Objective:To explore the role of tripartite motif-containing protein 21(TRIM21)in chronic apical periodontitis(CAP)and its potential mechanism.Methods:Human CAP tissue and normal periodontal tissue were collected.The expression of inflamma-tory factors(IL-1 β,IL-6,TNF-a,TGF-β1),osteoclast related genes(TRAP,RANKL,CTSK),macrophage polarization related genes(CD86,iNOS,CD206,Arg1)and TRIM21 were detected by RT-qPCR.TRIM21 protein was detected by immunohistochemical staining,and the osteoclasts was detected by tartrate resistant acid phosphatase(TRAP)staining.The inflammation cell model was es-tablished by stimulating Raw264.7 cells with lipoteichoic acid(LTA)or lipopolysaccharide(LPS),and the expression of the above factors was detected.The bone marrow-derived macrophages(BMDMs)extracted from wild-type and TRIM21-/-mice stimulated by LPS were used to verify the expression of the above factors by RT-qPCR,the osteoclasts were detected by TRAP staining,and the po-larization of macrophages was detected by immunofluorescence staining.Results:In CAP tissue the expression of inflammatory factors,osteoclast related genes,CD86,iNOS and TRIM21 increased,while CD206 and Arg1 decreased,and osteoclasts were more than that in normal tissue.The stimulation of LTA/LPS promoted the proliferation of Raw264.7 cells,and the expression of these factors in cells was consistent with that in tissues.After LPS stimulation,BMDMs of TRIM21-/-mice had lighter inflammation,lower expression of os-teoclast specific genes,fewer osteoclasts and lower M1 polarization than those of wild type mice.Conclusion:TRIM21 might promote the progress of CAP by promoting M1 polarization of macrophages.

Objective:To investigate the mechanism of immunomodulatory effects of umbilical cord mesenchymal stem cells(UC-MSCs)modified by miR-125b-5p on systemic lupus erythematosus(SLE).Methods:The expression level of miR-125b-5p was detected by real-time fluorescence quantitative PCR in UC-MSCs and peripheral blood mononuclear cells(PBMCs)from SLE patients and health checkers.Annexin V-FITC/PI apoptosis detection kit was used to detect the effect of miR-125b-5p on apoptosis of UC-MSCs.MRL/lpr mice in each group were injected with UC-MSCs via tail vein,and T-lymphocyte subsets in the spleen of the MRL/lpr mice were detected by flow cytometry after 5 weeks.The expression levels of interleukin(IL)-4 and IL-17A in serum of MRL/lpr mice were detected by ELISA.Hematoxylin-eosin staining was used to observe the pathological manifestations of the lungs and kidneys of the MRL/lpr mice.Results:miR-125b-5p was significantly down-regulated in PBMCs of SLE patients compared with healthy controls(P＜0.01).Compared with the UC-MSCs group,the expression of miR-125b-5p in UC-MSCs modified by miR-125b-5p group was increased(P＜0.01).The survival rate of UC-MSCs was significantly increased by miR-125b-5p(P＜0.01).Compared with the untreated group of MRL/lpr mice,the expression level of IL-4 in serum was increased(P＜0.05);the expression level of IL-17A was decreased(P＜0.05);the proportion of Th17 cells in the spleen of MRL/lpr mice was decreased(P＜0.05);the inflammatory cells infiltration and micro-thrombosis of lungs and kidneys of MRL/lpr mice were significantly reduced in the UC-MSCs modified by miR-125b-5p treatment group.Conclusion:UC-MSCs modified by miR-125b-5p have immunomodulatory effects on systemic lupus erythematosus.

Objective:To analyze the characteristics and possible influencing factors of cognitive impairment in patients with CSF1R related diseases (CRD), and provide a basis for the diagnosis, evaluation, treatment, and prognosis of CRD.Methods:A retrospective analysis was conducted on CRD patients diagnosed at the Shanghai Sixth People′s Hospital from April 1, 2018 to May 1, 2024. Information such as gender, age of onset, family history, Montreal Cognitive Assessment (MoCA) score, Mini Mental State Examination (MMSE) score, imaging features, and CSF1R gene mutations were collected to analyze the phenotypic characteristics of CRD patients with different cognitive levels. Multiple linear regression was used to identify factors that may be related to CRD cognitive dysfunction.Results:A total of 40 patients were collected, including 22 males and 18 females. 42.5%(17/40) of the patients had a family history, with an onset age of (39.6±7.9)years and an overall median disease duration of 1.25(1.00, 2.00)years. The MMSE score was (17.90±7.89)points and the MoCA score was (15.16±7.76)points. All patients had frontal leukoencephalopathies and no cerebellar involvement. The cognitive impairment of patients was multidimensional, mainly characterized by orientation disorders, structural barriers attention and calculation disorders, visual spatial and executive dysfunction, delayed recall disorders, and language dysfunction. Patients with onset age ≥40 years old had poorer abstract ability. In addition, patients with a positive family history had poorer immediate memory and naming abilities, while those with ventricular dilation had poorer scores in MMSE total score, MoCA total score, orientation, delayed recall ability, and naming ability.Conclusions:CRD patients generally exhibit significant impairment in multiple cognitive domains, mainly characterized by deficits in orientation, structure attention, and computational abilities. Patients with early onset, long course of illness, positive family history, and ventricular enlargement are more likely to experience partial cognitive decline.

Background: and Purpose X-linked Charcot-Marie-Tooth disease type 1 (CMTX1) is characterized by peripheral neuropathy with or without episodic neurological dysfunction. We performed clinical, neuropathological, and genetic investigations of a series of patients with mutations of the gap-junction beta-1 gene (GJB1) to extend the phenotypic and genetic description of CMTX1. Methods: Detailed clinical evaluations, sural nerve biopsy, and genetic analysis were applied to patients with CMTX1. Results: We collected 27 patients with CMTX1 with GJB1 mutations from 14 unrelated families. The age at onset (AAO) was 20.9±12.2 years (mean±standard deviation; range, 2–45 years). Walking difficulties, weakness in the legs, and pes cavus were common initial symptoms. Compared with female patients, males tended to have a younger AAO (males vs. females=15.4±9.6 vs. 32.0±8.8 years, p=0.002), a longer disease course (16.8±16.1 vs. 5.5±3.8 years, p=0.034), and more-severe electrophysiological results. Besides peripheral neuropathy, six of the patients had special episodic central nervous system (CNS) evidence from symptoms, signs, and/or reversible white-matter lesions. Neuropathology revealed the loss of large myelinated fibers, increased number of regenerated axon clusters with abnormally thin myelin sheaths, and excessively folded myelin. Genetic analysis identified 14 GJB1 variants, 6 of which were novel. Conclusions These findings expand the phenotypic and genetic spectrum of CMTX1. Although CMTX1 was found to have high phenotypic and CNS involvement variabilities, detailed neurological examinations and nerve conduction studies will provide critical clues for accurate diagnoses. Further exploration of the underlying mechanisms of connexin 32 involvement in neuropathy or CNS dysfunction is warranted to develop promising therapies.

Objective:To summarize and analyze the clinical and genetic characteristics of Chinese patients with adrenomyeloneuropathy (AMN).Methods:Clinical data were collected and analyzed retrospectively on AMN patients who were diagnosed by genetic testing in Shanghai Sixth People′s Hospital, Shanghai Jiao Tong University School of Medicine from May 2008 to August 2022. Clinical characteristics of AMN patients with different types of gene mutations were compared. Loe score was used to evaluate the severity of white matter demyelinating, and the serum levels of very long-chain fatty acids (VLCFA) in patients with or without white matter demyelinating were compared. The motor function of the AMN patients was assessed using the Expanded Disability Status Scale (EDSS), and the association between EDSS scores and the course of disease was analyzed.Results:A total of 23 male patients with onset age of (29.52±9.91) years were included in this study. The first symptom of all patients was abnormal lower extremities, of which 17 patients showed stiffness and weakness in their lower limbs (73.9%, 17/23), and 6 patients showed numbness and pain in both lower limbs (26.1%, 6/23). The occurrence of symptoms was not related to the type of gene mutation. White matter demyelination occurred in 33.3% (7/21) of patients over a disease duration of (7.67±4.46) years. There was no statistically significant difference in serum VLCFA level between the white-matter demyelination group and the non-demyelination group. The EDSS score was positively correlated with the disease duration ( r=0.57, P=0.006). Sixteen ABCD1 gene mutations were found in this study, among which c.5_19delinsTCTCCAGG (p.P2Lfs *12) was reported for the first time. Four probands belonging to different families carried the c.1415_1416del (p.Q472Rfs *83) variant. Conclusions:Lower limb movement disorders and sensory dysfunction are the prominent clinical manifestations in AMN patients, with deterioration of motor function associated with the course of disease. AMN may be converted to cerebral type and VLCFA concentration is not associated with the phenotypic changes. The c.1415_1416del (p.Q472Rfs *83) mutation is a hot spot mutation of the disease.

Parkinson's disease (PD) is one of the hotspots in the research field of neurodegenerative diseases, and its pathogenesis is still controversial. Trace metal elements play an important role in normal growth and development of the human body. Metal ions can cross the blood-brain barrier and enter the brain, leading to α-synapnuclein aggregation, mitochondrial dysfunction, and degeneration of dopaminergic neurons, and then inducing the occurrence of PD. This article mainly reviewed the potential mechanisms of metal elements in PD, discussed the role of metabolic imbalance of common trace metals (copper, iron, manganese, and zinc) in PD, and put forward new insights into the treatment of PD.

Objective:To investigate the risk factors for positive margins after endoscopic submucosal dissection (ESD) for early gastric cancer and precancerous lesions, and to follow up the recurrence.Methods:The endoscopic, clinical and pathological data of 489 patients with early gastric cancer or precancerous lesions treated by ESD in Fujian Provincial Hospital from January 2015 to December 2020 were retrospectively collected. They were categorized into a negative group (371 cases), a low-grade intraepithelial neoplasia (LGIN)-positive group (79 cases), and a high-grade intraepithelial neoplasia (HGIN) or cancer-positive group (39 cases) according to the different margins. Logistic regression was used to analyze the risk factors for positive margins, the Kaplan-Meier method and log-rank test to compare the risk of recurrence in different margin groups, and the Cox proportional risk regression model to explore the associated factors that caused recurrence in those with positive margins.Results:In the 489 patients, the positive resection margin rate was 24.1% (118/489), of which HGIN or cancer accounted for 33.1% (39/118). LGIN-positive margin was more likely to occur for lesions larger than 10 cm 2 ( OR=1.58, 95% CI: 1.13-2.08, P=0.033), in the presence of ulcers ( OR=2.92, 95% CI: 1.37-4.54, P=0.012) and for 1-2 years of ESD experience [ OR=1.69 (1-2 years VS 5-6 years), 95% CI: 1.51-1.94, P=0.026]. Those located in the upper 1/3 of the stomach [ OR=3.64 (upper 1/3 VS lower 1/3), 95% CI: 1.27-5.50 P=0.010] and submucosal infiltration (SM1 VS M1+M2: OR=2.37, 95% CI: 1.04-5.72, P=0.028; SM2 VS M1+M2: OR=6.08, 95% CI: 1.31-12.75, P=0.002) were high risk factors for HGIN/cancer-positive margin. Postoperative follow-up was completed in 337 patients, with a median follow-up time of 26.0 (22) months. The overall cumulative recurrence was 5.3% (18/337), 2.1% (5/239) in the negative margin group, 8.3% (6/72) in the LGIN-positive margin group, and 26.9% (7/26) in the HGIN/cancer-positive group, with statistically significant differences among the 3 groups ( P<0.05). Risk factors for recurrence in the positive margin group included positive basal margins ( HR=5.17, 95% CI: 1.47-14.09, P=0.011) and SM1 invasion ( HR=4.82, 95% CI: 1.38-14.77, P=0.013). Conclusion:Positive margins after ESD for early gastric cancer and precancerous lesions are related to lesion location, size, presence of ulceration, depth of infiltration, and endoscopists' experience. The overall risk of recurrence is higher in those with positive margins than in those with negative margins. Additional treatments need to be considered comprehensively for those with submucosal invasion and positive basal margins.

Objective:To investigate the clinical and genetic characteristics of patients with late-onset subtypes (adolescent or adult) of Krabbe disease.Methods:The clinical data of 7 patients with Krabbe disease admitted to Shanghai Jiao Tong University Affiliated Sixth People′s Hospital and Ruijin Hospital, Shanghai Jiao Tong University School of Medicine from September 2006 to June 2021 were analyzed and Sanger sequencing of the galactosylceramidase (GALC) gene (NM_000153) and detection of the activity of GALC were conducted. A total of 61 cases of Krabbe disease reported in domestic literature were reviewed and summarized.Results:Among the 7 patients with Krabbe disease, there were 4 males and 3 females. All of them had lower limb weakness or walking difficulty as the initial symptoms, and presented as spastic paraplegia. The symptoms were relatively mild in patients with late onset. There were 4 out of 5 patients undergoing magnetic resonance imaging examination, who showed abnormal signals: 2 had brain atrophy and the remaining 2 had white matter lesions. A total of 5 GALC gene mutations were detected by genetic analysis. Among these, c.1901T>C (p.L634S), c.908C>T(p.S303F) and c.461C>A(p.P154H) are known variants, while c.50_51insTT (p.M17Ifs) and c.1130delT(p.L337X) are novel variants reported for the first time in this paper.Conclusions:Krabbe disease is a rare neurodegenerative disease with phenotypic heterogeneity, which is inherited in an autosomal recessive mode. The severity of clinical manifestations of Krabbe disease is correlated with the age of onset.

Objective:To provide evidence for optimizing the screening strategy for gastric cancer (GC), we evaluated the risk of incident GC for individuals with different precancerous gastric lesions in a prospective cohort study.Methods:Based on the National Upper Gastrointestinal Cancer Early Detection Program launched in Linqu, Shandong, a high-risk area of gastric cancer in China, we included a total of 14 087 subjects diagnosed with different gastric lesions stages by endoscopic screening from 2012 to 2018. Study subjects were prospectively followed up until December 31, 2019. The incidence of GC during the follow-up was ascertained by repeated endoscopic examinations, cancer, death registry reports, and active follow-up of study subjects and was confirmed by reviewing medical records extracted from the hospital information management system. The Poisson regression model was applied to calculate the relative risk ( RR) and 95% CI for GC occurrence among subjects with different gastric lesions. Results:Among 14 087 subjects with different gastric lesions as determined by their first endoscopic examination in 2012-2018, 7 608 (54.00%) had a global diagnosis of superficial gastritis (SG), 2 848 (20.22%) had chronic atrophic gastritis (CAG), 3 103 (22.03%) had intestinal metaplasia (IM), and 520 (3.69%) had low-grade intestinal neoplasia (LGIN). During the follow-up, 109 subjects were diagnosed with GC, including 63 with high-grade intestinal neoplasia (HGIN) and 46 with invasive GC. Compared to subjects having normal gastric mucosa or SG, those with CAG ( RR=3.85, 95% CI: 2.04-7.28), IM ( RR=5.18, 95% CI: 2.79-9.60), and LGIN ( RR=19.08, 95% CI: 9.97-36.53) had significantly increased risk of progression to GC. Individuals with these gastric lesions had an elevated risk of developing HGIN and invasive GC. For subjects with LGIN, the RR was 22.96 (95% CI: 9.71-54.27) for developing HGIN and 14.64 (95% CI: 5.37-39.93) for developing invasive GC. Subgroup analyses found that all age group subjects with LGIN diagnosed during the initial endoscopic examination had a significantly increased risk of developing the GC. Conclusions:Our large-scale prospective study on a high-risk area of GC showed that most residents aged 40-69 years had gastric lesions of different stages. Subjects with more advanced gastric lesions had a significantly increased risk of progression to GC.

Objective:To understand the molecular epidemic characteristics and genes of human astrovirus (HAstV) in infantile diarrhea patients in Jilin province from 2017 to 2020.Methods:Fecal samples of hospitalized infants with diarrhea under 5 years of age from January 2017 to December 2020 were collected. The nucleic acids of fecal samples were amplified by reverse transcription-polymerase chain reaction (RT-PCR), the positive amplification products were sequenced, and the phylogenetic tree was constructed.Results:A total of 2 019 fecal samples were collected, of which 71 were positive for HAstV, with a positive rate of 3.5%. Among the cases with positive samples of HAstV, 42 had mixed infection with other viruses causing diarrhea, accounting for 59.2% of the total number of positive cases, half of which were mixed infection with rotavirus and HAstV. From 2017 to 2020, the positive rates of HAstV were 4.69%, 1.98%, 5.93% and 0.43% per year, respectively. There were two epidemic peaks every year and one epidemic peak year every two years. The positive rate of 36-47 months old was the highest, followed by 0-2 months old. A total of 55 sequences were obtained in this study. Phylogenetic tree analysis showed that they all belonged to classical HAstV, including 42 HAstV-1a subtypes, 8 HAstV-1b subtypes and 5 HAstV-5 subtypes.Conclusions:HAstV is one of the important pathogens of diarrhea in children under 5 years of age in Jilin province. The epidemic law has obvious seasonal and age differences. The dominant strain is HAstV-1a.