ObjectiveTo analyze the genomic characteristics of Streptococcus pyogenes (GAS) isolated from children with respiratory tract infections in a tertiary hospital in Jinshan District of Shanghai during 2013‒2024, to compare the changes in trend for genomic characteristics before and after 2000, and to provide scientific data for the prevention and control of GAS infections. MethodsGAS strains isolated from children with respiratory tract infections in this hospital were collected from 2013 to 2024. Antimicrobial susceptibility of the isolated strains to 12 antibiotics, including penicillin, cefotaxime, cefepime, linezolid, vancomycin, meropenem, chloramphenicol, ofloxacin, levofloxacin, erythromycin, clindamycin, and tetracycline, was determined using broth microdilution plate method. Besides, whole genome sequencing (WGS) was used to analyze multilocus sequence type (MLST), emm typing, carriage of superantigen genes, mobile genetic element (MGE), carriage of virulence gene, and genomic phylogenetic tree of the isolated strains. ResultsA total of 50 GAS strains were collected and identified from children with respiratory tract infections aged 4‒14 years old, and the resistance rates of those isolates to erythromycin, clindamycin, and tetracycline were 100.00%, 100.00%, and 86.00%, respectively. There were two emm types in the GAS isolates; the emm12 type accounted for 76.00% (38/50), corresponding to ST36 type, and the emm1 type accounted for 24.00% (12/50), corresponding to ST28, ST1274, and new-1 types. There was a statistically significant difference in the constitution of the MLST before and after 2020 (P=0.015). All the isolates carried the superantigen genes speC, speG, ssa, and smeZ. The predominant emm12 isolates belonged to the Clade Ⅱ, carrying the mobile elements ICE-emm12 (harboring erythromycin-resistance gene ermB and tetracycline-resistance gene tetM) and ΦHKU.vir (carrying virulence genes speC and ssa). The emm1 isolates carried the mobile elements ICE-HKU488 (harboring erythromycin-resistance gene ermB and tetracycline-resistance gene tetM) and ΦHKU488.vir (carrying virulence genes speC and ssa), and had close phylogenetical relationships with isolates from Hong Kong, China. No M1_UK new clone strains were found. The ST1274 isolates of emm1 were newly discovered in 2020‒2024, and belonged to a separate phylogenetic clade. ConclusionGAS strains isolated from children with respiratory tract infections in a tertiary hospital in Jinshan District of Shanghai exhibit a high resistance to erythromycin, clindamycin, and tetracycline. It is recommended that the clinical treatments change to use other antimicrobial drugs, such as penicillin, third-generation cephalosporins, and fluoroquinolones. During 2020‒2024, a new ST1274 clone strain is discovered in emm1 GAS isolates, without M1_UK new clone strains being found. It is essential to continuously concern locally prevalent GAS strains and perform early identification of MLST types to promptly monitor the internal changes of the bacterial population and potential prevalence of new clones.

Although cisplatin is a widely used chemotherapeutic agent, it is severely toxic and causes irreversible hearing loss, restricting its application in clinical settings. This study aimed to determine the molecular mechanism underlying cisplatin-induced ototoxicity. Here, we established in vitro and in vivo ototoxicity models of cisplatin-induced hair cell loss, and our results showed that reducing STING levels decreased inflammatory factor expression and hair cell death. In addition, we found that cisplatin-induced mitochondrial dysfunction was accompanied by cytosolic DNA, which may act as a critical linker between the cyclic GMP-AMP synthesis-stimulator of interferon genes (cGAS-STING) pathway and the pathogenesis of cisplatin-induced hearing loss. H-151, a specific inhibitor of STING, reduced hair cell damage and ameliorated the hearing loss caused by cisplatin in vivo. This study underscores the role of cGAS-STING in cisplatin ototoxicity and presents H-151 as a promising therapeutic for hearing loss.
Cisplatin/toxicity* ; Animals ; Nucleotidyltransferases/antagonists & inhibitors* ; Membrane Proteins/antagonists & inhibitors* ; Signal Transduction/drug effects* ; Mice ; Hair Cells, Auditory, Inner/pathology* ; Antineoplastic Agents/toxicity* ; Mice, Inbred C57BL ; Hearing Loss/metabolism* ; Male ; Ototoxicity/metabolism*

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder worldwide, causing dementia and affecting millions of individuals. One prominent characteristic in the brains of AD patients is glucose hypometabolism. In the context of galactose metabolism, intracellular glucose levels are heightened. Galactose mutarotase (GALM) plays a crucial role in maintaining normal galactose metabolism by catalyzing the conversion of β-D-galactose into α-D-galactose (α-D-G). The latter is then converted into glucose-6-phosphate, improving glucose metabolism levels. However, the involvement of GALM in AD progression is still unclear. In the present study, we found that the expression of GALM was significantly increased in AD patients and model mice. Genetic knockdown of GALM using adeno-associated virus did not change the expression of amyloid precursor protein (APP) and APP-cleaving enzymes including a disintegrin and metalloprotease 10 (ADAM10), β-site APP-cleaving enzyme 1 (BACE1), and presenilin-1 (PS1). Interestingly, genetic overexpression of GALM reduced APP and Aβ deposition by increasing the maturation of ADAM10, although it did not alter the expression of BACE1 and PS1. Further electrophysiological and behavioral experiments showed that GALM overexpression significantly ameliorated the deficits in hippocampal CA1 long-term potentiation (LTP) and spatial learning and memory in AD model mice. Importantly, direct α-D-G (20 mg/kg, i.p.) also inhibited Aβ deposition by increasing the maturation of ADAM10, thereby improving hippocampal CA1 LTP and spatial learning and memory in AD model mice. Taken together, our results indicate that GALM shifts APP processing towards α-cleavage, preventing Aβ generation by increasing the level of mature ADAM10. These findings indicate that GALM may be a potential therapeutic target for AD, and α-D-G has the potential to be used as a dietary supplement for the prevention and treatment of AD.
Animals ; ADAM10 Protein/metabolism* ; Alzheimer Disease/pathology* ; Amyloid Precursor Protein Secretases/metabolism* ; Disease Models, Animal ; Humans ; Mice ; Amyloid beta-Peptides/metabolism* ; Male ; Mice, Transgenic ; Membrane Proteins/metabolism* ; Cognitive Dysfunction/pathology* ; Mice, Inbred C57BL ; Amyloid beta-Protein Precursor/metabolism* ; Female ; Hippocampus/metabolism* ; Long-Term Potentiation/physiology*

Objective To investigate the causal relationship between gut microbiota and diffuse large B-cell lymphoma(DLBCL).Methods Employed a two-sample bidirectional Mendelian randomization approach,using summary statistics from genome-wide association studies(GWAS)to extract single nucleotide polymor-phisms(SNPs)associated with exposure and outcome as instrumental variables.Exposure instrumental varia-bles(P＜1×10-5)and outcome instrumental variables(P＜5×10-8)were selected based on the P-values of SNPs.Three different Mendelian randomization methods were used to analyze the relationship between gut microbiota and DLBCL,with sensitivity analyses including heterogeneity,pleiotropy,and leave-one-out tests.Results Bilophila(OR=2.043,95%CI:1.279-3.264),Coprobacter(OR=1.371,95%CI:1.035-1.816),Eubacterium eligens group(OR=1.996,95%CI:1.291-3.087)increased the risk of DLBCL.Alistipes(OR=0.588,95%CI:0.359-0.963),Eubacterium eligens group(OR=1.996,95%CI:1.291-3.087),Slackia(OR=0.688,95%CI:0.479-0.988)reduced the risk of DLBCL.Reverse Mendelian randomization a-nalysis failed to reveal any evidence of a causal relationship between DLBCL and the six gut microbiota.Con-clusion There is a causal association between gut microbiota and DLBCL.

Objective To explore the role and mechanism of ferroptosis in vitamin D3(VD3)improving the cytotoxicity of keratinocytes(HaCaT cells)induced by nitrogen mustard(NM).Methods HaCaT cells were treated with gradient concentrations of NM(5,10,20,and 50 μmol/L)alone or in combination with ferroptosis inhibitor ferrostatin-1 or liproxstatin-1(10 μmol/L),Nrf2-specific agonist tBHQ(10 μmol/L),and VD3(10 nmol/L),respectively.After co-culture for 24 h,cell viability was assessed,and the intracellular contents of glutathione(GSH)and malondialdehyde(MDA)were measured.Additionally,the expression levels of Nrf2,xCT,and GPX4 were detected.Results NM exerted inhibitory effect on the proliferation of HaCaT cells in a dose-dependent manner,and the cell viability was reduced to approximately 55%at an NM concentration of 20 μmol/L(P<0.05).Ferroptosis inhibitors significantly mitigated the cytotoxic damage induced by NM in HaCaT cells(P<0.05),but activation of nuclear factor E2 related factor 2(Nrf2)markedly attenuated NM-induced ferroptosis,as indicated by the restoration of intracellular GSH level and the decrease in MDA content(P<0.05).VD3 specifically targeted the Nrf2 signaling pathway,upregulated the expression of xCT and GPX4 protein,thereby inhibiting ferroptosis and reducing NM-induced cytotoxicity in HaCaT cells.Conclusion VD3 mitigates NM-induced cytotoxicity in HaCaT cells by inhibiting ferroptosis via Nrf2 activation.

Clinically,the surgical treatment of varicose veins of the lower extremities(VVLE)is now developing towards the direction of precision,minimally-invasive and individuation.Thus,comprehensive preoperative examination and evaluation of the venous system,and scientific marking of the target veins are prerequisite for achieving these goals.This paper describes the latest research progress in VVLE,focusing on the pathophysiology,risk factors,etiology,evaluation method of venous system,preoperative evaluation of commonly-seen secondary etiology,selection of surgical method,and marking technique of targeted veins,etc.So as to promote the development of surgical treatment for VVLE in clinical practice.

Objective:To explore the magnetic resonance imaging (MRI) features and classification of intraductal papillary neoplasm of the bile duct (IPNB).Methods:Data from 90 patients with intraductal papillary neoplasm of the bile duct confirmed pathologically between June 2010 and January 2023 were retrospectively analyzed. The image analysis included the shape and location of the tumor, whether bile ducts had dilatation and the degree of dilation, whether there was a history of liver disease, whether there was a history of schistosomiasis, whether there was cancerous transformation, whether there were concurrent bile duct stones, whether there was hepatic lobe atrophy, whether there was hilar or abdominal lymph node enlargement, whether there was invasion of the bile duct wall, whether there was invasion of surrounding blood vessels, whether the tumor appears on T1-and T2 weighted imaging (T 1WI and T 2WI), whether the diffusion was limited, whether there was concurrent bleeding, enhancement rate, and whether there was abdominal fluid accumulation. Intraductal papillary neoplasms of the bile duct were divided into four types according to the morphological classification standards: type I (local bile duct dilation), type II (cystic), type III (free tumor), and type IV (dilated bile duct). The differences in the clinical and MRI features of the four groups of lesions were analyzed. Statistical analysis was performed with a t-test, an analysis of variance, and an χ2-test according to the different data. Results:Among the 90 cases with hepatic IPNB, there were 31 cases of type I, 15 cases of type II, 16 cases of type III, and 28 cases of type IV, 41 cases of liver left lobe, 11 cases of right and left lobe liver span, 7 cases of liver right lobes, 2 cases of liver caudate lobe, and 13 cases of hepatic hilar. There were statistically significant differences between the four groups ( P ??0.05). Conclusion:MRI manifestations have certain features for different types of intraductal papillary neoplasm of the bile duct tumors; hence, MRI aids in the diagnosis and differential diagnosis of this disease.

Objective:To explore the MRI characteristics of the hepatic epithelioid hemangioendothelioma (HEHE) classification according to morphology and size.Methods:The clinical, pathological, and MRI imaging data of 40 cases with HEHE confirmed pathologically from December 2009 to September 2021 were retrospectively analyzed. A paired sample t-test was used for comparison between the two groups. Results:There were 40 cases (5 solitary, 24 multifocal, 9 local fusion, and 2 diffuse fusion) and 214 lesions (163 nodules, 31 masses, and 20 fusion foci). The most common features of lesions were subcapsular growth and capsular depression. The signal intensity of lesions ≤1cm was usually uniform with whole or ring enhancement. Nodules and mass-like lesions ≥1cm on a T1-weighted image had slightly reduced signal intensity or manifested as a halo sign. Target signs on a T2-weighted image were characterized by: target or centripetal enhancement; fusion-type lesions; irregular growth and hepatic capsular retraction, with ring or target-like enhancement in the early stage of fusion and patchy irregular enhancement in the late stage; blood vessels traversing or accompanied by malformed blood vessels; focal bleeding; an increasing proportion of extrahepatic metastases and abnormal liver function with the type of classified manifestation; primarily portal vein branches traversing; and reduced overall intralesional bleeding rate (17%). Lollipop signs were presented in 19 cases, with a high expression rate in mass-type lesions (42%). The fusion lesions were expressed, but the morphological manifestation was atypical. The diffusion-weighted imaging mostly showed high signal or target-like high signal. An average apparent diffusion coefficient of lesions was (1.56±0.36) ×10 -3mm 2/s, which was statistically significantly different compared with that of adjacent normal liver parenchyma ( t=8.28, P<0.001). Conclusion:The MRI manifestations for the HEHE classification are closely related to the morphology and size of the lesions and have certain differences and characteristics that are helpful for the diagnosis of the disease when combined with clinical and laboratory examinations.

Tuberous sclerosis complex(TSC)is a rare genetic disease that can lead to benign dysplasia in multiple organs such as the skin, brain, eyes, oral cavity, heart, lungs, kidneys, liver, and bones. Its main symptoms include epilepsy, intellectual disabilities, skin depigmentation, and facial angiofibromas, whilst incidence is approximately 1 in 10 000 to 1 in 6000 newborns. This case presents a middle-aged woman who initially manifested with epilepsy and nodular depigmentation. Later, she developed a lower abdominal mass, elevated creatinine, and severe anemia. Based on clinical features and whole exome sequencing, the primary diagnosis was confirmed as TSC. Laboratory and imaging examinations revealed that the lower abdominal mass originated from the uterus. CT-guided biopsy pathology and surgical pathology suggested a combination of leiomyoma and abscess. With the involvement of multiple organs and various complications beyond the main diagnosis, the diagnostic and therapeutic process for this patient highlights the importance of rigorous clinical thinking and multidisciplinary collaboration in the diagnosis and treatment of rare and challenging diseases.