BACKGROUND: Increasing evidence indicates that oxidative stress and interferon γ (IFNγ)-driven cellular immune responses are responsible for the pathogenesis of vitiligo. However, the connection between oxidative stress and the local production of IFNγ in early vitiligo remains unexplored. The aim of this study was to identify the mechanism underlying the production of IFNγ by mast cells and its impact on vitiligo pathogenesis. METHODS: Skin specimens from the central, marginal, and perilesional skin areas of active vitiligo lesions were collected to characterize changes of mast cells, CD8 + T cells, and IFNγ-producing cells. Cell supernatants from hydrogen peroxide (H 2 O 2 )-treated keratinocytes (KCs) were harvested to measure levels of soluble stem cell factor (sSCF) and matrix metalloproteinase (MMP)-9. A murine vitiligo model was established using Mas-related G protein-coupled receptor-B2 (MrgB2, mouse ortholog of human MrgX2) conditional knockout (MrgB2 -/- ) mice to investigate IFNγ production and inflammatory cell infiltrations in tail skin following the challenge with tyrosinase-related protein (Tyrp)-2 180 peptide. Potential interactions between the Tyrp-2 180 peptide and MrgX2 were predicted using molecular docking. The siRNAs targeting MrgX2 and the calcineurin inhibitor FK506 were also used to examine the signaling pathways involved in mast cell activation. RESULTS: IFNγ-producing mast cells were closely aligned with the recruitment of CD8 + T cells in the early phase of vitiligo skin. sSCF released by KCs through stress-enhanced MMP9-dependent proteolytic cleavage recruited mast cells into sites of inflamed skin (Perilesion vs . lesion, 13.00 ± 4.00/high-power fields [HPF] vs . 26.60 ± 5.72/HPF, P <0.05). Moreover, IFNγ-producing mast cells were also observed in mouse tail skin following challenge with Tyrp-2 180 (0 h vs . 48 h post-recall, 0/HPF vs . 3.80 ± 1.92/HPF, P <0.05). The IFNγ + mast cell and CD8 + T cell counts were lower in the skin of MrgB2 -/- mice than in those of wild-type mice (WT vs . KO 48 h post-recall, 4.20 ± 0.84/HPF vs . 0.80 ± 0.84/HPF, P <0.05). CONCLUSION Mast cells activated by MrgX2 serve as a local IFNγ producer that bridges between innate and adaptive immune responses against MCs in early vitiligo. Targeting MrgX2-mediated mast cell activation may represent a new strategy for treating vitiligo.
Vitiligo/metabolism* ; Mast Cells/immunology* ; Animals ; Interferon-gamma/metabolism* ; Mice ; Humans ; Melanocytes/metabolism* ; Receptors, G-Protein-Coupled/genetics* ; Mice, Knockout ; Mice, Inbred C57BL ; Male ; Female ; Matrix Metalloproteinase 9/metabolism* ; Stem Cell Factor/metabolism*

OBJECTIVE: To investigate the impact of bone mass and volume of low-density zones beneath the tibial plateau on the maximum von Mises stresses experienced by the cartilage and meniscus in the knee joint. METHODS: The study included one healthy adult volunteer, from whom CT scans were obtained, and one patient diagnosed with knee osteoarthrisis (KOA), for whom X-ray films were acquired. A static model of the knee joint featuring a low-density zone was established based on a normal knee model. In the finite element analysis, axial loads of 1 000 N and 1 800 N were applied to the weight-bearing region of the upper surface of the femoral head for model validation and subsequent finite element studies, respectively. The maximum von Mises stresses in the femoral cartilage, as well as the medial and lateral tibial cartilage and menisci, were observed, and the stress percentage of the medial and lateral components were concurrently analyzed. Additionally, HE staining, as well as alkaline magenta staining, were performed on the pathological specimens of patients with KOA in various low-density regions. RESULTS: The results of model validation indicated that the model was consistent with normal anatomical structures and correlated with previous calculations documented in the literature. Static analysis revealed that the maximum von Mises stress in the medial component of the normal knee was the lowest and increased with the advancement of the hypointensity zone. In contrast, the lateral component exhibited an opposing trend, with the maximum von Mises stress in the lateral component being the highest and decreasing as the hypointensity zone progressed. Additionally, the medial component experienced an increasing proportion of stress within the overall knee joint. HE staining demonstrated that the chondrocyte layer progressively deteriorated and may even disappear as the hypointensity zone expanded. Furthermore, alkaline magenta staining indicated that the severity of microfractures in the trabecular bone increased concurrently with the expansion of the hypointensity zone. CONCLUSION The presence of subtalar plateau low-density zone may aggravate joint degeneration. In clinical practice, it is necessary to pay attention to the changes in the subtalar plateau low-density zone and actively take effective measures to strengthen the bone status of the subtalar plateau low-density zone and restore the complete biomechanical function of the knee joint, in order to slow down or reverse the progression of osteoarthritis.
Humans ; Finite Element Analysis ; Knee Joint/physiology* ; Tibia/anatomy & histology* ; Cartilage, Articular/physiology* ; Menisci, Tibial/physiopathology* ; Tomography, X-Ray Computed ; Osteoarthritis, Knee/diagnostic imaging* ; Weight-Bearing ; Bone Density ; Adult ; Stress, Mechanical ; Male ; Middle Aged ; Biomechanical Phenomena ; Female

As an emerging drug delivery technology,microneedles can puncture the skin's stratum corneum to create micron-sized conduits,painlessly,minimally invasive,and efficiently deliver drugs into viable epidermis or dermis for local or systemic therapeutic effects.This paper reviews the current clinical trials of microneedles used in the treatment of various diseases,elaborates on the characteristics of various types of microneedles,and summarizes the latest research progress of microneedles used to treat skin tumors,including chemotherapy,photothermal and photodynamic therapy,immunotherapy,gene therapy,and combination therapy.This review provides ideas and directions for further research on microneedles in treating skin tumors.

Objective:The present study was designed to strengthen the education of research integrity, and to improve the awareness of academic misconduct and academic literacy of medical post-graduate students.Methods:A questionnaire survey was conducted with master post-graduate students of a university affiliated hospital, and statistical analysis on the education of research integrity and the perception of academic misconduct among the survey respondents was performed.Results:Academic master post-graduate students′ cognitions of the misconduct in scientific research process and overall academic misconduct were better than that of professional master post-graduate students, and there were significant differences ( P<0.05). The more times of participation in research integrity training, the better cognition of misconduct of scientific research process, research results publication process, and overall academic misconduct, with significant differences ( P<0.05). Conclusions:The education on scientific research integrity of medical post-graduates should be carried out systematically, while the content should be improved and the form should be enriched for scientific research integrity education, so that the medical post-graduates can have a deeper understanding of the code of academic practices, and an education model of scientific research integrity for medical post-graduate which is suitable for China′s national conditions can be gradually developed.

Despite being a common therapy for hepatocellular carcinoma (HCC), insufficient thermal ablation can leave behind tumor residues that can cause recurrence. This is believed to augment M2 inflammatory macrophages that usually play a pro-tumorigenic role. To address this problem, we designed d-mannose-chelated iron oxide nanoparticles (man-IONPs) to polarize M2-like macrophages into the antitumor M1 phenotype. In vitro and in vivo experiments demonstrated that man-IONPs specifically targeted M2-like macrophages and accumulated in peri-ablation zones after macrophage infiltration was augmented under insufficient microwave ablation (MWA). The nanoparticles simultaneously induced polarization of pro-tumorigenic M2 macrophages into antitumor M1 phenotypes, enabling the transformation of the immunosuppressive microenvironment into an immunoactivating one. Post-MWA macrophage polarization exerted robust inhibitory effects on HCC progression in a well-established orthotopic liver cancer mouse model. Thus, combining thermal ablation with man-IONPs can salvage residual tumors after insufficient MWA. These results have strong potential for clinical translation.

Objective:To explore the value of multi-parametric MRI for thyroid gland in differentiating benign and malignant thyroid nodules.Methods:From December 2018 to May 2020, 78 patients with 91 post-surgically pathologically confirmed thyroid nodules were enrolled in Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College. For each patient, the following MRI findings were obtained including the nodules′ location, size, shape, margin, signal intensity, cystic change, degree and pattern of contrast enhancement, involvement of surrounding structure, and ADC values. The time-intensity curve (TIC) were plotted and subtyped based on dynamic contrast enhancement MRI. The MRI findings between the benign and malignant thyroid nodules were compared using Mann-Whitney U test, χ 2 test or Fisher exact test. Multiple logistic regression analysis was used to select independent predictive variables and build a combined model, and the ROC curve was used to evaluate the diagnostic performance of each MRI finding and the combined model. Results:Between the benign and malignant thyroid nodules, the significant differences were found in size, shape, margin, presence of cystic changes, T 1WI signal intensity, ADC value, enhancement homogeneity, TIC subtypes and presence of thyroid capsule involvement ( P<0.05). Multivariate logistic analysis showed that ill-defined margin (OR=77.61), no presence of cystic changes (OR=36.11) and difference between TIC subtypes (OR=83.41) were independent predictive variables, and the area under the ROC curve (AUC) was 0.879, 0.788, and 0.751, respectively. The AUC, sensitivity and specificity of the combined model were 0.977, 0.986, and 0.904, respectively. Conclusions:Thyroid multi-parametric MRI derived findings can be used for the differential diagnosis of benign and malignant nodules. Combined with the independent risk factors with ill-defined margin, no presence of cystic changes, TIC of type plateau or washout, the diagnostic model has a higher diagnostic efficiency.

Objective:To investigate the expression and distribution of human dermal papillary fibroblasts (Fp) , reticular fibroblasts (Fr) , and myofibroblasts (MFB) in keloid tissues.Methods:Keloid tissues were collected from 15 outpatients (including 8 males and 7 females) aged 20-50 years, who were diagnosed in the Department of Dermatology, Renmin Hospital of Wuhan University from May to December 2019. Normal skin tissues were taken from 15 age-matched women who underwent mammoplasty, and served as controls. The distribution of fibroblast activation protein (FAP) , CD90 and alpha-smooth muscle actin (α-SMA) was observed in the keloid tissues and normal skin tissues by dual immunofluorescence staining. Furthermore, fibroblasts were isolated from 3 normal skin and 3 keloid tissue samples, and subjected to primary culture. Subsequently, the fibroblasts were treated with 10 ng/ml transforming growth factor-β1 (TGF-β1) for 48 hours in vitro, during which, changes in fibroblast phenotypes were observed in the 2 groups. Fluorescence-based quantitative RT-PCR and Western blot analysis were performed to determine the mRNA and protein expression of FAP, CD90 and α-SMA. Measurement data were compared between 2 groups by using t test. Results:Immunofluorescence staining of the normal skin tissues revealed that FAP +/CD90 - fibroblasts were predominantly distributed in the superficial dermis, FAP -/CD90 + fibroblasts in the deep dermis, and CD90 + cells hardly expressed α-SMA; however, a large number of FAP + fibroblasts and CD90 + fibroblasts were observed in the deep keloid tissues, and many CD90 + fibroblasts also expressed α-SMA. Dual immunofluorescence staining showed that normal tissue-derived fibroblasts hardly expressed α-SMA, and keloid-derived fibroblasts expressed α-SMA. The fluorescence intensity of α-SMA + cells significantly increased in the normal tissue-and keloid-derived fibroblasts after 24-hour treatment with TGF-β1 (21.058 ± 0.709, 27.112 ± 0.097, respectively) compared with that in the corresponding untreated fibroblasts (11.312 ± 0.636, 21.306 ± 0.464, t=22.430, 13.370, respectively, both P < 0.05) . RT-PCR and Western blot analysis showed that the mRNA and protein expression of FAP, CD90 and α-SMA significantly increased in the keloid-derived fibroblasts after 48-hour treatment with TGF-β1 (mRNA: 92.610 ± 3.667, 1.366 ± 0.105, 3.240 ± 0.141; protein: 0.652 ± 0.073, 1.046 ± 0.119, 0.946 ± 0.117, respectively) compared with the untreated keloid-derived fibroblasts (all P < 0.05) . Conclusion:CD90 + Fr aberrantly proliferated in the deep dermis of keloid tissues, suggesting that directional intervention in aberrantly proliferating FAP -/CD90 + Fr in the deep dermis may promote the efficacy for keloids.

Objective: To evaluate the pathogenicity of Acinetobacter venetum（Av），which is expected to be used as an environmental remediation agent，using Caenorhabditis elegans（C.elegans）. Methods: The C.elegans were cultured on the media loaded with E.coli OP50 and Av，respectively. The pathogenicity of Av was evaluated by observing the effects of Av on the growth，movement，digestive function，lifespan and reproduction of C.elegans，compared with that of another evaluation system according to NY 1109-2017 General Biosafety Standard for Microbial Fertilizers. Results: By C. elegans system，it was found that the body length，width，head thrash frequency，body bending frequency and average lifespan [（13.5±0.4）d vs.（13.7±0.4）d] of adult nematodes in the Av group were not significantly different from those in the OP50 group（all P>0.05）；while the average time of defecation cycle in the Av group shortened，the total number of progenies in the Av group increased by 18.7%（all P<0.05）. According to NY1109-2017 General Biosafety Standard for Microbial Fertilizers，it was found that the oral LD50 values for both male and female mice were more than 10 g/kgbw，which was practically non-toxic；the pathogenicity test of acute intraperitoneal injection showed that the animals did not have signs of poisoning，deaths or any abnormalities in gross anatomy；Av had no irritation to damaged skin and eyes of rabbits；the hemolysis test was negative；Av was sensitive to seven antibiotics and was medium to one antibiotic. Conclusion Av is not pathogenic. C. elegans can be used in early screening for the pathogenicity of environmental remediation agents.

Objective To investigate the therapeutic effect of damage control neurosurgery (DCNS) on patients with bilateral frontal contusion.Methods Thirty-three patients with bilateral frontal contusion,admitted to and accepted DCNS in our hospital from September 2017 to January 2019,were chosen in our study.According to DCNS rules,the disease condition changes of these patients were monitored,the internal environment disorders after trauma were adjusted,plasma osmotic pressure was increased,and blood oxygen saturation was maintained;once the patients grew worse,craniotomy and decompression should be undertaken immediately;the patients were followed up for 6 months after the injury and Glasgow outcome scale (GOS) was used to determine the prognoses of these patients.Results Among the 33 patients,25 (76％) received conservative treatment successfully,8 (24％) were converted to surgery during conservative treatment.Among the 8 patients,5 received unilateral craniotomy and three received bilateral craniotomy.The lower the Glasgow coma scale scores,the lower the proportion of conservative patients.GOS 6 months after injury showed good recovery in 11 patients,mild disability in 16 patients,severe disability in 4 patients,and plant survival in two patients;22 patients from the conservative treatment group and 5 from the surgery group had good recovery or mild disability.Conclusion DCNS can reduce the operation rate and its complications so as to make the patients recover earlier and better in the treatment of bilateral frontal contusion.

Objective To explore the effect and mechanism of preventing ankle instability through exer-cise, so as to provide evidence-based references for practice. Methods The randomized and controlled trials ( RCT) on preventing ankle instability through exercise published before December 2014 were searched for in the NCBI, CNKI, VIP and Wanfang databases by computer, supplemented by manual searching. Each study′s quality was evaluated according to the standards of the Cochrane handbook by 3 researchers. The outcome indexes were ex-tracted and analyzed using RevMan 5.2 software. Results After the initial selection, 665 papers (357 in English and 308 in Chinese) were retained. From these 92 were chosen after reading the titles and abstracts. Ultimately, 14 RCT studies ( 12 in English and 2 in Chinese) met the inclusion criteria. They showed that exercise improved ankle function and symptoms of ankle instability significantly [SMD=0.98, 95%CI (0.65,1.31), P≤0.01], improved muscle strength [SMD=1.50, 95%CI (0.99,2.01), P≤0.01], improved balance and postural stability [SMD=-0.54, 95%CI (-0.84,-0.25) ,P≤0.01] , but did not improve proprioception or neuromuscular functioning sig-nificantly. Conclusions Exercise can effectively improve muscle strength, balance and postural stability, but not proprioception or neuromuscular functioning. The details of these findings may be related to the exercise intervention chosen.