Abnormal metabolism in melanocytes participates in the activation of dendritic cell in halo nevus.

A comprehensive analysis of spatial transcriptomics was carried out to better understand the progress of halo nevus. We found that halo nevus was characterized by overactive immune responses, triggered by chemokines and dendritic cells (DCs), T cells, and macrophages. Consequently, we observed abnormal cell death, such as apoptosis and disulfidptosis in halo nevus, some were closely related to immunity. Interestingly, we identified aberrant metabolites such as uridine diphosphate glucose (UDP-G) within the halo nevus. UDP-G, accompanied by the infiltration of DCs and T cells, exhibited correlations with certain forms of cell death. Subsequent experiments confirmed that UDP-G was increased in vitiligo serum and could activate DCs. We also confirmed that oxidative response is an inducer of UDP-G. In summary, the immune response in halo nevus, including DC activation, was accompanied by abnormal cell death and metabolites. Especially, melanocyte-derived UDP-G may play a crucial role in DC activation.

Brain-derived extracellular vesicles: Potential diagnostic biomarkers for central nervous system diseases.

Extracellular vesicles (EVs) are membrane-enclosed nanovesicles secreted by cells into the extracellular space and contain functional biomolecules, e.g. signaling receptors, bioactive lipids, nucleic acids, and proteins, which can serve as biomarkers. Neurons and glial cells secrete EVs, contributing to various physiological and pathological aspects of brain diseases. EVs confer their role in the bidirectional crosstalk between the central nervous system (CNS) and the periphery owing to their distinctive ability to cross the unique blood-brain barrier (BBB). Thus, EVs in the blood, cerebrospinal fluid (CSF), and urine can be intriguing biomarkers, enabling the minimally invasive diagnosis of CNS diseases. Although there has been an enormous interest in evaluating EVs as promising biomarkers, the lack of ultra-sensitive approaches for isolating and detecting brain-derived EVs (BDEVs) has hindered the development of efficient biomarkers. This review presents the recent salient findings of exosomal biomarkers, focusing on brain disorders. We summarize highly sensitive sensors for EV detection and state-of-the-art methods for single EV detection. Finally, the prospect of developing advanced EV analysis approaches for the non-invasive diagnosis of brain diseases is presented.

Enhancement of the therapeutic efficacy of mesenchymal stem cell-derived exosomes in osteoarthritis.

Osteoarthritis (OA), a common joint disorder with articular cartilage degradation as the main pathological change, is the major source of pain and disability worldwide. Despite current treatments, the overall treatment outcome is unsatisfactory. Thus, patients with severe OA often require joint replacement surgery. In recent years, mesenchymal stem cells (MSCs) have emerged as a promising therapeutic option for preclinical and clinical palliation of OA. MSC-derived exosomes (MSC-Exos) carrying bioactive molecules of the parental cells, including non-coding RNAs (ncRNAs) and proteins, have demonstrated a significant impact on the modulation of various physiological behaviors of cells in the joint cavity, making them promising candidates for cell-free therapy for OA. This review provides a comprehensive overview of the biosynthesis and composition of MSC-Exos and their mechanisms of action in OA. We also discussed the potential of MSC-Exos as a therapeutic tool for modulating intercellular communication in OA. Additionally, we explored bioengineering approaches to enhance MSC-Exos' therapeutic potential, which may help to overcome challenges and achieve clinically meaningful OA therapies.

Effect of total knee arthroplasty for valgus knee correction on clinical outcome and patellar position.

PURPOSE: The purpose was to investigate the effect of different degrees of valgus deformity correction on patellar position and clinical outcome in patients with valgus knees after total knee arthroplasty (TKA). METHODS: We retrospectively analyzed and followed 118 patients with valgus knees. Based on the post-operative hip-knee-ankle (HKA), patients were divided into three groups: neutral (±3°), mild (3-6°), and severe (> 6°). Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), range of motion (ROM), and Knee Society Score (KSS) were used to evaluate post-operative clinical efficacy. Also, the patellar tilt angle (ε-angle), congruence angle (θ-angle), and Insall-Salvati index (ISI) were used to represent the patellar position. Post-operative observation indicators included HKA, angle of the femur (α-angle), tibial angle (ß-angle), femoral component flexion angle (γ-angle), and tibial component posterior slope angle (δ-angle). RESULTS: All patients showed significant improvements in HKA, ROM, WOMAC, and KSS after operation (P < 0.001). Regarding patellar position, the ISI values decreased to varying degrees (P < 0.05). The patellar tilt angle was significantly increased in the severe valgus group compared to that in the mild valgus and neutral groups (P < 0.001). Univariate analysis showed that the degree of post-operative residual valgus was significantly affected by WOMAC, KSS, α-, ε-, and θ-angles. CONCLUSION: Minor valgus undercorrection did not affect the short-term outcome after TKA; however, when the residual valgus angle was > 6°, the post-operative scores were significantly reduced. Inadequate valgus correction does not result in significant changes in patellar height but may increase the risk of poor patellar tracking.

Influence of lower-limb mechanical axis on the curative effect of medial high tibial osteotomy for knee osteoarthritis.

PURPOSE: To investigate the effect of the ratio of the medial tibial plateau width to the total tibial plateau width on the therapeutic efficacy of high tibial osteotomy (HTO) on the medial side for the treatment of knee osteoarthritis. METHODS: In this study, we retrospectively analyzed information of 278 patients who underwent medial HTO for knee osteoarthritis with varus deformity. The Tinetti Gait and Balance Assessment Tool, the Visual Analog Scale (VAS), and the Knee Society Scoring System (KSS) were used to comprehensively evaluate the function of the knee joint after HTO. RESULTS: After adjusting for potential confounding factors (i.e., age, gender, body mass index/BMI, and surgical site), the Tinetti assessment score was optimized when the degree of correction was 53.67%, with the ß-value on the left and right sides of the inflection point of 0.49 (confidence interval, CI: 0.20, 0.78, P = 0.0009) and- 0.26 (95% CI: - 0.30, - 0.22, P < 0.0001), respectively. The KSS score was optimized when the degree of correction was 55.45%, with the ß-value on the left and right sides of the inflection point of 2.77 (95% CI: 1.64, 3.90, P < 0.0001) and - 1.18 (95% CI: - 1.46, - 0.91, P < 0.0001), respectively. The VAS score was the lowest when the degree of correction was 55.00%, with the ß-value on the left and right sides of the inflection point of - 0.16 (95% CI: - 0.29, - 0.03, P = 0.0146) and 0.08 (95% CI: 0.05, 0.10, P < 0.0001), respectively. Stratified analysis showed that the BMI affected the Tinetti assessment score (ß = - 0.14, 95% CI: - 0.24, - 0.04, P = 0.0071). According to the smooth-curve fitting results, when the BMI was > 28, the Tinetti assessment score showed a negative trend. CONCLUSION: The degree of lower-limb mechanical axis correction correlated with the functional status of the knee joint after MOW HTO. When the ratio of the medial tibial plateau width to the total tibial plateau width was approximately 55%, the post-MOW HTO outcomes were optimized and the patients experienced the highest satisfaction. In addition, very high BMI was not conducive for the postoperative recovery of the knee joint function. LEVEL OF EVIDENCE: III Case-control study/Retrospective comparative study.

MTHFD1L as a folate cycle enzyme correlates with prognostic outcome and its knockdown impairs cell invasive behaviors in osteosarcoma via mediating the AKT/mTOR pathway.

Osteosarcoma (OS) is the most frequent primary malignancy initially in bone with multiple genomic aberrations. Methylenetetrahydrofolate dehydrogenase 1-like (MTHFD1L) is linked with the progression of diverse tumors. However, its function in OS is not understood completely. The expression pattern and prognostic significance of MTHFD1L in OS tissues were analyzed based on GEO database. The expression level of MTHFD1L in OS cell lines was explored by qRT-PCR. The cell proliferation, colony formation ability, invasion as well as migration in OS cells after MTHFD1L knockdown were determined using cell counting kit 8 (CCK-8) assay, colony formation and transwell methods. GSEA analysis was performed to predict the underlying mechanisms of MTHFD1L in OS development. Furthermore, the western blot was utilized to study the influence of MTHFD1L on AKT/mTOR pathway. Our results indicated that MTHFD1L expression was significantly up-regulated in OS tissues and cells compared with normal tissues and cells. High expression of MTHFD1L could lead to poor prognosis of OS patients. Cell proliferation, colony formation ability, migration and invasion were blocked because of reduced MTHFD1L in vitro. Moreover, cell cycle and AKT/mTOR pathway were all associated with MTHFD1L expression. In conclusion, the findings revealed that MTHFD1L might promote the development of OS via mediating cell cycle and AKT/mTOR pathway, indicating that MTHFD1L might act as a promising therapeutic target for OS treatment.

Respiratory Muscle Training Improves Strength and Decreases the Risk of Respiratory Complications in Stroke Survivors: A Systematic Review and Meta-analysis.

OBJECTIVE: To evaluate the effects of respiratory muscle training in a population of stroke patients. DATA SOURCES: The following databases were searched for clinical trials through December 2019: PubMed, EMBASE, Cochrane Library, CINAHL, and China National Knowledge Infrastructure. STUDY SELECTION: Randomized controlled trials (N=9) published in English met the inclusion criteria. DATA EXTRACTION: Data were extracted and assessed for accuracy by 2 reviewers. Any disagreements were resolved after discussions with an independent third reviewer. The quality of the included randomized controlled trials was assessed using the Cochrane bias tool. DATA SYNTHESIS: The meta-analysis showed increased maximal inspiratory pressure (standardized mean difference [SMD], 0.88; 95% confidence interval [CI], 0.62-1.15; P<.001; 12-wk follow-up period: SMD, 0.94; 95% CI, 0.42-1.45; P<.001), maximal expiratory pressure (SMD, 0.83; 95% CI, 0.15-1.52; P=.017; 12-wk follow-up period: SMD, 0.99; 95% CI, 0.47-1.51; P<.001), forced expiratory volume in 1 second (SMD, 1.41; 95% CI, 0.57-2.24; P=.001), forced vital capacity (SMD, 1.36; 95% CI, 0.55-2.16; P<.001), peak expiratory flow (SMD, 0.74; 95% CI, 0.16-1.32; P=.013), 6-minute walk test (SMD, 0.67; 95% CI, 0.11-1.23; P=.020), and decreased respiratory complications (odds ratio, 0.55; 95% CI, 0.30-1.00; P=.050) compared with no respiratory intervention or a sham intervention. CONCLUSIONS: Respiratory muscle training improved poststroke muscle strength and the benefits were carried over for up to 12 weeks, including improved lung function, walking capacity, and a reduced risk of respiratory impediments.