Objective To explore the value of diffusion kurtosis imaging(DKI)in the diagnosis of Parkinson's disease with mild cognitive impairment(PD-MCI)patients.Methods A total of 18 patients with Parkinson's disease cognitive normal(PDN),22 patients with PD-MCI,and 24 healthy controls(HC)were prospectively included.All participants underwent DKI,and regions of interest(ROI)were selected in the substantia nigra,red nucleus,striatum,and posterior cingulate gyrus for post-processing.The diagnostic efficacy of DKI parameters on PD patients' cognitive status was analyzed by the receiver operating characteristic(ROC)curve.Results Compared with the PDN group,the PD-MCI group had a longer disease duration and a higher H-Y stage.Compared with the HC group,the PD-MCI group showed significantly lower mean kurtosis(MK),radial kurtosis(RK),axial kurtosis(AK),and fractional anisotropy(FA)values in the substantia nigra and posterior cingulate gyrus.In the PDN group,FA and MK values in the substantia nigra were significantly decreased,while FA values in the striatum and posterior cingulate gyrus were significantly increased(P＜0.05).Compared with the PDN group,the PD-MCI group showed significantly decreased DKI parameter values in the substantia nigra and posterior cingulate gyrus,and significantly decreased RK,AK,and FA values in the striatum(P＜0.05).The FA values of striatum,posterior cingulate gyrus and joint predictors were the most effective in the diagnosis of PD-MCI and the area under the curve(AUC)were 0.826,0.853 and 0.960,respectively.Conclusion DKI can detect microstructural changes in PD patients.Microstructural alterations in the striatum and posterior cingulate gyrus have an impact on early cognitive function changes in PD patients.FA demonstrate high sensitivity and specificity in the diagnosis of PD-MCI,and the combined diagnostic efficacy across multiple regions is even higher.

BACKGROUND: T cell dysfunction, which includes exhaustion, anergy, and senescence, is a distinct T cell differentiation state that occurs after antigen exposure. Although T cell dysfunction has been a cornerstone of cancer immunotherapy, its potential in transplant research, while not yet as extensively explored, is attracting growing interest. Interferon regulatory factor 4 (IRF4) has been shown to play a pivotal role in inducing T cell dysfunction. METHODS: A novel ultra-low-dose combination of Trametinib and Rapamycin, targeting IRF4 inhibition, was employed to investigate T cell proliferation, apoptosis, cytokine secretion, expression of T-cell dysfunction-associated molecules, effects of mitogen-activated protein kinase (MAPK) and mammalian target of rapamycin (mTOR) signaling pathways, and allograft survival in both in vitro and BALB/c to C57BL/6 mouse cardiac transplantation models. RESULTS: In vitro , blockade of IRF4 in T cells effectively inhibited T cell proliferation, increased apoptosis, and significantly upregulated the expression of programmed cell death protein 1 (PD-1), Helios, CD160, and cytotoxic T lymphocyte-associated antigen (CTLA-4), markers of T cell dysfunction. Furthermore, it suppressed the secretion of pro-inflammatory cytokines interferon (IFN)-γ and interleukin (IL)-17. Combining ultra-low-dose Trametinib (0.1 mg·kg -1 ·day -1 ) and Rapamycin (0.1 mg·kg -1 ·day -1 ) demonstrably extended graft survival, with 4 out of 5 mice exceeding 100 days post-transplantation. Moreover, analysis of grafts at day 7 confirmed sustained IFN regulatory factor 4 (IRF4) inhibition, enhanced PD-1 expression, and suppressed IFN-γ secretion, reinforcing the in vivo efficacy of this IRF4-targeting approach. The combination of Trametinib and Rapamycin synergistically inhibited the MAPK and mTOR signaling network, leading to a more pronounced suppression of IRF4 expression. CONCLUSIONS Targeting IRF4, a key regulator of T cell dysfunction, presents a promising avenue for inducing transplant immune tolerance. In this study, we demonstrate that a novel ultra-low-dose combination of Trametinib and Rapamycin synergistically suppresses the MAPK and mTOR signaling network, leading to profound IRF4 inhibition, promoting allograft acceptance, and offering a potential new therapeutic strategy for improved transplant outcomes. However, further research is necessary to elucidate the underlying pharmacological mechanisms and facilitate translation to clinical practice.
Animals ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Interferon Regulatory Factors/metabolism* ; Heart Transplantation/methods* ; T-Lymphocytes/immunology* ; Sirolimus/therapeutic use* ; Pyridones/therapeutic use* ; Graft Survival/drug effects* ; Pyrimidinones/therapeutic use* ; Cell Proliferation/drug effects* ; Apoptosis/drug effects* ; Male ; Signal Transduction/drug effects*

Objective To explore the value of diffusion kurtosis imaging(DKI)in the diagnosis of Parkinson's disease with mild cognitive impairment(PD-MCI)patients.Methods A total of 18 patients with Parkinson's disease cognitive normal(PDN),22 patients with PD-MCI,and 24 healthy controls(HC)were prospectively included.All participants underwent DKI,and regions of interest(ROI)were selected in the substantia nigra,red nucleus,striatum,and posterior cingulate gyrus for post-processing.The diagnostic efficacy of DKI parameters on PD patients' cognitive status was analyzed by the receiver operating characteristic(ROC)curve.Results Compared with the PDN group,the PD-MCI group had a longer disease duration and a higher H-Y stage.Compared with the HC group,the PD-MCI group showed significantly lower mean kurtosis(MK),radial kurtosis(RK),axial kurtosis(AK),and fractional anisotropy(FA)values in the substantia nigra and posterior cingulate gyrus.In the PDN group,FA and MK values in the substantia nigra were significantly decreased,while FA values in the striatum and posterior cingulate gyrus were significantly increased(P＜0.05).Compared with the PDN group,the PD-MCI group showed significantly decreased DKI parameter values in the substantia nigra and posterior cingulate gyrus,and significantly decreased RK,AK,and FA values in the striatum(P＜0.05).The FA values of striatum,posterior cingulate gyrus and joint predictors were the most effective in the diagnosis of PD-MCI and the area under the curve(AUC)were 0.826,0.853 and 0.960,respectively.Conclusion DKI can detect microstructural changes in PD patients.Microstructural alterations in the striatum and posterior cingulate gyrus have an impact on early cognitive function changes in PD patients.FA demonstrate high sensitivity and specificity in the diagnosis of PD-MCI,and the combined diagnostic efficacy across multiple regions is even higher.

Background::Homoharringtonine (HHT) is an effective anti-inflammatory, anti-viral, and anti-tumor protein synthesis inhibitor that has been applied clinically. Here, we explored the therapeutic effects of HHT in a mouse heart transplant model.Methods::Healthy C57BL/6 mice were used to observe the toxicity of HHT in the liver, kidney, and hematology. A mouse heart transplantation model was constructed, and the potential mechanism of HHT prolonging allograft survival was evaluated using Kaplan–Meier analysis, immunostaining, and bulk RNA sequencing analysis. The HHT-T cell crosstalk was modeled ex vivo to further verify the molecular mechanism of HHT-induced regulatory T cells (Tregs) differentiation. Results::HHT inhibited the activation and proliferation of T cells and promoted their apoptosis ex vivo. Treatment of 0.5 mg/kg HHT for 10 days significantly prolonged the mean graft survival time of the allografts from 7 days to 48 days ( P <0.001) without non-immune toxicity. The allografts had long-term survival after continuous HHT treatment for 28 days. HHT significantly reduced lymphocyte infiltration in the graft, and interferon-γ-secreting CD4 + and CD8 + T cells in the spleen ( P <0.01). HHT significantly increased the number of peripheral Tregs (about 20%, P <0.001) and serum interleukin (IL)-10 levels. HHT downregulated the expression of T cell receptor (TCR) signaling pathway-related genes ( CD4, H2-Eb1, TRAT1, and CD74) and upregulated the expression of IL-10 and transforming growth factor (TGF) -β pathway-related genes and Treg signature genes ( CTLA4, Foxp3, CD74, and ICOS). HHT increased CD4 + Foxp3 + cells and Foxp3 expression ex vivo, and it enhanced the inhibitory function of inducible Tregs. Conclusions::HHT promotes Treg cell differentiation and enhances Treg suppressive function by attenuating the TCR signaling pathway and upregulating the expression of Treg signature genes and IL-10 levels, thereby promoting mouse heart allograft acceptance. These findings may have therapeutic implications for organ transplant recipients, particularly those with viral infections and malignancies, which require a more suitable anti-rejection medication.

Objective:To investigate the biological effects of acute high-dose radon exposure on mice.Methods:BALB/c male mice aged 6 to 8 weeks were exposed once in an HD-3 ecological radon chamber with an average radon concentration of 7 × 10 5 Bq/m 3 for 10 h. Mice were weighed, their lung tissues and blood samples were collected at 1, 2 and 3 months after exposure. Control groups were set up at the three time points with four mice in each group. For these mice, the lung tissue pathology was observed using hematoxylin-eosin (HE) staining method, routine blood tests were conducted using a hematology analyzer and the levels of superoxide dismutase (SOD) and malondialdehyde (MDA) in the serum and lung tissues were measured using corresponding assay kits. Results:The HE staining result revealed that compared to the control groups, the experimental groups exhibited thickening of alveolar walls and increased infiltration of granulocyte, whose degrees, however, reduced over time and displayed no significant difference at 3 months after exposure. There was no significant difference in body weight or blood routine between the experimental and control groups. The detection result revealed decreased SOD levels in the lung tissues at 2 months after exposure, which were (11.34 ± 1.03) U/mgprot and (9.75 ± 0.71) U/mgprot, respectively for the control and experimental groups ( t = 2.54, P < 0.05). The MDA levels in lung tissue increased at 1 month after exposure, which were(2.30 ± 0.24) and (2.77 ± 0.29) nmol/mgprot, respectively for the control and experimental groups ( t = 2.49, P < 0.05). At 3 months after exposure, the SOD and MDA levels differed insignificantly between the control and experimental groups ( P > 0.05). Conclusions:After acute high-dose radon exposure, the mice suffered damage to the lung tissue, with changes in their oxidative stress indicators being detected. However, these effects gradually diminished at 3 months after exposure. Additionally, acute high-dose radon exposure did not give rise to significant changes in the body weight or routine blood result of the mice.

Objective:To evaluate the effect of dexmedetomidine on pyroptosis in rats with endotoxin-induced acute lung injury (ALI).Methods:Sixty SPF male Sprague-Dawley rats, aged 6 weeks, weighing 200-220 g, were divided into 5 groups ( n=10 each) by a random number table method: control group (group C), ALI group and different doses of dexmedetomidine groups (D 1-3 groups). In ALI group and D 1-3 groups, LPS 5 mg/kg was intraperitoneally injected to establish endotoxin-induced ALI model.Immediately after establishing the model, dexmedetomidine 12.5, 25.0 and 50.0 μg/kg were intraperitoneally injected in D 1-3 groups, and the equal volume of normal saline was intraperitoneally injected in group C, once a day for 14 consecutive days.After the end of administration, the rats were sacrificed, the left bronchus was lavaged, and the left bronchoalveolar lavage fluid (BALF) was collected for determination of the concentrations of interleukin-1beta (IL-1β), IL-6 and tumor necrosis factor-alpha (TNF-α) (by enzyme-linked immunosorbent assay), and the lung tissue was taken for determination of the wet/dry weight ratio (W/D ratio) and expression of cleaved-caspase-1, N-terminal of the spliceosome (GSDMD-N), IL-18 and IL-1β (by Western blot) and for microscopic examination of the pathological changes (with a light microscope). Results:Compared with group C, the W/D ratio of lung tissues was significantly increased, the concentrations of IL-1β, IL-6 and TNF-α in BALF were increased, the expression of cleaved-caspase-1, GSDMD-N, IL-1β and IL-18 in lung tissues was up-regulated ( P<0.05), and the pathological damage was aggravated in ALI group and D 1-3 groups.Compared with group ALI, the W/D ratio of lung tissues was significantly decreased, and the concentrations of IL-1β, IL-6 and TNF-α in BALF were decreased, the expression of cleaved-caspase-1, GSDMD-N, IL-1β and IL-18 in lung tissues was down-regulated in a dose-dependent manner ( P<0.05), and the pathological damage was significantly reduced in D 1-3 groups. Conclusion:The mechanism by which dexmedetomidine attenuates endotoxin-induced ALI may be related to inhibition of pyroptosis and reduction of inflammatory responses in rats.

Objective: To assess the outcomes of partial cricotracheal resection (CTR) and extended cricotracheal resection (ECTR) for severe laryngotracheal stenosis. Methods: From November 2009 to September 2017, 18 patients underwent CTR and ECTR at the Department of Otorhinolaryngology Head and Neck Surgery, Tangdu Hospital, Air Force Medical University for severe laryngotracheal stenosis were reviewed retrospectively. There were 12-male and 6-female patients, with the age ranged from 4 to 56 years (median 25 years). The causes were postintubation in 11 cases, cervical trauma in 4, idiopathic in 3. The stenosis located in subglottic and tracheal (n=12), glottic and subglottic and tracheal (n=3), subglottic (n=2), and glottic and subglottic (n=1). Two patients had concurrent unilateral vocal cord palsy.One patient had undergone previous endoscopic balloon dilation and 8 patients had previous laryngotracheal reconstruction. The stenosis was graded according to modified Myer-Cotton classification as follows: Ⅲb (n=1), Ⅲc(n=1), Ⅳa (n=2), Ⅳb (n=12), Ⅳc (n=2). The surgical outcomes and complications were recorded. Results: Among 18 patients,11 of the 12 patients undergoing CTR were decannulated. Five of the 6 patients undergoing ECTR were decannulated. Resected airway length ranged from 1.5 to 4.0 cm (median 2.8 cm). Surgical complications included infection of incision wound in 2 cases, anastomotic granulation in 2, cervical subcutaneous emphysema in 1, aspiration in 1, and unilateral arytenoid prolapse in 1. No recurrent laryngeal nerve injury or tracheoesophageal fistula occurred. The median follow up was 11 months. Conclusions CTR is efficient for severe subglottic and upper tracheal stenosis while ECTR is efficient for subglottic stenosis extended to the glottis. Both procedures also provide a salvage therapy for patients with previous failed treatments.

Objective: The aim of this study is to o explore the diagnosis, treatment and prognosis of idiopathic subglottic stenosis （ISS） Method: The clinical data of 15 patients with idiopathic subglottic stenosis treated in our department were analyzed retrospectively. The degree of stenosis was classified by the Cotton Airway grading system of Myer, with 8 cases of gradeⅡ, 4 cases of grade Ⅲ and 3 cases of grade Ⅳ. Result: The time of follow-up of HTSS was 0.5-10 years. All 15 patients were successfully extubated without asphyxia, decannulation and wound nonunion. Conclusion For patients with idiopathic subglottic stenosis in the non-progressive stage, active surgical treatment strategy should be adopted and treated individually. The prognosis is satisfactory.

The aim of this study is to o explore the diagnosis, treatment and prognosis of idiopathic subglottic stenosis （ISS） The clinical data of 15 patients with idiopathic subglottic stenosis treated in our department were analyzed retrospectively. The degree of stenosis was classified by the Cotton Airway grading system of Myer, with 8 cases of gradeⅡ, 4 cases of grade Ⅲ and 3 cases of grade Ⅳ. The time of follow-up of HTSS was 0.5-10 years. All 15 patients were successfully extubated without asphyxia, decannulation and wound nonunion. For patients with idiopathic subglottic stenosis in the non-progressive stage, active surgical treatment strategy should be adopted and treated individually. The prognosis is satisfactory.

Objectives: . The simulation of microlaryngeal skills is rarely seen in surgical training, but it is particularly important in phonomicrosurgery. This study described and validated the laryngeal surgical simulator through surgical training. Methods: . A simple and low-cost simulator was developed for the fixation of the suspension laryngoscope and porcine larynges. Twenty participants with work skills and experience did preparation before training, and performed suture and carbon dioxide (CO2) laser cordectomy for simulator evaluation. The results were proposed by the aspects of time taken for each procedure, the global rating scale, a procedure-specific assessment, and a post-simulation questionnaire. Results: . All participants completed the preparation within 9 minutes and reached the conclusion that the microlaryngeal surgical simulator was helpful in improving their surgical skills. The performance of experts was superior to that of novices in both suture and CO2 laser cordectomy. Conclusion . This simulator could be easily assembled and was successfully validated by microlaryngeal surgical training both subjectively and objectively. It may be helpful to clinicians in microlaryngeal skills.