after 2-8 weeks. The expressions of Aggrecan, MMP13 and Runx2 in IVDs of mice receiving SMOi treatment were significantly decreased. In addition, chondrocyte apoptosis was significantly enhanced, while chondrocyte proliferation was significantly inhibited. Conclusions: Our study propose that systemic administration of vismodegib damages IVDs homeostasis via inhibition of Ihh signaling in adult mice. The clinical application of Ihh signaling antagonists such as vismodegib should be careful considering these side adverse. The Translational Potential of this Article: Vismodegib as an exogenous antagonist of Ihh signaling has been approved by the FDA for the clinical treatment of patients with basal cell carcinoma. However, it is still unknown whether vismodegib will has adverse effects on the patient or animal model of IVDs cartilage homeostasis. Based on our study, systemic administration of vismodegib damages IVDs homeostasis via inhibition of Ihh signaling in adult mice and special attention should be paid to the clinical application of vismodegib.

Expansion of FGFR3-positive nucleus pulposus cells plays important roles in postnatal nucleus pulposus growth and regeneration.

BACKGROUND: Intervertebral disc degeneration (IVDD) can cause low back pain, a major public health concern. IVDD is characterized with loss of cells especially those in nucleus pulposus (NP), due to the limited proliferative potential and regenerative ability. Few studies, however, have been carried out to investigate the in vivo proliferation events of NP cells and the cellular contribution of a specific subpopulation of NP during postnatal growth or regeneration. METHODS: We generated FGFR3-3*Flag-IRES-GFP mice and crossed FGFR3-CreERT2 mice with Rosa26-mTmG, Rosa26-DTA and Rosa26-Confetti mice, respectively, to perform inducible genetic tracing studies. RESULTS: Expression of FGFR3 was found in the outer region of NP with co-localized expressions of proliferating markers. By fate mapping studies, FGFR3-positive (FGFR3+) NP cells were found proliferate from outer region to inner region of NP during postnatal growth. Clonal lineage tracing by Confetti mice and ablation of FGFR3·+ NP cells by DTA mice further revealed that the expansion of the FGFR3+ cells was required for the morphogenesis and homeostasis of postnatal NP. Moreover, in degeneration and regeneration model of mouse intervertebral disc, FGFR3+ NP cells underwent extensive expansion during the recovery stage. CONCLUSION: Our present work demonstrates that FGFR3+ NP cells are novel subpopulation of postnatal NP with long-existing proliferative capacity shaping the adult NP structure and participating in the homeostasis maintenance and intrinsic repair of NP. These findings may facilitate the development of new therapeutic approaches for IVD regeneration.

Inhibition of aberrant Hif1α activation delays intervertebral disc degeneration in adult mice.

The intervertebral disc (IVD) is the largest avascular tissue. Hypoxia-inducible factors (HIFs) play essential roles in regulating cellular adaptation in the IVD under physiological conditions. Disc degeneration disease (DDD) is one of the leading causes of disability, and current therapies are ineffective. This study sought to explore the role of HIFs in DDD pathogenesis in mice. The findings of this study showed that among HIF family members, Hif1α was significantly upregulated in cartilaginous endplate (EP) and annulus fibrosus (AF) tissues from human DDD patients and two mouse models of DDD compared with controls. Conditional deletion of the E3 ubiquitin ligase Vhl in EP and AF tissues of adult mice resulted in upregulated Hif1α expression and age-dependent IVD degeneration. Aberrant Hif1α activation enhanced glycolytic metabolism and suppressed mitochondrial function. On the other hand, genetic ablation of the Hif1α gene delayed DDD pathogenesis in Vhl-deficient mice. Administration of 2-methoxyestradiol (2ME2), a selective Hif1α inhibitor, attenuated experimental IVD degeneration in mice. The findings of this study show that aberrant Hif1α activation in EP and AF tissues induces pathological changes in DDD, implying that inhibition of aberrant Hif1α activity is a potential therapeutic strategy for DDD.

Clinicopathological characteristics and treatment outcomes of luminal B1 breast cancer in Taiwan.

BACKGROUND: Hormone receptor-positive, human epidermal growth factor receptor II (HER2)-negative luminal B1 breast cancer is associated with a higher risk of disease relapse than luminal A breast cancer. Therefore, we assessed and compared the distant metastasis pattern and clinical outcomes associated with luminal B1 and luminal A breast cancer in an Asian population. METHODS: In this observational study, we assessed patients with estrogen receptor-positive, HER2-negative breast cancer who underwent surgery from 2009 to 2016. Patients were classified into luminal A or luminal B1 subsets via immunohistochemical analysis. Disease-free survival, post-metastasis survival, and overall survival were estimated; time to disease relapse and patterns of distant metastasis were compared. Risk of relapse and mortality were assessed using Cox proportional hazards model. RESULTS: Patients with luminal B1 breast cancer (n = 677) were significantly younger and had larger tumors and a higher degree of affected axillary lymph nodes, lymphovascular invasion, and tumor necrosis than those with luminal A breast cancer (n = 630). Higher rates of local recurrence and distant metastasis were observed for luminal B1 (both p < 0.05); however, no difference was observed in the specific distant metastatic sites. We observed a significant increase in disease relapse risk in luminal B1 patients compared with that in luminal A (hazard ratio: 2.157, 95% CI: 1.340-3.473, p < 0.05). Patient age, tumor size, stage, lymphovascular invasion, and receiving chemotherapy and hormone therapy were independent risk factors for metastasis and recurrence. Only the luminal B1 subtype (hazard ratio: 5.653, 95% CI: 1.166-27.409, p < 0.05) and stage (hazard ratio: 3.400, 95% CI: 1.512-7.649, p < 0.05) were identified as independent risk factors for post metastatic mortality. CONCLUSION: Luminal B1 breast cancer has aggressive tumor biology compared with luminal A breast cancer in the follow-up period. However, there was no significant difference in the disease relapse pattern between the groups.

A Novel Fatigue Driving State Recognition and Warning Method Based on EEG and EOG Signals.

Traffic accidents are easily caused by tired driving. If the fatigue state of the driver can be identified in time and a corresponding early warning can be provided, then the occurrence of traffic accidents could be avoided to a large extent. At present, the recognition of fatigue driving states is mostly based on recognition accuracy. Fatigue state is currently recognized by combining different features, such as facial expressions, electroencephalogram (EEG) signals, yawning, and the percentage of eyelid closure over the pupil over time (PERCLoS). The combination of these features increases the recognition time and lacks real-time performance. In addition, some features will increase error in the recognition result, such as yawning frequently with the onset of a cold or frequent blinking with dry eyes. On the premise of ensuring the recognition accuracy and improving the realistic feasibility and real-time recognition performance of fatigue driving states, a fast support vector machine (FSVM) algorithm based on EEGs and electrooculograms (EOGs) is proposed to recognize fatigue driving states. First, the collected EEG and EOG modal data are preprocessed. Second, multiple features are extracted from the preprocessed EEGs and EOGs. Finally, FSVM is used to classify and recognize the data features to obtain the recognition result of the fatigue state. Based on the recognition results, this paper designs a fatigue driving early warning system based on Internet of Things (IoT) technology. When the driver shows symptoms of fatigue, the system not only sends a warning signal to the driver but also informs other nearby vehicles using this system through IoT technology and manages the operation background.

Long term usage of dexamethasone accelerating accelerates the initiation of osteoarthritis via enhancing chondrocyte apoptosis and the extracellular matrix calcification and apoptosis of chondrocytes.

Systemic application of glucocorticoids is an essential anti-inflammatory and immune-modulating therapy for severe inflammatory or autoimmunity conditions. However, its long-term effects on articular cartilage of patients' health need to be further investigated. In this study, we studied the effects of dexamethasone (Dex) on the homeostasis of articular cartilage and the progress of destabilization of medial meniscus (DMM)-induced osteoarthritis (OA) in adult mice. Long-term administration of Dex aggravates the proteoglycan loss of articular cartilage and drastically accelerates cartilage degeneration under surgically induced OA conditions. In addition, Dex increases calcium content in calcified cartilage layer of mice and the samples from OA patients with a history of long-term Dex treatment. Moreover, long term usage of Dex results in decrease subchondral bone mass and bone density. Further studies showed that Dex leads to calcification of extracellular matrix of chondrocytes partially through activation of AKT, as well as promotes apoptosis of chondrocytes in calcified cartilage layer. Besides, Dex weakens the stress-response autophagy with the passage of time. Taken together, our data indicate that long-term application of Dex may predispose patients to OA and or even accelerate the OA disease progression development of OA patients.

Detection and genetic characterization of the novel torque teno virus group 6 in Taiwanese general population.

Torque teno virus (TTV) is one of the most common human viruses and can infect an individual with multiple genotypes chronically and persistently. TTV group 6 is a recently discovered phylogenetic group first isolated from eastern Taiwan indigenes, but whether the TTV group 6 was also prevalent in the general population still unknown. One hundred and three randomly collected blood samples from general population and 66 TTV positive DNA samples extracted from Taiwan indigenes were included. A group-6-specific PCR was developed for re-screen over TTV positive samples. Two TTV group 6 positive samples from general population were cloned and sequenced for identifying mix-infected TTVs and confirming their classification by maximum-likelihood and Bayesian inference phylogeny. TTV group 6 can be detected in 4.5% (4/89) and 7.6% (5/66) of TTV positive samples from Taiwanese general population and eastern Taiwan indigenes, respectively. Sample VC09 was mix-infected with TTV groups 3 and 6. Sample VC99 was mix-infected with TTV groups 3, 4 and 6. A highly diverse triple overlapping region was observed, which may represent a unique phenomenon of TTV. The group-6-specific PCR can successfully detect TTV group 6. TTV group 6 may be prevalent worldwide regardless of the geographic region and/or ethnic groups.

TGF-ß/Alk5 signaling prevents osteoarthritis initiation via regulating the senescence of articular cartilage stem cells.

Osteoarthritis (OA) is the most common joint disease. The surface of joint cartilage is a defensive and first affected structure of articular cartilage (AC) during the pathogenesis of OA. Alk5 signaling is critical for maintaining AC homeostasis, however, the role and underlying mechanism for the involvement of Alk5 signaling in the phenotypes of articular cartilage stem cells (ACSCs) at the surface of AC is still unclear. The role of Alk5 in OA development was explored using an ACSCs-specific Alk5-deficient (cKO) mouse model. Alterations in cartilage structure were evaluated histologically. Senescence was detected by SA-ß-gal, while reactive oxygen species (ROS), MitoTracker, and LysoTracker staining were used to detect changes related to senescence. In addition, mice were injected intra-articularly with ganciclovir to limit the detrimental roles of senescent cells (SnCs). Alk5 cKO mice showed a decreased number of the slow-cell cycle cells and less lubricant secretion at the surface accompanied with drastically accelerated cartilage degeneration under ageing and surgically induced OA conditions. Further studies showed that Alk5 deficient ACSCs exhibited senescence-like manifestations including decreased proliferation and differentiation, more SA-ß-gal-positive cells and ROS production, as well as significantly swollen mitochondria and lysosome breakdown. We further found that local limitation of the detrimental roles of SnCs can attenuate the development of posttraumatic OA. Taken together, our findings suggest that Alk5 signaling acts as an important regulator of the SnCs in the superficial layer during AC maintenance and OA initiation.

Multimodal MRI Brain Tumor Image Segmentation Using Sparse Subspace Clustering Algorithm.

Brain tumors are one of the most deadly diseases with a high mortality rate. The shape and size of the tumor are random during the growth process. Brain tumor segmentation is a brain tumor assisted diagnosis technology that separates different brain tumor structures such as edema and active and tumor necrosis tissues from normal brain tissue. Magnetic resonance imaging (MRI) technology has the advantages of no radiation impact on the human body, good imaging effect on structural tissues, and an ability to realize tomographic imaging of any orientation. Therefore, doctors often use MRI brain tumor images to analyze and process brain tumors. In these images, the tumor structure is only characterized by grayscale changes, and the developed images obtained by different equipment and different conditions may also be different. This makes it difficult for traditional image segmentation methods to deal well with the segmentation of brain tumor images. Considering that the traditional single-mode MRI brain tumor images contain incomplete brain tumor information, it is difficult to segment the single-mode brain tumor images to meet clinical needs. In this paper, a sparse subspace clustering (SSC) algorithm is introduced to process the diagnosis of multimodal MRI brain tumor images. In the absence of added noise, the proposed algorithm has better advantages than traditional methods. Compared with the top 15 in the Brats 2015 competition, the accuracy is not much different, being basically stable between 10 and 15. In order to verify the noise resistance of the proposed algorithm, this paper adds 5%, 10%, 15%, and 20% Gaussian noise to the test image. Experimental results show that the proposed algorithm has better noise immunity than a comparable algorithm.

Exosomes: roles and therapeutic potential in osteoarthritis.

Exosomes participate in many physiological and pathological processes by regulating cell-cell communication, which are involved in numerous diseases, including osteoarthritis (OA). Exosomes are detectable in the human articular cavity and were observed to change with OA progression. Several joint cells, including chondrocytes, synovial fibroblasts, osteoblasts, and tenocytes, can produce and secrete exosomes that influence the biological effects of targeted cells. In addition, exosomes from stem cells can protect the OA joint from damage by promoting cartilage repair, inhibiting synovitis, and mediating subchondral bone remodeling. This review summarizes the roles and therapeutic potential of exosomes in OA and discusses the perspectives and challenges related to exosome-based treatment for OA patients in the future.