Tenascin-C promotes endochondral ossification and fracture healing through Hedgehog and Hippo signaling.

Fractures are frequent and severe musculoskeletal injuries. This study aimed to investigate the function of tenascin-C (TNC) in regulating chondrogenic during fracture healing and elucidate the underlying molecular mechanisms. A well-established femur fracture model in male C57BL/6J mice was used to transect the middle diaphysis of the femur. To identify the essential role of TNC, shTNC lentiviruses or TNC protein were administered in the animal model. Micro-CT analysis, histologic analysis, immunostaining assays, and gene expression analysis were employed to investigate the effect of TNC during fracture healing. An in vitro mesenchymal stem cell culture system was developed to investigate the role and molecular mechanism of TNC in regulating chondrogenesis. TNC expression was induced at the inflammatory phase and peaked at the cartilaginous callus phase during fracture healing. Knockdown of TNC expression in callus results in decreased callus formation and impaired fracture healing. Conversely, administration of exogenous TNC promoted chondrogenic differentiation, cartilage template formation and ultimately improved fracture healing. Both the Hedgehog and Hippo signaling pathways were found to be involved in the pro-chondrogenic function of TNC. Our observations demonstrate that TNC is a crucial factor responsible for endochondral ossification in fracture healing and provide a potential therapeutic strategy for promoting fracture healing.

Estimated Pulse Wave Velocity Predicts All-Cause and Cardiovascular-Cause Mortality in Individuals With Hypertension　- Findings From a National Health and Nutrition Examination Study 1999-2018.

BACKGROUND: This study aimed to investigate the association between estimated pulse wave velocity (ePWV) and mortality outcomes among individuals with hypertension.Methods and Results: Based on the National Health and Nutrition Examination Survey (NHANES) 1999-2018, a total of 14,396 eligible participants with hypertension were enrolled. The ePWV was calculated using the equation based on blood pressure and age. The mortality outcomes of included participants were directly acquired from the National Death Index database. The multivariable Cox regression analysis was used to examine the relationship between ePWV and mortality outcomes. Moreover, the restricted cubic spline (RCS) was also used to explore this relationship. Receiver operating characteristics curves (ROC) were adopted to evaluate the prognostic ability of ePWV for predicting mortality outcomes of patients with hypertension. The median follow-up duration was 10.8 years; individuals with higher an ePWV had higher risks of mortality from both all causes (HR: 2.79, 95% CI: 2.43-3.20) and cardiovascular diseases (HR: 3.41, 95% CI: 2.50-4.64). After adjusting for confounding factors, each 1 m/s increase in ePWV was associated with a 43% increase in all-cause mortality risk (HR: 1.43, 95% CI: 1.37-1.48) and a 54% increase in cardiovascular mortality risk (HR: 1.54, 95% CI: 1.43-1.66). CONCLUSIONS: This study indicates that ePWV is a novel prognostic indicator for predicting the risks of mortality among patients with hypertension.

Sex dimorphism of IL-17-secreting peripheral blood mononuclear cells in ankylosing spondylitis based on bioinformatics analysis and machine learning.

BACKGROUND: Ankylosing spondylitis (AS) with radiographic damage is more prevalent in men than in women. IL-17, which is mainly secreted from peripheral blood mononuclear cells (PBMCs), plays an important role in the development of AS. Its expression is different between male and female. However, it is still unclear whether sex dimorphism of IL-17 contribute to sex differences in AS. METHODS: GSE221786, GSE73754, GSE25101, GSE181364 and GSE205812 datasets were collected from the Gene Expression Omnibus (GEO) database. Differential expressed genes (DEGs) were analyzed with the Gene Set Enrichment Analysis (GSEA), Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) methods. CIBERSORTx and EcoTyper algorithms were used for immune infiltration analyses. Machine learning based on the XGBoost algorithm model was used to identify the impact of DEGs. The Connectivity Map (CMAP) database was used as a drug discovery tool for exploring potential drugs based on the DEGs. RESULTS: According to immune infiltration analyses, T cells accounted for the largest proportion of IL-17-secreting PBMCs, and KEGG analyses suggested an enhanced activation of mast cells among male AS patients, whereas the expression of TNF was higher in female AS patients. Other signaling pathways, including those involving metastasis-associated 1 family member 3 (MAT3) or proteasome, were found to be more activated in male AS patients. Regarding metabolic patterns, oxidative phosphorylation pathways and lipid oxidation were significantly upregulated in male AS patients. In XGBoost algorithm model, DEGs including METRN and TMC4 played important roles in the disease process. we integrated the CMAP database for systematic analyses of polypharmacology and drug repurposing, which indicated that atorvastatin, famciclocir, ATN-161 and taselisib may be applicable to the treatment of AS. CONCLUSIONS: We analyzed the sex dimorphism of IL-17-secreting PBMCs in AS. The results showed that mast cell activation was stronger in males, while the expression of TNF was higher in females. In addition, through machine learning and the CMAP database, we found that genes such as METRN and TMC4 may promote the development of AS, and drugs such as atorvastatin potentially could be used for AS treatment.

The amino-terminal domain of GluA1 mediates LTP maintenance via interaction with neuroplastin-65.

Long-term potentiation (LTP) has long been considered as an important cellular mechanism for learning and memory. LTP expression involves NMDA receptor-dependent synaptic insertion of AMPA receptors (AMPARs). However, how AMPARs are recruited and anchored at the postsynaptic membrane during LTP remains largely unknown. In this study, using CRISPR/Cas9 to delete the endogenous AMPARs and replace them with the mutant forms in single neurons, we have found that the amino-terminal domain (ATD) of GluA1 is required for LTP maintenance. Moreover, we show that GluA1 ATD directly interacts with the cell adhesion molecule neuroplastin-65 (Np65). Neurons lacking Np65 exhibit severely impaired LTP maintenance, and Np65 deletion prevents GluA1 from rescuing LTP in AMPARs-deleted neurons. Thus, our study reveals an essential role for GluA1/Np65 binding in anchoring AMPARs at the postsynaptic membrane during LTP.

Tape Tarsorrhaphy in the Management of Lagophthalmos Caused by Severe Congenital Blepharoptosis Procedures.

BACKGROUND: Lagophthalmos, a common complication after blepharoptosis correction, has plagued oculoplastic surgeons. The goal of this study was to investigate the effect of tape eyelid closure on reducing the occurrence of lagophthalmos after blepharoptosis correction. METHODS: From April 2020 to June 2021, a total of 112 patients with severe congenital ptosis received corrective surgery at the Department of Plastic and Reconstructive Surgery, Xijing Hospital, Fourth Military Medical University. Of these, 48 underwent frontalis muscle advancement technique and 64 underwent conjoint fascial sheath suspension. Preoperative data collected included demographics, levator function, Bell's phenomenon, and marginal reflex distance 1 (MRD1). Postoperative data included surgery type, MRD1, eyelid closure function, aesthetic outcomes (including eyelid contour, eyelid symmetry, and eyelid crease), keratitis, and other complications. RESULTS: Frontalis muscle advancement technique group: the median of safe eye closure time was 7.3 months (positive Bell's phenomenon; interquartile range [IQR], 3.8-10.8 months) and 13.9 months (poor Bell's phenomenon; IQR, 11.6-16.1 months). There was a significant improvement between the preoperative and postoperative MRD1 (-1.52 ± 0.82 vs 3.85 ± 0.58 mm, P < 0.05). Conjoint fascial sheath suspension group: the median of safe eye closure time was 5.7 months (positive Bell's phenomenon; IQR, 2.9-8.5 months) and 12.4 months (poor Bell's phenomenon; IQR, 8.1-16.7 months). There was a significant improvement between the preoperative and postoperative MRD1 (-1.02 ± 0.91 vs 4.15 ± 1.03 mm, P < 0.05). All patients/guardians were satisfied with the aesthetic outcomes. CONCLUSIONS: Tape tarsorrhaphy is a safe, easy-to-learn method for treating lagophthalmos with a good aesthetic outcome.

The Aesthetic Evaluation of the Brow-Eye Continuum After Correction of Severe Congenital Ptosis in Children With Extended Frontalis Muscle Advancement Technique.

BACKGROUND: Severe congenital ptosis is a common ocular deformity in pediatric patients that can significantly impact visual development and aesthetic appearance, leading to negative psychosocial outcomes. The frontalis muscle advancement technique is a well-established surgical treatment for severe congenital ptosis. Aesthetic changes of the brow-eye continuum often plays an important role in ptosis surgery. METHODS: We conducted a single-center retrospective case series study of patients with severe congenital ptosis who underwent the frontalis muscle advancement technique at the Department of Plastic and Reconstructive Surgery, Xijing Hospital, Fourth Military Medical University between April 2020 and June 2021. The study aimed to evaluate the aesthetic changes of the eyebrow-eyelid continuum after surgery. The main outcome measurements included marginal reflex distance 1, palpebral fissure height, eyebrow position, upper eyelid to lower eyebrow distance, lower eyelid to upper eyebrow distance, and nasal base to lower eyelid distance. RESULTS: The study included 48 patients (66 eyelids), with 30 unilateral and 18 bilateral patients. Our analysis found that eyebrow height decreased by an average of 4.8% postoperatively relative to preoperatively in all patients. CONCLUSIONS: The frontalis muscle advancement technique has demonstrated effectiveness in achieving aesthetically pleasing outcomes in children with severe ptosis. It is crucial to pay careful attention to the brow-eye continuum during the correction process, as its harmony can greatly impact the final result.

Tape Eyelid Closure: An Effective Solution for Nocturnal Lagophthalmos in Patients with Ptosis and Poor Bell's Phenomenon.

BACKGROUND: Poor Bell's phenomenon is often considered a relative contraindication for ptosis surgery, as it increases the risk of corneal exposure and dry eye symptoms after surgery. However, the Bell's phenomenon may vary in different individuals and sleep stages, making it inaccurate to predict the position of the eye during sleep based on awake examination. This study aimed to investigate the role of Bell's phenomenon in ptosis surgery and the management of nocturnal lagophthalmos. METHODS: We conducted a retrospective case series of 23 patients with ptosis and poor Bell's phenomenon who underwent different surgical techniques at Xijing Hospital from April 2020 to June 2021. We assessed Bell's phenomenon at different stages of sleep and collected data on ptosis degree, surgical approach, lagophthalmos, complications, and outcomes. RESULTS: Of the total 23 patients originally considered for study, 9 with frontalis muscle advancement technique, 8 with conjoint fascial sheath suspension, 4 with levator resection technique, and 2 with levator aponeurosis plication technique. All patients achieved satisfactory correction of ptosis. One patient had prolonged lagophthalmos and underwent reoperation to lower the eyelid height. Other complications were minor and resolved with conservative treatment. CONCLUSION: We conclude that poor Bell's phenomenon is not a relative contraindication for ptosis surgery. Nocturnal lagophthalmos should be monitored after ptosis surgery regardless of the Bell's phenomenon results. Tape eyelid closure can be an effective solution to protect the corneal surface during nocturnal lagophthalmos. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Evaluation of combination treatment with DS-1205c, an AXL kinase inhibitor, and osimertinib in metastatic or unresectable EGFR-mutant non-small cell lung cancer: results from a multicenter, open-label phase 1 study.

The objective of this study was to evaluate the safety and tolerability of DS-1205c, an oral AXL-receptor inhibitor, in combination with osimertinib in metastatic or unresectable EFGR-mutant non-small cell lung cancer (NSCLC) patients who developed disease progression during EGFR tyrosine kinase inhibitor (TKI) treatment. An open-label, non-randomized phase 1 study was conducted in Taiwan, in which 13 patients received DS-1205c monotherapy at a dosage of 200, 400, 800, or 1200 mg twice daily for 7 days, followed by combination treatment with DS-1205c (same doses) plus osimertinib 80 mg once daily in 21-day cycles. Treatment continued until disease progression or other discontinuation criteria were met. At least one treatment-emergent adverse event (TEAE) was reported in all 13 patients treated with DS-1205c plus osimertinib; with ≥ 1 grade 3 TEAE in 6 patients (one of whom also had a grade 4 increased lipase level), and 6 patients having ≥ 1 serious TEAE. Eight patients experienced ≥ 1 treatment-related AE (TRAE). The most common (2 cases each) were anemia, diarrhea, fatigue, increased AST, increased ALT, increased blood creatinine phosphokinase, and increased lipase. All TRAEs were non-serious, with the exception of an overdose of osimertinib in 1 patient. No deaths were reported. Two-thirds of patients achieved stable disease (one-third for > 100 days), but none achieved a complete or partial response. No association between AXL positivity in tumor tissue and clinical efficacy was observed. DS-1205c was well-tolerated with no new safety signals in patients with advanced EGFR-mutant NSCLC when administered in combination with the EFGR TKI osimertinib. ClinicalTrials.gov ; NCT03255083.

Iodine-Catalyzed Regioselective Synthesis of Diphenyl-Substituted Carbazoles via [4 + 2] Annulation of ß-Formyl Ketones with Indoles.

The [4 + 2] annulation of ß-formyl ketones with an indole has been developed for the regioselective synthesis of diphenyl-substituted carbazoles in the presence of a catalytic amount of iodine. The 1,4-dicarbonyl compound containing a phenyl group at the α-position of an aldehyde group reacts more readily with indoles to form carbazole derivatives. Using this method, a variety of carbazole derivatives can be readily accessed under mild reaction conditions.

Can the apparent transverse relaxation rate (R2*) evaluate the efficacy of concurrent chemoradiotherapy in locally advanced nasopharyngeal carcinoma? a preliminary experience.

BACKGROUND: The use of the apparent transverse relaxation rate (R2*) in nasopharyngeal carcinoma (NPC) has not been previously reported in the literature. The aim of this study was to investigate the role of the R2* value in evaluating response to concurrent chemoradiotherapy (CCRT) in patients with NPC. METHODS: Forty-one patients with locoregionally advanced NPC confirmed by pathology were examined by blood oxygenation level-dependent (BOLD) magnetic resonance imaging (MRI) before and after CCRT, and conventional MRI was performed 3 months after the completion of CCRT. All patients were divided into a responding group (RG) and a nonresponding group (NRG), according to MRI findings 3 months after the end of treatment. The R2* values before (R2*preT) and after (R2*postT) CCRT and the ΔR2* (ΔR2*=R2*postT - R2*preT) were calculated in the tumor. RESULTS: Among the 41 patients, 26 were in the RG and 15 were in the NRG. There was no statistical difference in the R2*preT between RG and NRG (P = 0.307); however, there were significant differences in R2*postT and ΔR2* (P < 0.001). The area under the curve of R2*postT and ΔR2* for predicting the therapeutic response of NPC was 0.897 and 0.954, respectively, with cutoff values of 40.95 and 5.50 Hz, respectively. CONCLUSION: The R2* value can be used as a potential imaging indicator to evaluate the therapeutic response of locoregionally advanced NPC.

Clinical and genetic characterization of NEFL-related neuropathy in Taiwan.

BACKGROUND: Mutations in the neurofilament light polypeptide gene (NEFL) are an uncommon cause of Charcot-Marie-Tooth disease (CMT). The aim of this study is to elucidate the clinical characteristics and genetic spectrum of NEFL-related neuropathy in a Taiwanese CMT cohort. METHODS: Mutational analysis of the coding regions of NEFL was performed by Sanger sequencing or targeted resequencing. Twenty-one patients from nine CMT pedigrees, identified from a cohort of 508 unrelated CMT patients, were found to have a NEFL mutation. Genetic, clinical and electrophysiological features were analyzed. RESULTS: Six NEFL mutations were identified, including two novel ones (p.P8S, p.N98Y). NEFL p.E396K was the most common mutation, accounting for 33.3% of the patients in our cohort. All patients manifested sensorimotor polyneuropathy with a mean age of disease onset of 13.5 ± 9.6 (1-40) years. Their motor nerve conduction velocities (MNCVs) of the ulnar nerve ranged from 22.1 to 48.7 m/s. Seventy percent of the patients could be classified as intermediate CMT with ulnar MNCVs between 25 and 45 m/s. Six of the 21 patients (28.6%) had additional features of central nervous system (CNS) involvement, including motor developmental delay, spasticity, cerebellar signs, neuropathic pain and scoliosis. CONCLUSION: NEFL mutations account for 1.8% (9/508) of the CMT patients in Taiwan. The present study delineates the clinical and genetic characteristics of NEFL-related neuropathy in Taiwan, and highlights that ulnar MNCV above 25 m/s and CNS involvement may serve as diagnostic clues for NEFL-related neuropathy.

Modified Levator Resection Technique for Moderate Congenital Blepharoptosis.

BACKGROUND: For moderate ptosis associated with fair levator function (LF), the levator resection is the most commonly used procedure. However, the levator resection technique still has some disadvantages, such as residual lagophthalmos (RL), undercorrection, conjunctival prolapse, and eyelid contour abnormality. To solve the above problems, our team have made modifications to the levator resection technique in three aspects: releasing the levator muscle sufficiently, preserving the supporting structure of the conjunctiva, and placing multiple suture sites. METHODS: Fifty-seven patients (81 eyes) underwent the modified levator resection technique and were enrolled in the study. Preoperative data collected included age, sex, margin reflex distance 1 (MRD1), and LF. Postoperative data collected included MRD1, RL, patient satisfaction, complications, and length of follow-up. RESULTS: Mean MRD1 significantly increased from 1.45 ± 0.65 mm preoperatively to 3.57 ± 0.51 mm postoperatively. Mean LF significantly increased from 6.49 ± 1.12 mm preoperatively to 9.48 ± 1.39 mm postoperatively. Successful correction was obtained in 77 eyes (95.1%). Mean RL was 1.09 ± 0.57 and 72 eyes (88.9%) showed excellent or good eyelid closure function. Fifty-four patients (94.7%) were completely satisfied with the final result. Complications such as hematoma, infection, conjunctival prolapse, suture exposure, corneal abrasion, and keratitis were not found in any cases during follow-up. CONCLUSION: This modified levator resection technique introduced in this study is effective in correcting moderate congenital blepharoptosis, while minimizing RL, undercorrection, conjunctival prolapse, eyelid contour abnormality by releasing the levator muscle sufficiently, preserving the supporting structure of the conjunctiva, and placing multiple suture sites. LEVEL OF EVIDENCE IV: This journal requires that authors 42 assign a level of evidence to each article. For a full 43 description of these Evidence-Based Medicine ratings, 44 please refer to the Table of Contents or the online 45 Instructions to Authors www.springer.com/00266 .

[Effects of serum containing Shenrong Pill on oxidative stress damage in mouse Leydig cells].

OBJECTIVE: To explore the mechanism of Shenrong pills in improving oligoasthenospermia by inhibiting oxidative stress-induced Leydig cell apoptosis in mouse testis. METHODS: The oxidative stress model of mouse Leydig cells (TM3) was induced by 3% hydrogen peroxide (H2O2) of 600 µmol/L, and then TM3 cells were treated with 7.5%, 10% and 12.5% serum containing Shenrong pills, respectively. TM3 cells were divided into normal control group, model group, and low, medium and high dose groups of Shenrong pills containing serum. The cell viability of TM3 after treatment was detected by CCK-8 method, reactive oxygen species (ROS) were detected by DCFH probe method, and SOD-1, CAT, GSH-px, MDA and LPO in cell lysates were detected by ELISA method. The changes of apoptosis-related proteins Bcl-2, Bax in cell lysates were detected by Western Blot. RESULTS: After H2O2 treatment, compared with normal control group, cell viability was significantly decreased (P< 0.01), MDA and LPO contents were significantly increased (P<0.01), SOD-1, CAT and GSH-px contents were significantly decreased (P<0.01). Reactive oxygen species (ROS) were significantly increased, the relative expression ratio of Bcl-2 protein was significantly decreased (P<0.01, P<0.05), and the relative expression of Bax protein was increased. After the administration of Shenrong pills containing serum, the above indexes were reversed to varying degrees. CONCLUSION: Shenrong pills can resist oxidative stress, inhibit the apoptosis of TM3 cells in mice, maintain high levels of testosterone required for spermatogenic cells, and improve the sperm quality of mice with oligonasthenospermia.

Economic Analysis of Exclusionary EGFR Test Versus Up-Front NGS for Lung Adenocarcinoma in High EGFR Mutation Prevalence Areas.

BACKGROUND: This study sought to determine whether exclusionary EGFR mutation testing followed by next-generation sequencing (NGS) is a cost-efficient and timely strategy in areas with high prevalence rates of EGFR mutation. METHODS: We developed a decision tree model to compare exclusionary EGFR testing followed by NGS and up-front NGS. Patients entered the model upon diagnosis of metastatic lung adenocarcinoma. Gene alterations with FDA-approved targeted therapies included EGFR, ALK, ROS1, BRAF, RET, MET, NTRK, and KRAS. Model outcomes were testing-related costs; time-to-test results; monetary loss, taking both costs and time into consideration; and percentage of patients who could be treated by FDA-approved therapies. Stacked 1-way and 3-way sensitivity analyses were performed. RESULTS: Exclusionary EGFR testing incurred testing-related costs of US $1,387 per patient, a savings of US $1,091 compared with the costs of up-front NGS. The time-to-test results for exclusionary EGFR testing and up-front NGS were 13.0 and 13.6 days, respectively. Exclusionary EGFR testing resulted in a savings of US $1,116 in terms of net monetary loss, without a reduction of patients identified with FDA-approved therapies. The EGFR mutation rate and NGS cost had the greatest impact on minimizing monetary loss. Given that the tissue-based NGS turnaround time was shortened to 7 days, up-front NGS testing would become the best strategy if its price could be reduced to US $568 in Taiwan. CONCLUSIONS: In areas with high prevalence rates of EGFR mutation, exclusionary EGFR testing followed by NGS, rather than up-front NGS, is currently a cost-efficient strategy for metastatic lung adenocarcinoma.

Effects and parameters of community-based exercise on motor symptoms in Parkinson's disease: a meta-analysis.

BACKGROUND: Community-based exercise is a continuation and complement to inpatient rehabilitation for Parkinson's disease and does not require a professional physical therapist or equipment. The effects, parameters, and forms of each exercise are diverse, and the effect is affected by many factors. A meta-analysis was conducted to determine the effect and the best parameters for improving motor symptoms and to explore the possible factors affecting the effect of community-based exercise.  METHODS: We conducted a comprehensive search of six databases: PEDro, PubMed/Medline, CENTRAL, Scopus, Embase, and WOS. Studies that compared community-based exercise with usual care were included. The intervention mainly included dance, Chinese martial arts, Nordic walking, and home-based exercise. The primary outcome measure was the Unified Parkinson's Disease Rating Scale part III (UPDRS-III) score. The mean difference (95% CI) was used to calculate the treatment outcomes of continuous outcome variables, and the I2 statistic was used to estimate the heterogeneity of the statistical analysis. We conducted subgroup analysis and meta-regression analysis to determine the optimal parameters and the most important influencing factors of the exercise effect.  RESULTS: Twenty-two studies that enrolled a total of 809 subjects were included in the analysis. Exercise had a positive effect on the UPDRS-III (MD = -5.83; 95% CI, -8.29 to -3.37), Timed Up and Go test (MD = -2.22; 95% CI -3.02 to -1.42), UPDRS ((MD = -7.80; 95% CI -10.98 to -6.42), 6-Minute Walk Test (MD = 68.81; 95% CI, 32.14 to 105.48), and Berg Balance Scale (MD = 4.52; 95% CI, 2.72 to 5.78) scores. However, the heterogeneity of each included study was obvious. Weekly frequency, age, and duration of treatment were all factors that potentially influenced the effect. CONCLUSIONS: This meta-analysis suggests that community-based exercise may benefit motor function in patients with PD. The most commonly used modalities of exercise were tango and tai chi, and the most common prescription was 60 min twice a week. Future studies should consider the influence of age, duration of treatment, and weekly frequency on the effect of exercise. PROSPERO TRIAL REGISTRATION NUMBER: CRD42022327162.

Natural carbazole alkaloid murrayafoline A displays potent anti-neuroinflammatory effect by directly targeting transcription factor Sp1 in LPS-induced microglial cells.

Neuroinflammation is a leading cause for neurological disorders. Carbazole alkaloids, isolated from the medicinal plants of Murraya species (Rutaceae), have exhibited wide pharmacological activities particularly for neuroinflammation. However, its underlying cellular targets and molecular mechanisms still remain unclear. In current study, we found that murrayafoline A (MA), a carbazole alkaloid obtained from Murraya tetramera, potently inhibited the production of neuroinflammation mediators, such as nitric oxide (NO), TNF-α, IL-6 and IL-1ß in LPS-induced BV-2 microglial cells. Then, we performed thermal proteome profiling (TPP) strategy to identify Specificity protein 1 (Sp1) as a potential cellular target of MA. Moreover, we performed surface plasmon resonance (SPR), cellular thermal shift assay (CETSA) and drug affinity responsive target stability (DRATS) assays to confirm the direct interaction between MA and Sp1. Furthermore, we downregulated Sp1 expression in BV2 cells using siRNA transfection, and observed that Sp1 knockdown significantly antagonized MA-mediated inhibition of neuroinflammation mediator production. Meanwhile, Sp1 knockdown also markedly reversed MA-mediated inactivation of IKKß/NF-κB and p38/JNK MAPKs pathways. Finally, in vivo studies revealed that MA significantly suppressed the expression of Iba-1, TNF-α, and IL-6, while increased the number of Nissl bodies in the brains of LPS-induced mice. Taken together, our study demonstrated that MA exerted obvious anti-neuroinflammation effect by directly targeting Sp1, thereby inhibiting NF-κB and MAPK signaling pathways. Our findings also provided a promising direction of pharmacological targeting Sp1 for anti-neuroinflammation therapeutics as well as novel agent development.

Simultaneous Double Eyelid Blepharoplasty and Blepharoptosis Correction With Levator Aponeurosis Plication Technique: Clinical Experience of 108 Cases.

BACKGROUND: Fifty percent of Asians are born without a supratarsal fold (also called single eyelid), and double eyelid blepharoplasty is one of the most commonly performed and most popular facial cosmetic surgeries in the Asian population. However, patients with single eyelid frequently present with concomitant mild blepharoptosis (degree of ptosis, ≤2 mm), which often fails to cause the attention of surgeons and misses correction. METHODS: A retrospective study of all patients who underwent double eyelid blepharoplasty and blepharoptosis correction simultaneously with the modified levator aponeurosis plication technique was performed from June of 2017 to June of 2020. RESULTS: A total of 108 patients (155 eyelids) underwent double eyelid blepharoplasty and blepharoptosis correction simultaneously with the modified levator aponeurosis plication technique and were enrolled in the study. The average follow-up period was 11.8 ± 4.5 months. There was a statistically significant difference between the preoperative margin reflex distance 1 (MRD1) and postoperative MRD1 (2.93 ± 0.37 vs 4.21 ± 0.39 mm, P = 0.000), and the mean MRD1 improvement was 1.28 ± 0.50 mm. Sufficient correction was obtained in 148 eyelids (95.5%), whereas undercorrection was observed in 5 eyelids (3.2%) and overcorrection was observed in 2 eyelids (1.3%). One hundred two patients (94.4%) were completely satisfied with the final result.All patients had smooth and elegant upper eyelid margin curve, and no patients complained of distortion of the eyelid margin contour and foreign body sensation.There were no cases of hematoma, infection, suture exposure, corneal abrasion, and keratitis in any patient. CONCLUSIONS: This modified levator aponeurosis plication introduced in this study is a simple and effective method for creating double-eyelid crease and correcting mild blepharoptosis simultaneously, and provides a satisfactory outcome. As such, we recommend this method in treating patients with both single eyelid and mild blepharoptosis.

Investigating ZFYVE26 mutations in a Taiwanese cohort with hereditary spastic paraplegia.

BACKGROUND/PURPOSE: Hereditary spastic paraplegia (HSP) is a heterogeneous group of inherited neurodegenerative disorders characterized by slowly progressive lower limbs spasticity and weakness. HSP type 15 (SPG15) is an autosomal recessive subtype caused by ZFYVE26 mutations. The aim of this study was to investigate the frequency and clinical and genetic features of ZFYVE26 mutations in a Taiwanese HSP cohort. METHODS: Mutational analysis of the coding regions of ZFYVE26 was performed by targeted resequencing in the 195 unrelated Taiwanese patients with HSP. All of the patients were of Han Chinese ethnicity. Clinical, neuropsychological, electrophysiological evaluations and imaging studies were collected. RESULTS: Among the 195 patients, only one SPG15 patient was identified. The patient had a novel recessive ZFYVE26 frameshift truncating mutation, p.R1806Gfs∗36 (c.5415delC), and presented with insidious onset spastic weakness of lower-extremities and cognitive impairment. Neuropsychological assessment revealed deficits in executive function, visual naming, category verbal fluency, and manual dexterity. Brain MRI showed thin corpus callosum and the "ears of lynx" sign. CONCLUSION: SPG15 accounts for approximately 0.5% (1/195) of the Taiwanese HSP cohort. This study identified the first Taiwanese SPG15 case and delineated the clinical, genetic, neuropsychological, and neuroimaging features. These findings expand the mutational spectrum of ZFYVE26 and also broaden the knowledge of clinical and neuropsychological characteristics of SPG15.

Conjoint Fascial Sheath Suspension for Correction of Recurrent Blepharoptosis.

BACKGROUND: Blepharoptosis is defined as an abnormally low-positioned upper eyelid margin in the primary gaze position, which results in cosmetic discomfort and functional visual dysfunction. Recurrence is one of the common complications after ptosis correction and requires further revision. Conjoint fascial sheath (CFS) suspension has become increasingly popular for ptosis. In this article, we described our experience of CFS suspension in the treatment of recurrent blepharoptosis and evaluated the postoperative outcomes so as to guide the clinical application of CFS suspension. METHODS: Thirty-eight patients (48 eyelids) who had recurrent blepharoptosis and received CFS suspension were included in this study. Before the surgery, the degree of ptosis and levator function were assessed. The postoperative evaluation consisted of the correction effect, eyelid symmetry, protective closure function of eyelid, and surgical complications. RESULTS: At the final follow-up, 46 eyelids (95.8%) showed an ideal correction, of which 24 eyelids (50%) showed sufficient correction and 22 eyelids (45.8%) showed normal correction. The remaining 2 eyelids (4.2%) showed under-correction. Among all 38 patients, 26 patients (68.4%) achieved good symmetry, and 10 patients (26.3%) achieved fair symmetry, while only 2 patients (5.3%) showed poor symmetry. Recovery time of eyelid protective closure function was 3.9 ± 1.04 months (range, 2.5-6 months). There were no complications except residual lagophthalmos (9 eyelids) residual conjunctival prolapse (10 eyelids). CONCLUSION: CFS suspension is an effective method for the correction of recurrent blepharoptosis due to its sufficient correction effect, recovery of eyelid protective closure function, and less complication rate. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Aesthetic Changes of Brow-Eyelid Continuum After Correction of Moderate-Severe Blepharoptosis with Conjoint Fascial Sheath Suspension.

BACKGROUND: As periorbital aesthetic commonly improved in blepharoptosis patients after correction surgery, the aim of this study was to elaborate the brow-eyelid continuum changes in moderate-severe ptosis patients who underwent conjoint fascial sheath suspension systematically. METHODS: Patients with moderate-severe ptosis who underwent conjoint fascial sheath suspension were assessed by using pre- and post-operative digital photographs in the primary gaze position of the eye. The main outcome measurements included marginal reflex distance1 (MRD1), palpebral fissure height (PFH), eyebrow position, the symmetry of face and the horizontal forehead lines condition. RESULTS: There were 43 patients (53 eyelids) in our study, including 33 unilateral and 10 bilateral patients. The mean levator function was 3.00 ± 1.07 mm. Before surgery, the mean MRD1 and PFH were 0.60 ± 1.14 mm and 6.75 ± 1.71 mm, respectively. The mean eyebrow height at medial, center, lateral position was 33.16 ± 3.95 mm, 35.99 ± 4.02 mm and 34.35 ± 4.80 mm, respectively. It was found that MRD1 and PFH symmetry both were 23.26% and eyebrow symmetry was 62.79%. For forehead wrinkles, 48.84% of the patients was mild, 34.88% was moderate, and 16.28% was severe. The average follow-up was 12.78 months (ranged from 12 to 18 months). One month after surgery, the mean MRD1 and PFH were 5.68 ± 0.86 mm, 11.61 ± 0.97 mm, respectively, both of which improved significantly (P < 0.0001). The mean eyebrow height at medial, center, lateral position descended to 28.22 ± 4.77 mm (P = 0.017), 31.41 ± 4.58 mm (P = 0.033) and 30.28 ± 3.41 mm (P = 0.018), respectively. The result showed that the rate of patients with MRD1 symmetry was 32.56%, PFH symmetry was 30.23%, and eyebrow symmetry was 90.7%. For forehead wrinkles, 69.77% was mild and 30.23% was moderate. Then, patients' eyebrow gradually elevated, while their upper eyelid dropped. At the last follow-up, the mean MRD1 and PFH were 3.83 ± 0.98 mm and 9.84 ± 1.56 mm, respectively. The mean eyebrow height at medial, center, lateral position improved to 30.52 ± 4.59 mm (P = 0.031), 32.40 ± 4.68 mm (P = 0.033), 31.19 ± 4.16 mm (P = 0.028), respectively. The patients with MRD1 symmetry accounted for 86.05%, PFH symmetry 86.05%, and eyebrow symmetry 90.7%. For forehead wrinkles, 67.44% was mild and 32.56% was moderate. CONCLUSION: CFS suspension can effectively reconstruct moderate-severe ptosis patients' aesthetics of the brow-eyelid continuum by descending elevated eyebrow, improving facial symmetry and reducing forehead rhytids. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .