ObjectiveTo investigate the antidepressant effects and mechanisms of total flavonoids from Cuscutae Semen （TFCC） in the mouse model of chronic unpredictable mild stress （CUMS）. MethodsFifty male 4-week-old ICR mice were randomized into five groups （n=10 per group）： blank control， model， Cuscutae Semen decoction （10.2 g·kg^-1·d^-1）， paroxetine （2.6 mg·kg^-1·d^-1）， and TFCC （173.2 mg·kg^-1·d^-1）. The other groups except the blank control group underwent chronic unpredictable mild stress （CUMS） for 4 weeks. Behavioral assessments were conducted post-modeling. Then， the model group received distilled water （10 mL·kg^-1·d^-1）， while treatment groups were administrated with respective agents via oral gavage （10 mL·kg^-1） for 4 weeks. Depression-like behaviors were evaluated by the sucrose preference test （SPT）， forced swimming test （FST）， and tail suspension test （TST）. Hippocampal neuronal morphology was observed via hematoxylin-eosin staining， and apoptosis in the brain tissue was assessed via terminal- deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling （TUNEL）. Enzyme-linked immunosorbent assay （ELISA） was employed to measure the hippocampal levels of inflammatory cytokines ［interleukin （IL）-1β， IL-6， and TNF-α）］ and neurotransmitters ［5-hydroxytryptamine （5-HT）， dopamine （DA）， and brain-derived neurotrophic factor （BDNF）］， while the reactive oxygen species （ROS） levels were quantified via the DCFH-DA probe. Real-time PCR was performed to measure the mRNA levels of NOD-like receptor protein 3 （NLRP3）， apoptosis-associated Speck-like protein containing a CARD （ASC）， cysteinyl aspartate-specific proteinase-1 （Caspase-1）， IL-1β， and inducible nitric oxide synthase （iNOS）. Western blot was employed to evaluate the protein levels of NLRP3， ASC， Caspase-1， uncoupling protein 2 （UCP2）， and thioredoxin-interacting protein （TXNIP）. ResultsCompared with the blank control group， the model group exhibited weight loss （P<0.01）， reduced sucrose preference （P<0.01）， prolonged immobility time in FST and TST （P<0.01）， neuron disarrangement with nuclear pyknosis in hippocampal CA3 region， increased apoptosis in the brain tissue， elevated levels of IL-1β， IL-6， and TNF-α （P<0.01）， declined levels of 5-HT， DA， and BDNF （P<0.01）， increased ROS accumulation （P<0.01）， upregulated mRNA levels of NLRP3， ASC， Caspase-1， IL-1β， and iNOS （P<0.01）， down-regulated protein level of UCP2 （P<0.01）， and up-regulated protein levels of NLRP3， ASC， Caspase-1， and TXNIP （P<0.01）. Compared with the model group， the interventions restored sucrose preference （P<0.01）， shortened immobility time （P<0.01）， repaired hippocampal neuronal structure， reduced apoptosis， lowered the levels of inflammatory cytokines （P<0.01）， restored the levels of neurotransmitters （P<0.01）， alleviated ROS accumulation （P<0.01）， downregulated the mRNA levels of NLRP3， ASC， Caspase-1， IL-1β， and iNOS （P<0.01）， upregulated the protein level of UCP2 （P<0.01）， and reduced the protein levels of NLRP3， ASC， Caspase-1， and TXNIP （P<0.01）. Moreover， TFCC outperformed Cuscutae Semen decoction in ameliorating depressive behaviors. TFCC excelled in neuronal repair， neurotransmitter regulation， anti-inflammatory effects， and modulation of the UCP2/TXNIP/NLRP3 pathway （P<0.05）. ConclusionTFCC modulates the hippocampal UCP2/TXNIP/NLRP3 pathway to inhibit inflammasome activation， reduce oxidative stress， restore neurotransmitters， thus suppressing neuronal apoptosis and promoting the rearrangement and morphology recovery of hippocampal cells. It outperforms Cuscutae Semen decoction in the antidepressant efficacy.

ObjectiveTo investigate the antidepressant effects and mechanisms of total flavonoids from Cuscutae Semen （TFCC） in the mouse model of chronic unpredictable mild stress （CUMS）. MethodsFifty male 4-week-old ICR mice were randomized into five groups （n=10 per group）： blank control， model， Cuscutae Semen decoction （10.2 g·kg^-1·d^-1）， paroxetine （2.6 mg·kg^-1·d^-1）， and TFCC （173.2 mg·kg^-1·d^-1）. The other groups except the blank control group underwent chronic unpredictable mild stress （CUMS） for 4 weeks. Behavioral assessments were conducted post-modeling. Then， the model group received distilled water （10 mL·kg^-1·d^-1）， while treatment groups were administrated with respective agents via oral gavage （10 mL·kg^-1） for 4 weeks. Depression-like behaviors were evaluated by the sucrose preference test （SPT）， forced swimming test （FST）， and tail suspension test （TST）. Hippocampal neuronal morphology was observed via hematoxylin-eosin staining， and apoptosis in the brain tissue was assessed via terminal- deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling （TUNEL）. Enzyme-linked immunosorbent assay （ELISA） was employed to measure the hippocampal levels of inflammatory cytokines ［interleukin （IL）-1β， IL-6， and TNF-α）］ and neurotransmitters ［5-hydroxytryptamine （5-HT）， dopamine （DA）， and brain-derived neurotrophic factor （BDNF）］， while the reactive oxygen species （ROS） levels were quantified via the DCFH-DA probe. Real-time PCR was performed to measure the mRNA levels of NOD-like receptor protein 3 （NLRP3）， apoptosis-associated Speck-like protein containing a CARD （ASC）， cysteinyl aspartate-specific proteinase-1 （Caspase-1）， IL-1β， and inducible nitric oxide synthase （iNOS）. Western blot was employed to evaluate the protein levels of NLRP3， ASC， Caspase-1， uncoupling protein 2 （UCP2）， and thioredoxin-interacting protein （TXNIP）. ResultsCompared with the blank control group， the model group exhibited weight loss （P<0.01）， reduced sucrose preference （P<0.01）， prolonged immobility time in FST and TST （P<0.01）， neuron disarrangement with nuclear pyknosis in hippocampal CA3 region， increased apoptosis in the brain tissue， elevated levels of IL-1β， IL-6， and TNF-α （P<0.01）， declined levels of 5-HT， DA， and BDNF （P<0.01）， increased ROS accumulation （P<0.01）， upregulated mRNA levels of NLRP3， ASC， Caspase-1， IL-1β， and iNOS （P<0.01）， down-regulated protein level of UCP2 （P<0.01）， and up-regulated protein levels of NLRP3， ASC， Caspase-1， and TXNIP （P<0.01）. Compared with the model group， the interventions restored sucrose preference （P<0.01）， shortened immobility time （P<0.01）， repaired hippocampal neuronal structure， reduced apoptosis， lowered the levels of inflammatory cytokines （P<0.01）， restored the levels of neurotransmitters （P<0.01）， alleviated ROS accumulation （P<0.01）， downregulated the mRNA levels of NLRP3， ASC， Caspase-1， IL-1β， and iNOS （P<0.01）， upregulated the protein level of UCP2 （P<0.01）， and reduced the protein levels of NLRP3， ASC， Caspase-1， and TXNIP （P<0.01）. Moreover， TFCC outperformed Cuscutae Semen decoction in ameliorating depressive behaviors. TFCC excelled in neuronal repair， neurotransmitter regulation， anti-inflammatory effects， and modulation of the UCP2/TXNIP/NLRP3 pathway （P<0.05）. ConclusionTFCC modulates the hippocampal UCP2/TXNIP/NLRP3 pathway to inhibit inflammasome activation， reduce oxidative stress， restore neurotransmitters， thus suppressing neuronal apoptosis and promoting the rearrangement and morphology recovery of hippocampal cells. It outperforms Cuscutae Semen decoction in the antidepressant efficacy.

Photodynamic immunotherapy is a promising strategy for cancer treatment. However, the dysfunctional tumor vasculature results in tumor hypoxia and the low efficiency of drug delivery, which in turn restricts the anticancer effect of photodynamic immunotherapy. In this study, we designed photosensitive lipid nanoparticles. The synthesized PFBT@Rox Lip nanoparticles could produce type I/II reactive oxygen species (ROS) by electron or energy transfer through PFBT under light irradiation. Moreover, this nanosystem could alleviate tumor hypoxia and promote vascular normalization through Roxadustat. Upon irradiation with white light, the ROS produced by PFBT@Rox Lip nanoparticles in situ dysregulated calcium homeostasis and triggered endoplasmic reticulum stress, which further promoted the release of damage-associated molecular patterns, enhanced antigen presentation, and stimulated an effective adaptive immune response, ultimately priming the tumor microenvironment (TME) together with the hypoxia alleviation and vessel normalization by Roxadustat. Indeed, in vivo results indicated that PFBT@Rox Lip nanoparticles promoted M1 polarization of tumor-associated macrophages, recruited more natural killer cells, and augmented infiltration of T cells, thereby leading to efficient photodynamic immunotherapy and potentiating the anti-primary and metastatic tumor efficacy of PD-1 antibody. Collectively, photodynamic immunotherapy with PFBT@Rox Lip nanoparticles efficiently program TME through the induction of immunogenicity and oxygenation, and effectively suppress tumor growth through immunogenic cell death and enhanced anti-tumor immunity.

Objective:To explore potential predictors of refractory Mycoplasma pneumoniae pneumonia (RMPP) in early stage. Methods:The prospective multicenter study was conducted in Zhejiang, China from May 1 st, 2019 to January 31 st, 2020. A total of 1 428 patients with fever >48 hours to <120 hours were studied. Their clinical data and oral pharyngeal swab samples were collected; Mycoplasma pneumoniae DNA in pharyngeal swab specimens was detected. Patients with positive Mycoplasma pneumoniae DNA results underwent a series of tests, including chest X-ray, complete blood count, C-reactive protein, lactate dehydrogenase (LDH), and procalcitonin. According to the occurrence of RMPP, the patients were divided into two groups, RMPP group and general Mycoplasma pneumoniae pneumonia (GMPP) group. Measurement data between the 2 groups were compared using Mann-Whitney U test. Logistic regression analyses were used to examine the associations between clinical data and RMPP. Receiver operating characteristic (ROC) curves were used to analyse the power of the markers for predicting RMPP. Results:A total of 1 428 patients finished the study, with 801 boys and 627 girls, aged 4.3 (2.7, 6.3) years. Mycoplasma pneumoniae DNA was positive in 534 cases (37.4%), of whom 446 cases (83.5%) were diagnosed with Mycoplasma pneumoniae pneumonia, including 251 boys and 195 girls, aged 5.2 (3.3, 6.9) years. Macrolides-resistant variation was positive in 410 cases (91.9%). Fifty-five cases were with RMPP, 391 cases with GMPP. The peak body temperature before the first visit and LDH levels in RMPP patients were higher than that in GMPP patients (39.6 (39.1, 40.0) vs. 39.2 (38.9, 39.7) ℃, 333 (279, 392) vs. 311 (259, 359) U/L, both P<0.05). Logistic regression showed the prediction probability π=exp (-29.7+0.667×Peak body temperature (℃)+0.004×LDH (U/L))/(1+exp (-29.7+0.667×Peak body temperature (℃)+0.004 × LDH (U/L))), the cut-off value to predict RMPP was 0.12, with a consensus of probability forecast of 0.89, sensitivity of 0.89, and specificity of 0.67; and the area under ROC curve was 0.682 (95% CI 0.593-0.771, P<0.01). Conclusion:In MPP patients with fever over 48 to <120 hours, a prediction probability π of RMPP can be calculated based on the peak body temperature and LDH level before the first visit, which can facilitate early identification of RMPP.

Objective:To investigate the efficacy of osteochondral fragment fixation using bioabsorbable pins for Hepple Ⅱ osteochondral lesions of the talus (OLT) in adolescents.Methods:Retrospective case analysis was used. The clinical data and follow-up results of 13 adolescent patients (13 feet) with Hepple Ⅱ OLT were all treated with osteochondral fragment fixation using bioabsorbable pins admitted to Shanghai Sixth People′s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine from January 2017 to December 2021 were retrospectively analyzed. There were 7 males and 6 females, with 13 right feet. The age was (14.85±2.23) years old, ranged from 12 to 18 years old. According to the American orthopedic foot and ankle society (AOFAS) ankle-hindfoot score, visual analogue scale (VAS) and SF-36 score before operation and at the last follow-up were used to evaluate the efficacy and function of the patients. Measurement data with normal distribution were represented as mean ± standard deviation( ± s), and the comparison between groups was conducted using the t-test; The mearsurement data with skewness distribution were expressed by M( Q1, Q3), and rank-sum test was used for inter-group comparison. Results:Thirteen adolescent patients (13 feet) with Hepple Ⅱ OLT underwent surgery successfully and were followed up for (25.54±9.95) months. All wounds healed by first intention, and no complications such as wound infection and delayed healing occurred. Preoperative AOFAS ankle-posterior foot score, VAS and SF-36 score were 58.62±3.55, 7.00 (6.50, 8.00) and 68.38±4.81, respectively. At the last follow-up, the scores were 97.38±2.73, 1.00 (0.00, 1.00), 91.15±4.28, respectively, and the results were significantly improved at the last follow-up, with the difference between the two groups statistically significant( P<0.05). Conclusion:Osteochondral fragment fixation using bioabsorbable pins which can promote cartilage repair, significantly improve symptoms, and achieve better clinical satisfaction with fewer complications, is a safe and effective surgical treatment option for Hepple Ⅱ OLT in adolescents with satisfactory short-term clinical outcomes.

BACKGROUND: LY01005 (Goserelin acetate sustained-release microsphere injection) is a modified gonadotropin-releasing hormone (GnRH) agonist injected monthly. This phase III trial study aimed to evaluated the efficacy and safety of LY01005 in Chinese patients with prostate cancer. METHODS: We conducted a randomized controlled, open-label, non-inferiority trial across 49 sites in China. This study included 290 patients with prostate cancer who received either LY01005 or goserelin implants every 28 days for three injections. The primary efficacy endpoints were the percentage of patients with testosterone suppression ≤50 ng/dL at day 29 and the cumulative probability of testosterone ≤50 ng/dL from day 29 to 85. Non-inferiority was prespecified at a margin of -10%. Secondary endpoints included significant castration (≤20 ng/dL), testosterone surge within 72 h following repeated dosing, and changes in luteinizing hormone, follicle-stimulating hormone, and prostate specific antigen levels. RESULTS: On day 29, in the LY01005 and goserelin implant groups, testosterone concentrations fell below medical-castration levels in 99.3% (142/143) and 100% (140/140) of patients, respectively, with a difference of -0.7% (95% confidence interval [CI], -3.9% to 2.0%) between the two groups. The cumulative probabilities of maintaining castration from days 29 to 85 were 99.3% and 97.8%, respectively, with a between-group difference of 1.5% (95% CI, -1.3% to 4.4%). Both results met the criterion for non-inferiority. Secondary endpoints were similar between groups. Both treatments were well-tolerated. LY01005 was associated with fewer injection-site reactions than the goserelin implant (0% vs . 1.4% [2/145]). CONCLUSION: LY01005 is as effective as goserelin implants in reducing testosterone to castration levels, with a similar safety profile. TRIAL REGISTRATION ClinicalTrials.gov, NCT04563936.
Humans ; Male ; Antineoplastic Agents, Hormonal/therapeutic use* ; East Asian People ; Gonadotropin-Releasing Hormone/agonists* ; Goserelin/therapeutic use* ; Prostate-Specific Antigen ; Prostatic Neoplasms/drug therapy* ; Testosterone

Objective:To evaluate the mid-term efficacy of surgery for sub-acute injury to distal tibiofibular syndesmosis associated with ankle fracture.Methods:From July 2014 to October 2019, 14 patients were treated at Foot & Ankle Section, Department of Orthopaedics, Shanghai Sixth People’s Hospital for sub-acute injury to distal tibiofibular syndesmosis associated with ankle fracture.There were 11 males and 3 females, aged from 17 to 61 years (mean, 35.9 years).According to Danis-Weber classification, 6 cases were type B and 8 type C; according to Lauge-Hansen classification, 7 cases belonged to supination-external rotation, one to pronation-abduction, and 6 to pronation-external rotation (Maisonneuve fracture in 4).The syndesmosis injury was treated by fixation with distal tibiofibular screws in 11 cases, by Tightrope elastic fixation in one, by hybrid fixation with distal tibiofibular screws and Tightrope in one, and by distal tibiofibular fusion in one.Postoperative complications were recorded.Their visual analogue scale (VAS) and American Orthopaedic Foot and Ankle Society ankle-hindfoot scores (AOFAS-AH) were compared between preoperation and the last follow-up.Results:The 14 patients were followed up for 24 to 85 months (mean, 46.8 months). Of the 9 patients whose distal tibiofibular screws had been removed (including one with hybrid fixation), wound infection occurred in one after removal of all the internal fixation, distal tibiofibular widening in 2, ankle degeneration in 5 and fibular nonunion in one. Of the other 3 patients whose distal tibiofibular screws had not been removed, screw breakage happened in 2, screw loosening in one and distal tibiofibular widening in one. The VAS scores were significantly improved from preoperative 6.8±0.9 to 1.4±1.3 at the last follow-up; the AOFAS-AH scores were increased significantly from preoperative 35.3±6.3 to 86.8±11.7 at the last follow-up (both P<0.001). According to AOFAS-AH scores, 8 cases were excellent, 4 good and 2 moderate. Conclusion:Surgery for sub-acute injury to distal tibiofibular syndesmosis associated with ankle fracture can restabilize the distal tibiofibular syndesmosis and ankle joint, reduce pain and improve ankle function, leading to fine mid-term efficacy.

Objective:To study the morphology of dorsal medial talar neck osteophyte (DMTNO) and its association with anteromedial ankle impingement syndrome (AAIS) using CT 3D reconstruction images.Methods:The present retrospective study included 23 patients with AAIS due to DMTNO (case group) and 23 patients with DMTNO but without AAIS (control group) who had been admitted from February 2019 to June 2021. Multi-slice CT data (DICOM) of DMTNO in both groups were collected and imported into Arigin 3D Pro 3D reconstruction software to reconstruct and observe the 3D morphology of DMTNO. The dorsal convex distance, medial convex distance and anterior convex distance of DMTNO were measured to find their association with AAIS.Results:In the case group, DMTNO clearly showed a flat polyhedral shape with a large base and a small top; in the control group, DMTNO showed various shapes that were different mainly in an irregular top but similar in a large, long and narrow base. The dorsal convex distance [(8.07±2.30) mm] and medial convex distance [(6.70±2.62) mm] in the case group were significantly larger than those in the control group [(3.59±1.10) mm and (1.98±0.93) mm] ( P<0.05), but there was no significant difference between the 2 groups in the anterior convex distance ( P>0.05). Conclusions:The DMTNO leading to AAIS shows a flat polyhedral shape with a large base and a small top. No correlation is found between the anterior convex and AAIS whereas the dorsal convex and medial convex of DMTNO may be closely associated with AAIS.

Objective:To explore the surgical method and therapeutic effect of repairing soft tissue defect of digit-tip with single subcutaneous pedicle V-Y advancing flap combined with skin grafting.Methods:From August 2013 to December 2020, 25 soft tissue defects of digit-tip were repaired by a single subcutaneous pedicle V-Y advancing flap combined with pedicle skin grafting. The area of the defects was 0.8 cm× 0.8 cm to 1.6 cm× 1.4 cm. The flaps were harvested from palm or lateral side of the wound and the area of flap was 0.5 cm×1.0 cm to 0.8 cm×2.5 cm. In order to make the flap transfer to a further distance, the subcutaneous fibre connection of the flap was cut-off during the operation. At the same time, cut off 1 side of subcutaneous pedicle. Finally, the advanced distance of the flap reached 0.5-1.2 cm. After the flap harvested, the medium thickness skin was removed for graft to close the donor site from the wrist striations. After the surgery, follow-up visits were conducted regularly by outpatient clinic, or via telephone or WeChat review or by home visit. Throughout the follow-up, the flap appearance, sensation and recovery of the function of digital joint were observed, together with the patient satisfaction. Results:After the surgery, the postoperative follow-up lasted for 4 months to 8 years. All 25 flaps and skin grafts were survived in first stage wound healing. The flaps and skin grafting areas had excellent texture. The fingerprint had been reconstructed with good appearance. The TPD was 4-9 mm, the functions of digital joint recovered well, and there was no complain about a discomfort at the donor site. According to the evaluation standard of Michigan hand function questionnaire, all 25 patients were very satisfied with the overall appearance and function of the hand. According to Total Angle of Motion (TAM) evaluation standard, finger mobility was excellent in all 25 patients.Conclusion:Subcutaneous V-Y advancing flap combined with skin grafting is an ideal method for repairing soft tissue defect of digit-tip. The surgery characterises a simple flap cutting, less traumatic damage, long advancing distance of flap and good repair effect.

Objective:To evaluate the short-term outcome of arthroscopic modified Brostr?m procedure plus minimally invasive calcaneal osteotomy for the treatment of chronic lateral ankle instability combined with subtle cavus foot.Methods:A retrospective cohort study was conducted to analyze the clinical data of 12 patients suffering chronic lateral ankle instability combined with subtle cavus foot admitted to Shanghai Sixth People′s Hospital Affiliated to Shanghai Jiao Tong University from November 2016 to November 2020, including 5 males and 7 females, aged 16-62 years [(40.3±15.1)years]. All patients were treated with arthroscopic modified Brostr?m procedure plus minimally invasive calcaneal osteotomy. The calcaneal pitch angle, Meary′s angle and medial cuneiform height on the foot weight-bearing lateral view plus calcaneus valgus angle on the hindfoot long axial view were compared to evaluate the improvement of bony structure and foot alignment preoperatively and at 3 months and 1 year postoperatively. At the same time, American Orthopedic Foot and Ankle Society (AOFAS) ankle-hindfoot score and visual analogue scale (VAS) were used to evaluate the improvement of ankle function and pain. Postoperative complications were also observed and recorded.Results:All patients were followed up for 1-3 years [(1.6±0.6)years]. The calcaneal pitch angle was decreased from (24.6±5.3)° preoperatively to (22.5±4.9)° at postoperative 3 months and (22.3±5.0)° at postoperative 1 year; the Meary′s angle was decreased from 6.6°(5.2°,7.6°) preoperatively to 2.5°(0.5°,3.8°) at postoperative 3 months and 2.1°(0.5°,3.2°) at postoperative 1 year; the medial cuneiform height was decreased from (24.3±5.3)mm preoperatively to (22.3±4.8)mm at postoperative 3 months and (22.3±4.6)mm at postoperative 1 year; the calcaneus valgus angle was increased from -7.1°(-10.3°,-5.9°) preoperatively to 2.3°(-2.5°,4.5°) at postoperative 3 months and 2.4°(-1.6°,3.8°) at postoperative 1 year (all P<0.01). However, there were no significant differences in the calcaneal pitch angle, Meary′s angle, medial cuneiform height, and calcaneus valgus angle at postoperative 3 months and 1 year (all P>0.05). AOFAS ankle-hindfoot score was increased from (66.8±8.7)points preoperatively to (81.0±5.9)points at postoperative 3 months and (88.6±3.6)points at postoperative 1 year (all P<0.01). According to AOFAS ankle-hindfoot score, the results were excellent in four patients and good in eight patients at postoperative 1 year, with the excellent and good rate of 100%. VAS was decreased from 2.5(2.0,4.0)points preoperatively to 2.0(1.3,2.8)points at postoperative 3 months and 1.0(0,2.0)points at postoperative 1 year (all P<0.01). There were significant differences in the AOFAS ankle-hindfoot score and VAS at postoperative 3 months and 1 year (all P<0.05). Wound malunion was seen in one patient, and healed with a dress changing. All patients had no complications such as vascular or nerve injury. There was no recurrence of malformation or joint instability during 1-year follow-up. Conclusion:For chronic lateral ankle instability combined with subtle cavus foot, arthroscopic modified Brostr?m procedure plus minimally invasive calcaneal osteotomy can stabilize ankle joint, correct hindfoot alignment, improve function and relieve pain.