Corticotomy is a clinical procedure to accelerate orthodontic tooth movement characterized by the regional acceleratory phenomenon (RAP). Despite its therapeutic effects, the surgical risk and unclear mechanism hamper the clinical application. Numerous evidences support macrophages as the key immune cells during bone remodeling. Our study discovered that the monocyte-derived macrophages primarily exhibited a pro-inflammatory phenotype that dominated bone remodeling in corticotomy by CX3CR1^CreERT2; R26^GFP lineage tracing system. Fluorescence staining, flow cytometry analysis, and western blot determined the significantly enhanced expression of binding immunoglobulin protein (BiP) and emphasized the activation of sensor activating transcription factor 6 (ATF6) in macrophages. Then, we verified that macrophage specific ATF6 deletion (ATF6^f/f; CX3CR1^CreERT2 mice) decreased the proportion of pro-inflammatory macrophages and therefore blocked the acceleration effect of corticotomy. In contrast, macrophage ATF6 overexpression exaggerated the acceleration of orthodontic tooth movement. In vitro experiments also proved that higher proportion of pro-inflammatory macrophages was positively correlated with higher expression of ATF6. At the mechanism level, RNA-seq and CUT&Tag analysis demonstrated that ATF6 modulated the macrophage-orchestrated inflammation through interacting with Tnfα promotor and augmenting its transcription. Additionally, molecular docking simulation and dual-luciferase reporter system indicated the possible binding sites outside of the traditional endoplasmic reticulum-stress response element (ERSE). Taken together, ATF6 may aggravate orthodontic bone remodeling by promoting Tnfα transcription in macrophages, suggesting that ATF6 may represent a promising therapeutic target for non-invasive accelerated orthodontics.
Animals ; Mice ; Macrophages/metabolism* ; Tumor Necrosis Factor-alpha/genetics* ; Tooth Movement Techniques/methods* ; Activating Transcription Factor 6/metabolism* ; Bone Remodeling ; Flow Cytometry ; Blotting, Western

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Objective:To analyze the influencing factors of skull base reconstruction failure after endoscopic endonasal skull base surgery (EESBS).Methods:A retrospective analysis was performed on 228 EESBS cases at the Affiliated Hospital of Qingdao University from 2018 to 2023. The clinical features associated with skull base reconstruction and postoperative cerebrospinal fluid leakage were collected and analyzed. Lasso regression was initially used for exploratory analysis, and risk factors for reconstruction failure were subsequently evaluated using multifactorial logistic regression.Results:A total of 157 cases of EESBS were included, with an overall reconstruction failure rate of 11.5% (18/157). No patients who underwent second-stage reconstruction with a tipped mucosal flap or multilayered free mucosal and fascial repair experienced further postoperative cerebrospinal fluid leakage. Variables identified through Lasso regression included history of surgery, history of radiotherapy, and site of leakage. Multifactorial logistic analysis showed that history of radiotherapy ( OR=5.96, P=0.021) and site of leakage in the posterior skull base ( OR=8.70, P=0.003) were significant risk factors for failure of skull base reconstruction. Conclusion:In cases with a history of radiotherapy and/or posterior skull base lesions in the operative area, reconstruction strategies should be strengthened to improve the success rate of one-stage repair, in particular, when intraoperative cerebrospinal fluid leakage occurs.

Objectives:To identify the two-dimensional speckle tracking imaging (2D-STI)-derived longitudinal strain indices that reflect the myocardial functional characteristics of patients with apical hypertrophic cardiomyopathy (AHCM). Methods:This retrospective study included 30 patients with typical AHCM diagnosed at the First Affiliated Hospital of Fujian Medical University from January 2015 to May 2019 (AHCM group),35 patients with essential hypertensive left ventricular hypertrophy (HTLVH group),and 45 healthy volunteers (normal control group) were also included.Two-dimensional echocardiography was used to measure the cardiac chamber size and wall thickness,and 2D-STI was used to analyze the longitudinal strain during the left ventricular systolic phase,the global longitudinal strain (GLS) and the longitudinal strain of the apical,mid,and basal segments (LSA,LSM,LSB) were assessed.The ratios of the apical to the overall and other segmental longitudinal strains were used as the apical relative longitudinal strain indices,including the apical to basal longitudinal strain ratio (ABLR,LSA/LSB),the apical to global longitudinal strain ratio (AGLR,LSA/GLS),and the apical to basal-mid segment longitudinal strain ratio (ABMLR,LSA/[LSB+LSM]). Results:GLS was significantly lower in the AHCM group and HTLVH group than in the normal control group (both P<0.05),and was similar between the AHCM group and HTLVH group (P>0.05).The LSA,LSM,and LSB were also significantly lower in the AHCM group and HTLVH group than in the normal control group,LSA decrease was more significant in the AHCM group as compared to the HTLVH group,while the HTLVH group was mainly characterized by a decrease in LSB,which was significantly lower as compared to the AHCM group (all P<0.05).Compared with the normal control group,the ABLR,AGLR,and ABMLR were significantly reduced in the AHCM group,while significantly increased in the HTLVH group (all P<0.05).The ROC curve showed that the AUC of ABLR,AGLR,ABMLR,and LSA was 0.873 to 0.916,using<1.28 as the cutoff value of ABLR,the sensitivity was 90.0％ and specificity was 88.7％ for diagnosing AHCM. Conclusions:The apical relative longitudinal strain indices can reflect the myocardial functional characteristics of AHCM patients,which are better than single apical longitudinal strain value.As the most representative indice,ABLR may be useful in distinguishing AHCM from left ventricular hypertrophy caused by other diseases,and can be used as a parameter for the evaluation of myocardial function damage in AHCM.

Objective To construct a predictive model for septic shock based on the propensity score matching (PSM) method and validate its effectiveness. Methods A total of 114 patients with sepsis were enrolled as study objects, and were divided into septic shock group (40 patients) and sepsis group (74 patients) according to whether they developed septic shock. PSM was performed with a ratio of septic shock to sepsis of 1∶2, resulting in the inclusion of 30 patients in the septic shock group and 60 patients in the sepsis group after matching. The levels of C-reactive protein (CRP), procalcitonin (PCT), interleukin-6 (IL-6), serum amyloid A (SAA), soluble endothelial protein C receptor (sEPCR), endothelial cell-specific molecule 1 (ESM-1), clusterin (CLU), and the Acute Physiology and Chronic Health Evaluation Ⅱ (APACHE Ⅱ) score and Sequential Organ Failure Assessment (SOFA) score at admission were compared between the two groups. Cox proportional hazards regression analysis was used to identify the factors influencing septic shock, and a predictive model for septic shock was constructed and internally validated using the receiver operating characteristic (ROC) curve. Kaplan-Meier survival curves were plotted to analyze the differences in survival prognosis among patients with different expression levels of the indicators. Results After matching, there were no statistically significant differences in general information between the two groups (P>0.05). At admission, the septic shock group had higher levels of serum PCT, CRP, SAA, IL-6, sEPCR, ESM-1, and higher APACHE Ⅱ and SOFA scores, as well as a lower level of serum CLU compared with the sepsis group (P < 0.05). Cox regression analysis showed that PCT, CRP, SAA, IL-6, sEPCR, ESM-1, APACHE Ⅱ score, and SOFA score were independent risk factors for septic shock (P < 0.05), while CLU was an independent protective factor (P < 0.05). The predictive model for septic shock, constructed based on these factors, showed an internal validation accuracy of 94.44%, an area under the curve of 0.950, a sensitivity of 93.33%, and a specificity of 96.67%. Dead patients had higher levels of PCT, CRP, SAA, IL-6, sEPCR, ESM-1, and higher APACHE Ⅱ and SOFA scores, as well as a lower level of CLU at admission compared with survivors (P < 0.05). Compared with patients with low expression levels or low scores, patients with high expression levels of PCT, CRP, SAA, IL-6, sEPCR, ESM-1, and high APACHE Ⅱ and SOFA scores had higher fatality rates, while patients with high CLU expression levels had a lower fatality rate (P < 0.05). Conclusion The serum biomarkers including PCT, CRP, SAA, IL-6, sEPCR, ESM-1, CLU, and the APACHE Ⅱ and SOFA scores in sepsis patients are closely related to the occurrence of septic shock and survival prognosis. The predictive model constructed by combining these indicators can accurately predict the occurrence of septic shock.

Objective:To investigate the pharmacokinetics of cerebrospinal fluid pemetrexed following intrathecal injection chemotherapy in patients with leptomeningeal metastasis (LM) from lung adenocarcinoma and provide a basis for clinical intrathecal injection chemotherapy.Methods:A total of 21 patients with lung adenocarcinoma LM who underwent pemetrexed intrathecal injection chemotherapy via Ommaya capsule at Nanjing Drum Tower Hospital, Aiffilitated Hospital of Nanjing University Medical School from November 2019 to November 2022 were collected, and divided into 30, 40 and 50 mg groups ( n=10, n=4, n=7) according to pemetrexed dose. Cerebrospinal fluid was collected at 0, 0.5, 1, 2, 4, 6, 12, 24 and 48 h after the first intrathecal injection chemotherapy, and day 8 of each cycle for three groups. Reversed phase high performance liquid chromatography was used to determine the drug concentration in cerebrospinal fluid, to clarify the drug-related pharmacokinetic parameters, and to compare the differences in pemetrexed concentration among groups. Finally, cerebrospinal fluid pemetrexed concentration changes were observed and compared after different intrathecal injection chemotherapy cycles. Results:There were statistically significant differences in cerebrospinal fluid drug concentrations of patients in three groups at 0, 0.5, 1, 2, 4, 6, 12, 24 and 48 h after the first intrathecal injection chemotherapy (30 mg group: F=20.56, P<0.001; 40 mg group: F=27.06, P<0.001; 50 mg group: F=28.63, P<0.001), and there were statistically significant differences in the concentration of cerebrospinal fluid drugs in each dose group at 0.5, 1, 2, 4, 6 and 12 h compared to 0 h after intrathecal injection chemotherapy (all P<0.05). Compared to the 30 mg group, cerebrospinal fluid drug concentrations in the 50 mg group increased at 1, 2, 4, 6, 12 and 24 h after intrathecal injection chemotherapy, with statistically significant differences (all P<0.05). Pharmacokinetic analysis of cerebrospinal fluid pemetrexed showed that area under the concentration-time curve (AUC) 0-∞ of the 30, 40 and 50 mg groups were (5 696.12±283.32), (7 886.29±396.57), and (14 202.70±440.19) h·mg/L, respectively, with a statistically significant difference ( F=1 159.00, P<0.001) ; AUC 0-∞ increased in the 50 mg group compared to the 30 and 40 mg groups (both P<0.05) ; AUC 0-∞ increased in the 40 mg group compared to the 30 mg group ( P<0.05). The half-lives of three groups were (8.75±0.23), (11.29±0.59) and (16.42±1.23) h, respectively, with a statistically significant difference ( F=206.80, P<0.001) ; half-life was longer in the 50 mg group compared to the 30 and 40 mg groups (both P<0.05) ; half-life was longer in the 40 mg group compared to the 30 mg group ( P<0.05). The peak time of three groups were (1.55±0.10), (1.00±0.01), (1.43±0.11) h, respectively, with a statistically significant difference ( F=48.11, P<0.001) ; the peak time was shorter in the 40 and 50 mg groups compared to the 30 mg group (both P<0.05). Clearance of three groups were (7.02±2.46), (5.80±1.25) and (3.66±1.32) L/h, respectively, with a statistically significant difference ( F=6.02, P=0.009) ; clearance was decreased in the 50 mg group compared to the 30 mg group ( P<0.05). The peak concentration of three groups were (540.45±32.25), (820.75±46.47) and (1 014.78±64.96) mg/L, respectively, with a statistically significant difference ( F=207.70, P<0.001) ; peak concentration increased in the 50 mg group compared to the 30 and 40 mg groups (both P<0.05) ; peak concentration increased in the 40 mg group compared to the 30 mg group ( P<0.05). Cerebrospinal fluid drug concentrations were dynamically monitored after 4 cycles of intrathecal injection chemotherapy, in which cerebrospinal fluid pemetrexed concentrations in 30 mg group were (13.76±4.79), (11.41±7.08), (9.41±2.59) and (7.86±4.02) mg/L, respectively; 40 mg group were (14.45±6.59), (12.87±15.73), (11.24±2.48) and (9.09±3.38) mg/L, respectively; 50 mg group were (12.94±10.34), (9.72±7.62), (8.15±8.17) and (4.34±4.21) mg/L, respectively. There was a statistically significant difference in cerebrospinal fluid drug concentrations among different intrathecal injection chemotherapy cycles in 30 mg group ( F=4.04, P=0.016), and the cerebrospinal fluid drug concentration decreased in cycles 3 and 4 compared to cycle 1 (both P<0.05). There were no statistically significant differences in cerebrospinal fluid drug concentrations among different treatment cycles in 40 and 50 mg groups ( F=0.28, P=0.837; F=3.57, P=0.066) . Conclusion:Reversed phase high performance liquid chromatography method can effectively detect the pemetrexed concentration in cerebrospinal fluid; dynamic monitoring of cerebrospinal fluid pemetrexed concentration can provide a basis for the dosage and the treatment cycle of intrathecal injection chemotherapy in LM patients with lung adenocarcinoma.

OBJECTIVE To study the improvement effects of different polar parts fro m total f lavonoids of Scutellaria amoena on non-alcoholic fatty liver disease （NAFLD）model rats. METHODS The total flavonoids of S. amoena （SAF）were extracted by reflux extraction with ethanol ，suspended with water ，and then extracted with ethyl acetate and n-butanol in order to obtain the extraction parts of SAF （recorded as SAFA and SAFB respectively ）. Thirty-six rats were randomly divided into normal group （n＝ 6）and modeling group （n＝30）. Modeling group was given high-lipid diet to induce NAFLD model. After modeling ，modeling group was randomly divided into model group （normal saline ），fenofibrate group （positive control ，20 mg/kg），SAF group （300 mg/kg），SAFA group （300 mg/kg）and SAFB group （300 mg/kg）；they were given relevant intragastical administration ，once a day，for consecutive 6 weeks. After last administration ，the liver index was calculated ；the levels of total cholesterol （TC）， triacylglycerol（TG），aspartate transaminase （AST），alanine transaminase （ALT），high-density lipoprotein cholesterol （HDL-C）， low-density lipoprotein cholesterol （LDL-C） in serum ，the levels of superoxide dismutase （SOD），glutathione peroxidase （GSH-Px），malondialdehyde（MDA），interleukin-1β（IL-1β），IL-6 and tumor necrosis factor-α（TNF-α）in liver tissue were detected；the pathomorphological changes of liver tissue were observed. RESULTS Compared with normal group ，the liver index ， the levels of TC ，TG，AST，ALT，LDL-C，MDA，IL-1β， IL-6 and TNF-α in serum/liver tissue of model group were all increased significantly （P＜0.05）， while the levels of HDL-C，SOD and GSH-Px were all decreased significantly （P＜0.05）. Compared with model group ，except there was no statistical significance in the serum levels of HDL-C and ALT in SAFA group （P＞0.05），above indexes in serum/liver tissue of rats in groups of polar parts from total flavonoids of S. amoena were significantly improved （P＜0.05）；inflammatory cell infiltration and fatty vacuoles in liver tissue were significantly improved. Compared with SAF group and SAFA group ，the levels of TC，TG，AST，MDA，IL-6 and TNF-α were decreased significantly in SAFB group（P＜0.05），while the level of SOD was increased significantly （P＜0.05）；pathomorphological changes of liver tissue were improved more significantly. CONCLUSIONS Each polar part from total flavonoids of S. amoena can improve NAFLD by regulating oxidative stress and inhibiting the secretion of inflammatory factors. The n-butanol polar part has more obvious effect .

Antipyretic-analgesics are currently one of the most prescribed drugs in children.The clinical application of antipyretic-analgesics for children in our country still have irrational phenomenon, which affects the therapeutic effect and even poses hidden dangers to the safety of children.In this paper, suggestions were put forward from the indications, dosage form/route, dosage suitability, pathophysiological characteristics of children with individual differences and drug interactions in the symptomatic treatment of febrile children, so as to provide reference for the general pharmacists when conducting prescription review.

IL-37 is a member of the IL-1 family of cytokines, which functions as a natural suppressor of inflammatory and immune responses. IL-37 likely functions to limit excessive inflammation, accordingly, IL-37 levels are abnormal in patients with inflammatory and autoimmune diseases. In this review, we provide an overview of the anti-inflammatory mechanism of IL-37. It also summarizes the research progress of expression and its role in bronchial asthma, a heterogeneous chronic airway inflammatory disease.

Objective:To investigate the clinical significance of the transforming growth factor-β receptor I (TGF-βRⅠ) expression in na?ve CD4 + T cells from patients with systemic lupus erythematosus (SLE). Methods:Na?ve CD4 + T cells were purified using magnetic microbeads from peripheral blood mononuclear cells of SLE patients and healthy controls. Real-time quantitative PCR was used to detect TGF-βRⅠ mRNA level, and flow cytometry was used to detect the percentage of CD69 +CD4 + T cells. Data were analyzed by t test and Pearson correlation analysis. Results:The level of TGF-βR Ⅰ mRNA in na?ve CD4 + T cells from SLE patients was significantly lower than that in healthy controls [(0.674±0.873) vs (1.445±1.112), t=2.301, P<0.05]. The TGF-βR Ⅰ mRNA level was negatively correlated with systemic lupus erythematosus disease activity index (SLEDAI) ( r=-0.376, P<0.05), erythrocyte sedimentation rate (ESR) ( r=-0.376, P<0.05), serum creatinine ( r=-0.323, P<0.05) and 24 h urine protein ( r=-0.331, P<0.05), and positively correlated with serum com-plement C3 ( r=0.528, P<0.01). The level of TGF-βRⅠ mRNA level in na?ve CD4 + T cells in SLE patients with renal involvement was lower than that in SLE patients without renal involvement [(0.525±0.536) vs (1.071±1.007), t=2.198, P<0.05]. The TGF-βR Ⅰ mRNA level in the na?ve CD4 + T cells in anti-dsDNA antibody positive group was lower than that in the anti-dsDNA antibody negative group [(0.344±0.315) vs (0.958±1.076), t=2.277, P<0.05]. The expression of TGF-βRⅠ mRNA in na?ve CD4 + T cells from SLE patients was reduced after 24 h stimulation with anti-CD3/CD28 beads [(0.047±0.013) vs (1.008±0.129), t=14.38, P<0.01], which was partially reversed by dexamethasone treatment [(0.240±0.042) vs (0.047±0.013), t=7.845, P<0.01]. Meanwhile, dexamethasone significantly decreased the expression of CD69 in CD4 + T cells [(15.0±2.1)% vs(34.9±2.0)%, t=32.57, P<0.01]. Conclusion:The abnormally low expression of TGF-βRⅠ in na?ve CD4 + T cells may be involved in the pathogenesis of SLE. Glucocorticoid treatment can upregulate the expression of TGF-βRI and inhibit the activation of T cells, This suggests suggesting that TGF-βRⅠ may be a potential target for SLE treatment.