Objectives: . This study aimed to investigate the regulatory functions of gamma-aminobutyric acid (GABA)ergic neural circuits from the inferior colliculus (IC) to the medial geniculate body (MGB) in salicylate-induced tinnitus. Methods: . Mice were treated with salicylate to induce tinnitus, and tinnitus-like behaviors were evaluated via gap prepulse inhibition of acoustic startle. Using combined viral tracing methodologies, we identified and mapped the pathways and connections from the IC to the MGB. Furthermore, we employed Gq-coupled human M3 designer receptors exclusively activated by designer drugs (DREADDs) and Gi-coupled human M4 DREADDs to achieve targeted excitation or suppression of GABAergic neurons in the IC and MGB. Following the administration of clozapine N-oxide, which binds to these receptors, we modulated these neural circuits to assess their impact on tinnitus severity in a mouse model. Results: . Our findings demonstrated that mice exposed to salicylate exhibited tinnitus-like behaviors. GABAergic neurons projecting retrogradely from the MGB to the IC were primarily concentrated in the external nucleus of the IC. After clozapine N-oxide administration, chemogenetic activation of IC-MGB GABAergic neurons aggravated salicylate-induced tinnitus. Additionally, activation of GABAergic neurons between the IC and MGB induced the perception of tinnitus even without salicylate. However, chemogenetic inhibition of the IC-MGB GABAergic circuit did not reverse salicylate-induced tinnitus. Conclusion . These findings suggest that activation of the IC-MGB GABAergic neural circuit may contribute to tinnitus generation through a mechanism distinct from that of salicylate-induced tinnitus. This study provides novel insights into the mechanisms underlying tinnitus.

ObjectiveTo investigate the influence of histone deacetylase 3 (HDAC3) on the occurrence, development of psoriasis-like inflammation in mice, and the relative immune mechanisms. MethodsHealthy C57BL/6 mice aged 6-8 weeks were selected and randomly divided into 3 groups: control group (Control), psoriasis model group (IMQ), and HDAC3 inhibitor RGFP966-treated psoriasis model group (IMQ+RGFP966). One day prior to the experiment, the back hair of the mice was shaved. After a one-day stabilization period, the mice in Control group was treated with an equal amount of vaseline, while the mice in IMQ group was treated with imiquimod (62.5 mg/d) applied topically on the back to establish a psoriasis-like inflammation model. The mice in IMQ+RGFP966 group received intervention with a high dose of the HDAC3-selective inhibitor RGFP966 (30 mg/kg) based on the psoriasis-like model. All groups were treated continuously for 5 d, during which psoriasis-like inflammation symptoms (scaling, erythema, skin thickness), body weight, and mental status were observed and recorded, with photographs taken for documentation. After euthanasia, hematoxylin-eosin (HE) staining was used to assess the effect of RGFP966 on the skin tissue structure of the mice, and skin thickness was measured. The mRNA and protein expression levels of HDAC3 in skin tissues were detected using reverse transcription real-time quantitative polymerase chain reaction (RT-qPCR) and Western blot (WB), respectively. Flow cytometry was employed to analyze neutrophils in peripheral blood and lymph nodes, CD4⁺ T lymphocytes, CD8⁺ T lymphocytes in peripheral blood, and IL-17A secretion by peripheral blood CD4⁺ T lymphocytes. Additionally, spleen CD4⁺ T lymphocyte expression of HDAC3, CCR6, CCR8, and IL-17A secretion levels were analyzed. Immunohistochemistry was used to detect the localization and expression levels of HDAC3, IL-17A, and IL-10 in skin tissues. ResultsCompared with the Control group, the IMQ group exhibited significant psoriasis-like inflammation, characterized by erythema, scaling, and skin wrinkling. Compared with the IMQ group, RGFP966 exacerbated psoriasis-like inflammatory symptoms, leading to increased hyperkeratosis. The psoriasis area and severity index (PASI) skin symptom scores were higher in the IMQ group than those in the Control group, and the scores were further elevated in the IMQ+RGFP966 group compared to the IMQ group. Skin thickness measurements showed a trend of IMQ+RGFP966>IMQ>Control. The numbers of neutrophils in the blood and lymph nodes increased sequentially in the Control, IMQ, and IMQ+RGFP966 groups, with a similar trend observed for CD4⁺ and CD8⁺ T lymphocytes in the blood. In skin tissues, compared with the Control group, the mRNA and protein levels of HDAC3 decreased in the IMQ group, but RGFP966 did not further reduce these expressions. HDAC3 was primarily located in the nucleus. Compared with the Control group, the nuclear HDAC3 content decreased in the skin tissues of the IMQ group, and RGFP966 further reduced nuclear HDAC3. Compared with the Control and IMQ groups, RGFP966 treatment decreased HDAC3 expression in splenic CD4⁺ and CD8⁺ T cells. RGFP966 treatment increased the expression of CCR6 and CCR8 in splenic CD4⁺ T cells and enhanced IL-17A secretion by peripheral blood and splenic CD4⁺ T lymphocytes. Additionally, compared with the IMQ group, RGFP966 reduced IL-10 protein levels and upregulated IL-17A expression in skin tissues. ConclusionRGFP966 exacerbates psoriatic-like inflammatory responses by inhibiting HDAC3, increasing the secretion of the cytokine IL-17A, and upregulating the expression of chemokines CCR8 and CCR6.

Objective:To analyze the application of antitoxin therapy in severe infant botulism.Methods:A retrospective analysis was conducted on 14 cases of severe infant botulism treated at 3 pediatric medical centers from July 2020 to August 2024. This study investigated antitoxin dosage, treatment duration, discontinuation criteria and adverse reactions.Results:A total of 14 cases (12 males and 2 females) were included, with an age of 5.0 (3.8, 7.0) months. Botulinum toxin typing revealed 10 cases of Type B, 2 cases of Type A and 2 untyped cases. The interval from symptom onset to antitoxin administration was 9.0 (6.0, 11.5) d. The initial dosage of type A antitoxin was 12 500 (10 000, 22 500) U, while type B was 5 000 (5 000, 5 000) U. The dosage was tapered in some cases after symptom improvement, the duration of treatment was 16.5 (9.8, 25.3) d. In total, 11 infants discontinued medications after improvement in muscle strength, while 3 infants discontinued treatment after obtaining negative results from fecal mouse bioassays. Adverse events were reported in 2 cases, both of which resulted in rash, and 1 case was complicated with anaphylactic shock. All the patients survived upon discharge with a follow-up period of 11 d to 3 years and 8 months. Totally 12 infants had fully recovered, while 2 infants were still recovering after discharge.Conclusion:Antitoxin therapy is a feasible and safe approach which showed favorable prognosis in severe infant botulism.

Objective:To understand the management of children with pediatric acute liver failure (PALF) in pediatric intensive care unit (PICU).Methods:A retrospective case-control study was conducted. A total of 101 children with PALF hospitalized in PICU of Beijing Children′s Hospital from July 2017 to October 2022 were included. Demographic, clinical management and prognosis data were collected. According to whether PALF was the main diagnosis, the patients were divided into primary diagnosis group and complication group. The primary diagnosis group was subdivided into effective group and ineffective group with routine treatment (except liver transplantation). The intergroup comparisons were performed using independent samples t-test, Mann-Whitney U test, χ2 test or Fisher exact test. Multivariate Logistic regression analysis was employed to identify risk factors associated with prognosis. Results:Among the 101 children with PALF, 58 were male and 43 were female, with an age of 30 (10, 103) months, 60 cases in primary diagnosis group and 41 cases in complication group. There were no significant differences in prothrombin time (PT) and international normalized ratio (INR) between the two groups (both P>0.05), while the total bilirubin, direct bilirubin and blood ammonia were all significantly higher in the primary diagnosis group (all P<0.05). Unoriginal liver failure (25 cases (42%)) and poisoning (13 cases (22%)) were the most common causes of PALF in the primary diagnosis group, while shock (17 cases, 43%) and hemophagocytic syndrome (14 cases (34%)) in the complication group. The mortality rate of the main diagnosis group was significantly lower than that of the complication group (25% (15/60) vs. 61% (25/41), χ2=13.18, P<0.001), as well as the incidence of combined organ function injury, while the amount of plasma used and the ratio of plasma exchange times to PICU hospitalization days were significantly higher (all P<0.05). In the primary diagnosis group, there were 32 cases (53%) in the effective group and 28 cases (47%) in the ineffective group. In the ineffective group, 15 cases (54%) died and 13 cases (46%) were transferred to another site for liver transplantation assessment. The hospitalization time of PICU in the effective group was significantly longer than that in the ineffective group, while the ratio of plasma exchange times to PICU hospitalization days, the average daily hours of continuous renal replacement therapy (CRRT), the rate of CRRT and the average daily plasma dosage in the effective group were all significantly lower than those in the ineffective group (all P<0.05). The worst PT, INR and blood ammonia, and the stage 4 hepatic encephalopathy morbidity and significant bleeding rate in the effective group were all significantly lower than those in the ineffective group (all P<0.05). Multivariate Logistic regression analysis showed that after adjusting for age, sex, total bilirubin, INR and blood ammonia, stage 4 hepatic encephalopathy was the independent risk factor for the failure of routine treatment of PALF ( OR=84.16,95% CI 4.04-1752.37, P=0.004). Conclusions:PT and INR could not specifically represent liver synthetic function in some PICU patients, so current PALF diagnostic criteria for PICU children has limitations. Complicated with stage 4 hepatic encephalopathy was an independent risk factor of the failure of conventional treatment in patients with PALF.

Objective:To explore the impact of different blood transfusion thresholds on clinical outcomes in children with severe traumatic brain injury (TBI).Methods:A retrospective cohort study was conducted. Clinical data was collected from 64 children with severe TBI who received red blood cell transfusions and were admitted to the Pediatric Intensive Care Unit (PICU) of Beijing Children′s Hospital between January 2020 and December 2024. Data included basic clinical characteristics, mortality rate, neurological recovery (measured by Glasgow coma scale (GCS) at discharge, pediatric cerebral performance category (PCPC) score), length of stay in the PICU, duration of mechanical ventilation, and incidence of complications. Patients were divided into a liberal transfusion group (hemoglobin >70-<100 g/L at first transfusion) and a restrictive transfusion group (hemoglobin ≤70 g/L at first transfusion). Stratified analysis was performed based on age (children >5 and children ≤5 years old). Comparisons between groups were conducted using the independent samples t test, Mann-Whitney U test, χ2 test or Fisher′s exact test. Results:Among the 64 children with severe TBI (43 males and 21 females), the age was 4.9 (2.3, 10.0) years. There were 33 cases in the liberal transfusion group and 31 cases in the restrictive transfusion group. No statistically significant differences were observed in baseline data, including gender, age, trauma mechanism, GCS at admission, surgical intervention, presence of multiple injuries, or comorbidities (sepsis, shock, ventilator-associated pneumonia and acute kidney injury) between the 2 groups (all P>0.05). There were no statistically significant differences between the liberal and restrictive transfusion groups in mortality rate, GCS and PCPC score at discharge, length of PICU stay, duration of mechanical ventilation, or transfusion volume (all P>0.05). In the stratified analysis, 38 children aged over 5 years were included. The restrictive transfusion subgroup, which included 19 children, had a significantly longer PICU length of stay compared to the liberal transfusion subgroup, which also included 19 children (29.5 (18.0, 36.3) vs. 17.0 (6.3, 25.8) d, Z=2.11, P=0.035). Conclusions:There were no significant differences in PICU mortality or neurological functional recovery between the liberal and restrictive blood transfusion strategies in children with severe TBI. However, among children aged over than 5 years, a restrictive transfusion strategy might be associated with a longer length of PICU stay.

Objective To investigate the impact of risk prevention and control on the quality efficiency of medical equipment procurement.Methods The medical equipment procurement projects with enhanced risk prevention measures during 2023(119 items)were assigned to an observation group,while those without strengthened risk control during 2022(118 items)were enrolled into a control group.The two groups were compared in terms of bid failure/rejection rates,procurement completion cycles(including procurement execution cycle and total procurement cycle)and procurement satisfaction.Statistical analysis was performed using SPSS 20.0 software.Results The observation group demonstrated significantly lower bid failure/rejection rates when compared with the control group(≥2 occurrences:5.88％vs.15.25％,P＜0.05).The procurement execution cycle was notably shorter in the observation group((69.16±78.65)d vs.(97.67±49.84)d,P＜0.05),though no significant difference was observed in total procurement cycle(P＞0.05).The observation group behaved better significantly than the control group in procurement efficiency,equipment performance,procedural compliance and post-purchase service satisfaction(all P＜0.05).Conclusion Risk prevention and control measures in medical equipment procurement effectively reduce bid failure/rejection risks while enhancing procurement quality efficiency.[Chinese Medical Equipment Journal,2025,46(3):81-85]

BACKGROUND: Disease-modifying therapies have been approved for the treatment of relapsing multiple sclerosis (RMS). The present study aims to examine the safety of teriflunomide in Chinese patients with RMS. METHODS: This non-randomized, multi-center, 24-week, prospective study enrolled RMS patients with variant (c.421C>A) or wild type ABCG2 who received once-daily oral teriflunomide 14 mg. The primary endpoint was the relationship between ABCG2 polymorphisms and teriflunomide exposure over 24 weeks. Safety was assessed over the 24-week treatment with teriflunomide. RESULTS: Eighty-two patients were assigned to variant ( n  = 42) and wild type groups ( n  = 40), respectively. Geometric mean and geometric standard deviation (SD) of pre-dose concentration (variant, 54.9 [38.0] μg/mL; wild type, 49.1 [32.0] μg/mL) and area under plasma concentration-time curve over a dosing interval (AUC tau ) (variant, 1731.3 [769.0] μg∙h/mL; wild type, 1564.5 [1053.0] μg∙h/mL) values at steady state were approximately similar between the two groups. Safety profile was similar and well tolerated across variant and wild type groups in terms of rates of treatment emergent adverse events (TEAE), treatment-related TEAE, grade ≥3 TEAE, and serious adverse events (AEs). No new specific safety concerns or deaths were reported in the study. CONCLUSION: ABCG2 polymorphisms did not affect the steady-state exposure of teriflunomide, suggesting a similar efficacy and safety profile between variant and wild type RMS patients. REGISTRATION NCT04410965, https://clinicaltrials.gov .
Humans ; Crotonates/adverse effects* ; Toluidines/adverse effects* ; Nitriles ; Hydroxybutyrates ; Female ; Male ; Adult ; ATP Binding Cassette Transporter, Subfamily G, Member 2/genetics* ; Middle Aged ; Multiple Sclerosis, Relapsing-Remitting/genetics* ; Prospective Studies ; Young Adult ; Neoplasm Proteins/genetics* ; East Asian People

OBJECTIVE: To investigate the effect of the sequence of intermediate instrumentation and distraction-reduction of the injured vertebra on the surgical efficacy of short-segment percutaneous pedicle screw fixation for thoracolumbar burst fractures with high rate of spinal canal encroachment. METHODS: From January 2016 to January 2022, 38 patients with thoracolumbar burst fractures with high rate of spinal canal encroachment (spinal canal encroachment rate >40%, complete posterior longitudinal ligament, no flipping bone block in the posterior marginal of the vertebra) without spinal cord injury who were were treated with short-segment percutaneous pedicle screw fixation were retrospectively analyzed. During the operation, 18 cases were used distraction-reduction first and then intermediate instrumentation on injured vertebral and sequential distraction-reduction again(the distraction-reduction first group) including 8 females and 10 males with a mean age of 46.5 (38.5, 50.0) years old, and the other 20 cases were used intermediate instrumentation on injured vertebral first and then direct distraction-reduction(the intermediate instrumentation first group) including 10 males and 10 females with a mean age of 46.0 (35.8, 50.8) years. The anterior height ratio of the injured vertebra, local Cobb's angle of the injured vertebrae, the spinal canal encroachment rate, and the improvement rate of spinal canal encroachment were compared and evaluated. RESULTS: All patients were followed up for more than 1 year, and no complications such as spinal cord and root injury, screw loosening and screw rod fracture were found. The anterior height ratio of the injured vertebra, local Cobb' angle of the injured vertebra in the two groups were significantly improved compared with preoperative data(P<0.05), and those at 3 months and 1 year after operation was lost compared with that at the previous time point(P<0.05). Although the spinal canal encroachment rate of the two groups 1 day and 1 year after operation was improved compared with that before operation(P<0.05), the improvement of spinal canal volume in the distraction-reduction first group was significantly better than that in the intermediate instrumentation first group (P<0.01). CONCLUSION In the treatment of patients with thoracolumbar fractures with high rate of spinal canal encroachment, short-segment percutaneous pedicle screw internal fixation with distraction-reduction first and then intermediate instrumentation and sequential distraction-reduction again can more effectively reduce the bony encroachment in the spinal canal and achieve indirect decompression effect better.
Humans ; Female ; Male ; Adult ; Middle Aged ; Spinal Fractures/surgery* ; Thoracic Vertebrae/surgery* ; Lumbar Vertebrae/surgery* ; Fracture Fixation, Internal/instrumentation* ; Pedicle Screws ; Retrospective Studies ; Spinal Canal/surgery*

Detection of poor-water-soluble substances typically requires an organic solvent containing solution,and therefore,the biosensors that can operate in such conditions are highly promising for practical applications.However,most existing biosensors have been developed in aqueous solution and it is hard to work effectively in organic solvent systems.In this work,we uncovered that the G-quadruplex(G4)/hemin DNAzyme(G4HD)could be strongly reactivated by NH4 in organic solvents at concentration up to 30％,and the activity was significantly higher than that in aqueous solutions containing K+.Based on this discovery,a biosensing system was developed for small molecule in 40％methanol by coupling G4HD with our previously identified RNA-cleaving DNAzyme(E3).This system comprised an ATP-activated aptazyme that was made of E3 and a G4HD that was activated by the cleavage product of the aptazyme.By using a manmade pipette tip filter to separate the reaction products,the subsequent colorimetric reaction of the G4HD could be triggered.This biosensing system enabled the visualization of target molecules in organic cosolvents without any other instruments.The activable DNAzyme-cascade sensing system had potential in point-of-care detection of poor-water-soluble pollutants,thereby enhancing the practical values of functional nucleic acid-based biosensors in real-world detection conditions.

Heart failure(HF)is a cardiovascular disease with a high prevalence and mortality rate worldwide,and despite the widespread use of existing drugs,device intervetions and surgical procedures,the clinical outcomes are still unsatisfactory.The exploration of new methods to treat HF is still an urgent problem.Gene therapy provides a new therapeutic strategy for HF by targeting the regulation of pathogenic genes.This article systematically reviewed the delivery system optimization,key targets and clinical translational challenges of gene therapy for HF,aiming to provide a theoretical basis for the optimization of treatment strategies.