A 19-year-old male patient with a history of congenital left oval window defect has had recurrent admissions to a children’s hospital for bacterial meningitis since the age of 7. Investigations revealed a left-sided type 1 incomplete partition deformity of the left ear with a congenital oval window defect, leading to communication between the cranium and the middle ear. The patient underwent a left canal wall down mastoidectomy and oval window defect repair, remaining well for 3 years. He experienced two more episodes of bacterial meningitis as he got older, prompting repeated exploratory tympanotomy and repair of the cerebrospinal fluid (CSF) leak after each episode. Recently, he was referred again for recurrent meningitis. Investigations showed a recurrent oval window defect. After undergoing left external ear canal transection, mastoid and middle ear obliteration, and left Eustachian tube obliteration, he remained well without further leaks or meningitis. Congenital oval window defect is rare and may present with recurrent bacterial meningitis secondary to spontaneous CSF leak via the oval window. Radiology plays a crucial role in identifying the source of the CSF leak, facilitating more precise preoperative counseling and surgical intervention.

A 19-year-old male patient with a history of congenital left oval window defect has had recurrent admissions to a children’s hospital for bacterial meningitis since the age of 7. Investigations revealed a left-sided type 1 incomplete partition deformity of the left ear with a congenital oval window defect, leading to communication between the cranium and the middle ear. The patient underwent a left canal wall down mastoidectomy and oval window defect repair, remaining well for 3 years. He experienced two more episodes of bacterial meningitis as he got older, prompting repeated exploratory tympanotomy and repair of the cerebrospinal fluid (CSF) leak after each episode. Recently, he was referred again for recurrent meningitis. Investigations showed a recurrent oval window defect. After undergoing left external ear canal transection, mastoid and middle ear obliteration, and left Eustachian tube obliteration, he remained well without further leaks or meningitis. Congenital oval window defect is rare and may present with recurrent bacterial meningitis secondary to spontaneous CSF leak via the oval window. Radiology plays a crucial role in identifying the source of the CSF leak, facilitating more precise preoperative counseling and surgical intervention.

A 19-year-old male patient with a history of congenital left oval window defect has had recurrent admissions to a children’s hospital for bacterial meningitis since the age of 7. Investigations revealed a left-sided type 1 incomplete partition deformity of the left ear with a congenital oval window defect, leading to communication between the cranium and the middle ear. The patient underwent a left canal wall down mastoidectomy and oval window defect repair, remaining well for 3 years. He experienced two more episodes of bacterial meningitis as he got older, prompting repeated exploratory tympanotomy and repair of the cerebrospinal fluid (CSF) leak after each episode. Recently, he was referred again for recurrent meningitis. Investigations showed a recurrent oval window defect. After undergoing left external ear canal transection, mastoid and middle ear obliteration, and left Eustachian tube obliteration, he remained well without further leaks or meningitis. Congenital oval window defect is rare and may present with recurrent bacterial meningitis secondary to spontaneous CSF leak via the oval window. Radiology plays a crucial role in identifying the source of the CSF leak, facilitating more precise preoperative counseling and surgical intervention.

OBJECTIVE: To investigate the effects of removing microglia from spinal cord on nerve repair and functional recovery after spinal cord injury (SCI) in mice. METHODS: Thirty-nine 6-week-old female C57BL/6 mice were randomly divided into control group ( n=12), SCI group ( n=12), and PLX3397+SCI group ( n=15). The PLX3397+SCI group received continuous feeding of PLX3397, a colony-stimulating factor 1 receptor inhibitor, while the other two groups were fed a standard diet. After 14 days, both the SCI group and the PLX3397+SCI group were tested for ionized calcium binding adapter molecule 1 (Iba1) to confirm that the PLX3397+SCI group had completely depleted the spinal cord microglia. The SCI model was then prepared by clamping the spinal cord in both the SCI group and the PLX3397+SCI group, while the control group underwent laminectomy. Preoperatively and at 1, 3, 7, 14, 21, and 28 days postoperatively, the Basso Mouse Scale (BMS) was used to assess the hind limb function of mice in each group. At 28 days, a footprint test was conducted to observe the gait of the mice. After SCI, spinal cord tissue from the injury site was taken, and Iba1 immunofluorescence staining was performed at 7 days to observe the aggregation and proliferation of microglia in the spinal cord. HE staining was used to observe the formation of glial scars at the injury site at 28 days; glial fibrillary acidic protein (GFAP) immunofluorescence staining was applied to astrocytes to assess the extent of the injured area; neuronal nuclei antigen (NeuN) immunofluorescence staining was used to evaluate neuronal survival. And 5-hydroxytryptamine (5-HT) immunofluorescence staining was performed to assess axonal survival at 60 days. RESULTS: All mice survived until the end of the experiment. Immunofluorescence staining revealed that the microglia in the spinal cord of the PLX3397+SCI group decreased by more than 95% compared to the control group after 14 days of continuous feeding with PLX3397 ( P<0.05). Compared to the control group, the BMS scores in the PLX3397+SCI group and the SCI group significantly decreased at different time points after SCI ( P<0.05). Moreover, the PLX3397+SCI group showed a further decrease in BMS scores compared to the SCI group, and exhibited a dragging gait. The differences between the two groups were significant at 14, 21, and 28 days ( P<0.05). HE staining at 28 days revealed that the SCI group had formed a well-defined and dense gliotic scar, while the PLX3397+SCI group also developed a gliotic scar, but with a more blurred and loose boundary. Immunofluorescence staining revealed that the number of microglia near the injury center at 7 days increased in the SCI group than in the control group, but the difference between groups was not significant ( P>0.05). In contrast, the PLX3397+SCI group showed a significant reduction in microglia compared to both the control and SCI groups ( P<0.05). At 28 days after SCI, the area of spinal cord injury in the PLX3397+SCI group was significantly larger than that in SCI group ( P<0.05); the surviving neurons significantly reduced compared with the control group and SCI group ( P<0.05). The axonal necrosis and retraction at 60 days after SCI were more obvious. CONCLUSION The removal of microglia in the spinal cord aggravate the tissue damage after SCI and affecte the recovery of motor function in mice, suggesting that microglia played a neuroprotective role in SCI.
Animals ; Spinal Cord Injuries/surgery* ; Microglia/pathology* ; Female ; Mice ; Mice, Inbred C57BL ; Nerve Regeneration/drug effects* ; Spinal Cord/pathology* ; Pyrroles/administration & dosage* ; Aminopyridines/administration & dosage* ; Recovery of Function ; Disease Models, Animal ; Calcium-Binding Proteins/metabolism* ; Receptors, Granulocyte-Macrophage Colony-Stimulating Factor/antagonists & inhibitors* ; Microfilament Proteins/metabolism* ; Glial Fibrillary Acidic Protein/metabolism*

High mobility group box 1 (HMGB1), when released extracellularly, plays a pivotal role in the development of spinal cord synapses and exacerbates autoimmune diseases within the central nervous system. In experimental autoimmune encephalomyelitis (EAE), a condition that models multiple sclerosis, the levels of extracellular HMGB1 and interleukin-33 (IL-33) have been found to be inversely correlated. However, the mechanism by which IL-33 deficiency enhances HMGB1 release during EAE remains elusive. Our study elucidates a potential signaling pathway whereby the absence of IL-33 leads to increased binding of P300/CBP-associated factor with HMGB1 in the nuclei of astrocytes, upregulating HMGB1 acetylation and promoting its release from astrocyte nuclei in the spinal cord of EAE mice. Conversely, the addition of IL-33 counteracts the TNF-α-induced increase in HMGB1 and acetylated HMGB1 levels in primary astrocytes. These findings underscore the potential of IL-33-associated signaling pathways as a therapeutic target for EAE treatment.
Animals ; Encephalomyelitis, Autoimmune, Experimental/metabolism* ; Astrocytes/metabolism* ; Interleukin-33/metabolism* ; HMGB1 Protein/metabolism* ; Acetylation ; Mice, Knockout ; Mice, Inbred C57BL ; p300-CBP Transcription Factors/metabolism* ; Mice ; Spinal Cord/metabolism* ; Cells, Cultured ; Female ; Signal Transduction

In this study, araucarene diterpenes, characterized by a pimarene skeleton with a variably oxidized side chain at C-13, were investigated. A total of 16 araucarene diterpenoids and their derivatives were isolated from the woods of Agathis dammara, including 11 previously unreported compounds: dammaradione (1), dammarones D-G (2, 5, 14, 15), dammaric acids B-F (8-12), and dammarol (16). The structures of these new compounds were elucidated using high-resolution electrospray ionization mass spectroscopy (HR-ESI-MS) and one-dimensional/two-dimensional (1D/2D) nuclear magnetic resonance (NMR), while their absolute configurations were determined through the electronic circular dichroism (ECD) exciton chirality method and Snatzke's method. The hypoglycemic activity of all isolated compounds was evaluated using a transgenic zebrafish model, and a structure-activity relationship (SAR) analysis was conducted. Araucarone (3) and dammaric acid C (9), serving as representative compounds, demonstrated significant hypoglycemic effects on zebrafish. The primary mechanism involves the promotion of pancreatic β cell regeneration and glucose uptake. Specifically, these compounds enhance the differentiation of pancreatic endocrine precursor cells (PEP cells) into β cells in zebrafish.
Zebrafish ; Animals ; Diterpenes/isolation & purification* ; Insulin-Secreting Cells/cytology* ; Glucose/metabolism* ; Hypoglycemic Agents/isolation & purification* ; Molecular Structure ; Structure-Activity Relationship ; Plant Extracts/pharmacology* ; Regeneration/drug effects*

Objective To quantitatively analyze and evaluate the content of rehabilitation policy for people with disabilities in China. Methods This study focused on ten national policies of disability rehabilitation issued from 2021 to 2023.It employed text mining techniques to process policy texts and constructed a policy modeling consistency index model for dis-ability rehabilitation policies in China.The relevant policies were evaluated and analyzed quantitatively. Results The disability rehabilitation policies in China were relatively comprehensive in terms of policy transparency,op-erational mechanisms and policy nature.However,there was still a need for optimization in terms of policy per-spectives,target groups,incentive mechanisms,and other aspects. Conclusion The overall quality of disability rehabilitation policy texts at the national level in China is relatively good.There is a need to further enhance the predictability of policy objectives,clarify the responsibilities and division of labor among various departments,and improve policy incentive mechanisms in future policy formulation,which will further refine China's disability rehabilitation policy system and contribute to high-quality develop-ment of the disability cause.

Objective In this study,Knoevenagel derivatives of curcumin were synthesized,and their oil-water partition coefficient were determined.Our aim is to provide an experimental basis for further development of curcumin derivatives.Methods Two Knoevenagel derivatives of curcumin,including 4-(thiophen-2-ylidene)curcumin(3a)and 4-(pyridine-4-ylidene)curcumin(3b),were obtained by using the methylene group of curcumin as the modification site and purified by column chromatography.The structures of these derivatives were confirmed by nuclear magnetic resonance spectroscopy(NMR),infrared(IR)and high-resolution liquid mass spectrometry(HRLC-MS).The oil-water partition coefficient of the derivatives in n-octanol aqueous solution was determined by quantitative analysis using HPLC.Results Knoevenagel derivatives of curcumin were successfully synthesis.The oil-water partition coefficients(lgPap)of curcumin derivatives 3a and 3b are 0.96 and 0.82,respectively.Compared with the oil-water partition coefficient of curcumin(lgPap=3.85),it suggested that curcumin derivatives showed better water solubility than curcumin.Conclusion Compared to the curcumin prototype,Knoevenagel derivatives of curcumin increased water solubility and improved bioavailability.Thus,it may provide experimental basis for introducing heteroarylene moiety of the methylene position of curcumin to enhance pharmacological activity.

AIM:To investigate of the effect of Shenqifuzheng injection(SFI)combined with PD-L1 antibody on tumor immune microenvironment and its efficacy.METHODS:A subcutaneous transplanta-tion tumor model for B16F10-LUC melanoma was created.The expression of Ki67,CD31,CD8,CD16,CD163,FOXP3,LY6C,LY6G with labeling antibodies was used to detect CD8+T cells,Treg cells,NK cells,MDSCs cells,centrocytes,and granulocytes in the tumor tissues via immunohistochemistry.Flow cy-tometry was used to measure the ratios of CD11c+,IA/IE+,and CD80+cells in splenic tissue,as well as the ratios of CD8+T,CD4+T,and Treg cells in tumor tissue.Additionally,granulocyte count and NK cell expression were analyzed.RESULTS:The immuno-histochemistry results indicate that the drug admin-istration group effectively suppressed tumor angio-genesis and cell proliferation,while decreasing the expression level of immunosuppressive cytokines CD4+T cells,Treg cells,MDSCs and centroblasts.Ad-ditionally,CD8 and NK cell infiltration was promot-ed compared to the control group.The results of the flow analysis demonstrated a significant in-crease in the expression level of CD8+T cells within tumor tissues,as well as inhibition of CD4+T,Treg,and DC cell infiltration within the spleen in the drug administration group.Additionally,the tumor volume analysis indicated that the drug administra-tion group effectively inhibited tumor growth.The flow results illustrate that the group administering treatment exhibited significant increases in CD8+T cell expression levels in tumor tissue and DC cells in the spleen.Furthermore,the treatment effec-tively inhibited the infiltration of CD4+T and Treg cells.The results also indicate that the treatment significantly reduced tumor growth,with the tumor inhibition rate being better with PD-L1 antibody alone than with the SFI group.Additionally,combin-ing drugs resulted in superior results compared to the PD-L1 antibody group alone.CONCLUSION:SFI combined with a PD-L1 antibody can have synergis-tic anti-tumor effects,potentially enhancing DC cell infiltration and promoting T cell activation.Immu-nohistochemistry results indicate a positive impact on the tumor immune microenvironment.

ObjectiveTo investigate the therapeutic effect of Baihe Wuyaotang （BWT） on non-alcoholic fatty liver disease （NAFLD） and elucidate its underlying mechanism. MethodC57BL/6J mice were randomly assigned to six groups： normal control， model， positive drug （pioglitazone hydrochloride 1.95×10^-3 g·kg^-1）， and low-， medium-， and high-dose BWT （1.3，2.5 and 5.1 g·kg^-1）. Following a 12-week high-fat diet （HFD） inducement， the mice underwent six weeks of therapeutic intervention with twice-daily drug administration. Body weight was monitored weekly throughout the treatment period. At the fifth week， glucose tolerance （GTT） and insulin tolerance （ITT） tests were conducted. Subsequently， the mice were euthanized for the collection of liver tissue and serum， and the subcutaneous adipose tissue （iWAT） and epididymal adipose tissue （eWAT） were weighed. Serum levels of total triglycerides （TG） and liver function indicators，such as alanine aminotransferase （ALT） and aspartate aminotransferase （AST）， were determined. Histological examinations， including oil red O staining， hematoxylin-eosin （HE） staining， Masson staining， and transmission electron microscopy， were performed to evaluate hepatic lipid deposition， pathological morphology， and ultrastructural changes， respectively. Meanwhile， Western blot and real-time quantitative polymerase chain reaction （Real-time PCR） were employed to analyze alterations， at both gene and protein levels， the insulin signaling pathway molecules， including insulin receptor substrate 1/2/protein kinase B/forkhead box gene O1 （IRS1/2/Akt/FoxO1）， glycogen synthesis enzymes phosphoenolpyruvate carboxy kinase （Pepck） and glucose-6-phosphatase （G6Pase）， lipid metabolism-related genes stearoyl-coA desaturase-1 （SCD-1） and carnitine palmitoyltransferase-1 （CPT-1）， fibrosis-associated molecules α-smooth muscle actin （α-SMA）， type Ⅰ collagen （CollagenⅠ）， and the fibrosis canonical signaling pathway transforming growth factor-β₁/drosophila mothers against decapentaplegic protein2/3（TGF-β₁/p-Smad/Smad2/3）， inflammatory factors such as interleukin（IL）-6， IL-8， IL-11， and IL-1β， autophagy markers LC3B Ⅱ/Ⅰ and p62/SQSTM1， and the expression of mammalian target of rapamycin （mTOR）. ResultCompared with the model group， BWT reduced the body weight and liver weight of NAFLD mice（P<0.05， P<0.01）， inhibited liver lipid accumulation， and reduced the weight of white fat： it reduced the weight of eWAT and iWAT（P<0.05， P<0.01） as well as the serum TG content（P<0.05， P<0.01）. BWT improved the liver function as reflected by the reduced ALT and AST content（P<0.05， P<0.01）. It improved liver insulin resistance by upregulating IRS2， p-Akt/Akt， p-FoxO1/FoxO1 expressions（P<0.05）. Besides， it improved glucose and lipid metabolism disorders： it reduced fasting blood glucose and postprandial blood glucose（P<0.05， P<0.01）， improved GTT and ITT（P<0.05， P<0.01）， reduced the expression of Pepck， G6Pase， and SCD-1（P<0.01）， and increased the expression of CPT-1（P<0.01）. The expressions of α-SMA， Collagen1， and TGF-β₁ proteins were down-regulated（P<0.05， P<0.01）， while the expression of p-Smad/Smad2/3 was downregulated（P<0.05）， suggesting BWT reduced liver fibrosis. BWT inhibited inflammation-related factors as it reduced the gene expression of IL-6， IL-8， IL-11 and IL-1β（P<0.01） and it enhanced autophagy by upregulating LC3B Ⅱ/Ⅰ expression（P<0.05）while downregulating the expression of p62/SQSTM1 and mTOR（P<0.05）. ConclusionBWT ameliorates NAFLD by multifaceted improvements， including improving IR and glucose and lipid metabolism， anti-inflammation， anti-fibrosis， and enhancing autophagy. In particular， BWT may enhance liver autophagy by inhibiting the mTOR-mediated signaling pathway.