Machado-Joseph disease, or spinocerebellar ataxia type 3 (SCA3), represents the most common autosomal dominant cerebellar ataxia worldwide. Despite its progressive and debilitating nature, disease-modifying therapies remain elusive. Repetitive transcranial magnetic stimulation (rTMS) has emerged as a promising non-invasive intervention; however, its clinical application has been hindered by inconsistent protocols and a lack of mechanistic understanding. A recent landmark study published in Brain Stimulation by Chen et al. addressed these challenges by combining a high-dose intermittent theta-burst stimulation (iTBS) protocol with concurrent transcranial magnetic stimulation-electroencephalography (TMS-EEG). This commentary provides an in-depth analysis of their findings, highlighting the restoration of cerebello-cortical inhibition (CBI) as a key therapeutic mechanism. Furthermore, we discuss the broader implications of this work, proposing that future translational research should integrate accelerated iTBS (aiTBS) paradigms, cortical response measurements (CRM), and individualized neuro-navigation to establish a new era of precision neuromodulation for ataxia.

Machado-Joseph disease, or spinocerebellar ataxia type 3 (SCA3), represents the most common autosomal dominant cerebellar ataxia worldwide. Despite its progressive and debilitating nature, disease-modifying therapies remain elusive. Repetitive transcranial magnetic stimulation (rTMS) has emerged as a promising non-invasive intervention; however, its clinical application has been hindered by inconsistent protocols and a lack of mechanistic understanding. A recent landmark study published in Brain Stimulation by Chen et al. addressed these challenges by combining a high-dose intermittent theta-burst stimulation (iTBS) protocol with concurrent transcranial magnetic stimulation-electroencephalography (TMS-EEG). This commentary provides an in-depth analysis of their findings, highlighting the restoration of cerebello-cortical inhibition (CBI) as a key therapeutic mechanism. Furthermore, we discuss the broader implications of this work, proposing that future translational research should integrate accelerated iTBS (aiTBS) paradigms, cortical response measurements (CRM), and individualized neuro-navigation to establish a new era of precision neuromodulation for ataxia.

Objective:To construct the inflammation score(IS)and nutrition-immunity score(NIS)for patients with multiple myeloma(MM),and to verify their prognostic stratification effects and significance.Methods:The clinical data of 129 newly diagnosed MM patients admitted to our hospital from August 2011 to September 2022 were retrospectively analyzed.Univariate and multivariate Cox regression analysis of overall survival(OS)were comducted on clinical parameters,including inflammatory indicators such as red blood cell volume distribution width(RDW)and platelet count(PLT),nutritional-immune indicators such as albumin(ALB),absolute lymphocyte count(ALC),and suppressed immunoglobulin count(S-Ig count).To construct IS and NIS for prognosis,X-tile software and multivariate Cox regression analysis were used to verify the prognostic stratification role and significance of IS and NIS.The time-dependent receiver operating characteristic(ROC)curve,C-index curve,calibration curve,and decision curve analysis(DCA)were used to evaluate the discrimination,accuracy,and clinical net benefit of IS and NIS in predicting overall survival(OS),and compared to the international staging system(ISS).Results:IS was constructed based on the scores of RDW and PLT,and NIS was constructed based on the scores of ALB,ALC,and S-Ig count.According to X-tile analysis and multivariate Cox regression analysis,IS and NIS can divide the patients into three risk strata respectively:low,medium and high IS and NIS groups.The differences in OS and hazard ratio(HR)between the low,medium,and high strata were statistically significant(P＜0.05).IS and NIS are both independent prognostic predictors for MM.The area under the ROC curve(AUC)and C index of IS and NIS for predicting 1-to 7-year OS were greater than those of ISS,and both were greater than 0.7.The prediction results of IS and NIS for 1-,3-,and 5-year OS rates were well consistent with the actual observed results.The DC A curves of IS and NIS for predicting 1-,3-,and 5-year OS were higher than that of ISS in a wide range of threshold probability intervals.Conclusion:IS and NIS have independent predictive significance for OS in MM patients.Their predictive discrimination,accuracy,and clinical net benefit are higher and better than ISS,and they may have potential application value in MM prognosis.

AIM To observe the effects of Yiqi Jiedu Tongluo Formula(YQJDTL)on renal microvascular endothelial function and prevention of renal injury in a rat model of type 2 diabetes mellitus(T2DM).METHODS The SD rats were randomly divided into a normal group and a model group.The model group was administered with high-fat diet combined with a single intraperitoneal injection of STZ to establish the T2DM model.The successfully modeled rats were randomly divided into the model group,the canagliflozin group(9 mg/kg),and the low-dose and high-dose YQJDTL groups(4.77,9.45 g/kg).The corresponding doses of the drug were administered by gavage for a total of 12 weeks,during which the rats underwent observation of their general condition and blood glucose changes.After the end of administration,the rats had their levels of renal index,24-hour UP,serum SCr,BUN,TC,TG,HDL-C,LDL-C,ET-1 and NOS measured;their changes in renal microvasculature and the degree of renal fibrosis observed using HE staining,Masson staining,PAS staining,and PASM staining;their ultrastructure of the glomeruli observed using transmission electron microscopy;their renal protein expressions of TGF-β,SMAD2,SMAD3,Col-1,VEGFA and PKC detected by immunohistochemical staining and Western blot;and their renal mRNA expressions of VEGFA,TGF-β,SMAD2 determined by RT-qPCR.RESULTS Compared with the model group,the high-dose YQJDTL group showed decreased levels of renal index,blood glucose,TG,TC,HDL,24 h UP,BUN,SCr and ET-1(P＜0.05,P＜0.01);increased LDL and NOS levels(P＜0.05,P＜0.01);reduced renal inflammatory infiltration and fibrosis degree,inhibited fusion of foot processes and thickening of basement membrane;decreased renal protein expressions of TGF-β,SMAD2,SMAD3,VEGFA,PKC and Col-1(P＜0.05,P＜0.01);and decreased mRNA expressions of VEGFA,TGF-β and SMAD2(P＜0.01).CONCLUSION In the rat models of T2DM,YQJDTL can reduce their levels of blood glucose and lipids by improving the renal indices levels and the renal microvascular endothelial functions to alleviate renal fibrosis and microangiopathy as well,and the mechanism may be associated with the down-regulated expressions of TGF-β/SMAD and VEGF pathway-related proteins.

Objective To investigate the epidemiological and demographic characteristics of Mycoplasma pneumoniae(Mp),respiratory syncytial virus(RSV),influenza A(FluA),and influenza B(FluB)in a single center in Minhang District,Shanghai after the end of the COVID-19 pandemic.Methods A retrospective analysis of data from Apr 2023 to Jul 2024 of patients who underwent testing for Mp,RSV,FluA,and FluB due to respiratory tract infections in Minhang Hospital,Fudan University was conducted.Differences in pathogen infections were analyzed among different seasons and age groups.Results A total of 39 103 individuals of respiratory tract infections with simultaneous testing for all four pathogens were included in this analysis,with a total detection rate of 44.7%(17 490/39 103).The detection rates were as follows:Mp 25.2%,FluA 13.1%,FluB 10.9%,and RSV 1.5%.Co-infections accounted for 5.9%,predominantly with Mp and FluA.The detection rate of Mp was>38%in children under 14 years old,gradually decreasing with age.In the child group(≤14 years),both FluA and FluB had the highest detection rates in the 7-14 years age group(FluA,16.5%;FluB,10.4%).In the adult group(≥15 years),the highest detection rates for FluA and FluB were found in the 15-24 years age group(12.5%)and the 35-44 years age group(15.9%),respectively.The detection rates of pathogens varied significantly across different months(P<0.001),with an increasing trend in the total number and overall detection rate of the four pathogens after Sept 2023(P<0.001).Conclusion After the end of the COVID-19 pandemic,there was an abnormal increase in Mp in a single center in Minhang District,Shanghai.Mp,along with influenza viruses,became the main pathogens causing respiratory tract infections.Targeted prevention and control measures based on the epidemiological characteristics of infections should be implemented to guide clinical diagnosis and treatment.

Aim To investigate the antidepressant mechanism of hyperforin via the utilization of single-cell sequencing technology.Methods C57BL/6 mice were randomly divided into the control group,depres-sion model group,and hyperforin intervention group.The chronic unpredictable mild stress(CUMS)model was induced and drug interventions were administered for 28 d.Behavioral experiments were conducted to as-sess depressive symptoms,and hippocampal tissue was collected for single-cell RNA sequencing.Key cell populations and differentially expressed genes across groups were identified,followed by PPI network,GO,and KEGG enrichment analysis.Results Behavioral experiments indicated that CUMS successfully induced depressive symptoms in mice,while hyperforin im-proved depressive behavior.In the depression model group,the proportion of brain perivascular macrophages(PVM)increased,and this proportion decreased after hyperforin intervention,approaching the level seen in the control group.The top 20 common differentially ex-pressed genes in the PVM subpopulation were Saa3,Hbb-bs and Ccl24.PPI network analysis identified core targets,including Ccl2,Dhx9,C3,Msr1,Cxcl2 and Cx3cr1.KEGG enrichment analysis revealed pathways related to chemokines,phagosome formation,and inosi-tol phosphate metabolism.Conclusion The antide-pressant mechanism of hyperforin may be related to the regulation of Ccl24 and its related chemokine signaling pathway by PVM.

Objective To compare the efficacy of stenting in the treatment of idiopathic intracranial hypertension(IIH)complicated by different types of venous sinus stenosis(VSS).Methods The clinical data of 48 patients with IIH complicated by VSS,who received stenting therapy at the First Affiliated Hospital of Zhengzhou University of China from January 2019 to September 2023,were retrospectively analyzed.According to the type of VSS,the patients were divided into intrinsic stenosis group(n=20)and the extrinsic stenosis group(n=28).The improvement of symptoms,Frisén grade of papilledema,lumbar puncture opening pressure(LPOP),trans-stenosis pressure gradient(△P)of VSS,and surgery-related complications were compared between the two groups.Results The mean age of the patients in the intrinsic stenosis group was greater than that of the patients in the extrinsic stenosis group(41.60 years vs.35.25 years,P=0.049).The length of the narrowed segment in the extrinsic stenosis group was 22.5 mm,which was significantly longer than 19.0 mm in the intrinsic stenosis group(P=0.007).The postoperative Frisén grade of papilledema in the extrinsic stenosis group was obviously lower than that in the intrinsic stenosis group(P=0.037).No statistically significant differences in the other clinical data existed between the two groups(all P＞0.05).After stenting,all of the median △P,mean LPOP,and median Frisén grade of papilledema were decreased significantly when compared with their preoperative values(all P＜0.001),and the postoperative 3-day median Frisén grade of papilledema in the extrinsic stenosis group was much lower(P=0.037).The patients were followed up for one year,the clinical symptoms of the patients in both groups were improved to varying degrees.At the time of discharge,the proportion of patients having no symptoms of papilledema in the extrinsic stenosis group was 57.1％,which was higher than 22.2％in the intrinsic stenosis group(P=0.049),and no statistically significant differences in the improvements of other symptoms existed between the two groups(all P＞0.05).There was no significant difference in the incidence of complications between the two groups(P=0.563).Conclusion Venous sinus stenting can effectively treat patients with IIH complicated by different types of VSS.

Aim To investigate the antidepressant mechanism of hyperforin via the utilization of single-cell sequencing technology.Methods C57BL/6 mice were randomly divided into the control group,depres-sion model group,and hyperforin intervention group.The chronic unpredictable mild stress(CUMS)model was induced and drug interventions were administered for 28 d.Behavioral experiments were conducted to as-sess depressive symptoms,and hippocampal tissue was collected for single-cell RNA sequencing.Key cell populations and differentially expressed genes across groups were identified,followed by PPI network,GO,and KEGG enrichment analysis.Results Behavioral experiments indicated that CUMS successfully induced depressive symptoms in mice,while hyperforin im-proved depressive behavior.In the depression model group,the proportion of brain perivascular macrophages(PVM)increased,and this proportion decreased after hyperforin intervention,approaching the level seen in the control group.The top 20 common differentially ex-pressed genes in the PVM subpopulation were Saa3,Hbb-bs and Ccl24.PPI network analysis identified core targets,including Ccl2,Dhx9,C3,Msr1,Cxcl2 and Cx3cr1.KEGG enrichment analysis revealed pathways related to chemokines,phagosome formation,and inosi-tol phosphate metabolism.Conclusion The antide-pressant mechanism of hyperforin may be related to the regulation of Ccl24 and its related chemokine signaling pathway by PVM.

AIM To establish the preparation process and quality standard for Zhenggu Pills.METHODS With decoction time,decoction frequency and water addition as influencing factors,comprehensive score for extract yield and transfer rates of epicatechin and naringin as an evaluation index,the decoction process was optimized by orthogonal test.With sugarless paste relative density,medicinal powder fineness,sugarless paste-corn starch ratio,drying temperature and drying time as influencing factors,soft material traits,pill formability,moisture and disintegration time limit as evaluation indices,the formability process was optimized by single factor test.TLC was adopted in the qualitative identification of Dipsaci Radix,salt-processed Psoraleae Fructus,cooked Rhei Radix et Rhizoma and Notoginseng Radix et Rhizoma.HPLC was used for the content determination of paeoniflorin and naringin.RESULTS The optimal decoction process was determined to be 0.5 h for decoction time,two times for decoction frequency,and 10 times for water addition,the comprehensive score was 0.93.The optimal formability process was determined to be 1.21-1.22 for sugarless paste relative density,80 mesh for medicinal powder fineness,1∶0.17-1∶0.18 for sugarless paste-corn starch ratio,70 ℃ for drying temperature,and 24 h for drying time,good soft material traits and pill formability were observable,and moisture and disintegration time limit accored with 2020 edition of Chinese Pharmacopoeia requirements.The TLC spots were clear without negative interference.Two constituents showed good linear relationships within 61.30-490.41 μg/mL(r=0.999 8)and 3.27-26.18 μg/mL(r=0.999 8),whose average recoveries were 100.15％and 98.15％with the RSDs of 0.55％and 2.30％,respectively.CONCLUSION This stable,reliable and specific method can be used for the production and quality evaluation of Zhenggu Pills.

Objectives:To investigate the enhancement of tumor penetration and photodynamic therapy (PDT) efficacy in triple-negative breast cancer by hyaluronidase (HAase) using a novel pH-responsive IR780-loaded photosensitive micelle.Methods:The pH-responsive IR780-loaded photosensitive micelles were prepared using the nanoprecipitation method, and their morphology, size, and encapsulation efficiency were characterized. The in vitro stability and pH-responsive drug release of the micelles were also evaluated. The cytotoxicity of the micelles on triple-negative breast cancer cells (MDA-MB-231) was assessed using a cell counting kit. A nude mouse breast cancer model was established, and HAase was injected intratumorally 24 hours before intravenous injection of the photosensitive micelles. The effect of HAase on the biodistribution and tumor uptake of the micelles was detected using small animal in vivo imaging. CD31 and HIF-1α immunofluorescence staining were performed to investigate the mechanism of HAase-enhanced tumor penetration. The body weight and tumor volume of the mice were measured, and necrosis and apoptosis of tumor tissues were assessed using HE staining and TUNEL staining, respectively. Results:Transmission electron microscopy showed that the micelles had a uniform particle size of approximately 60-70 nm, with a hydrated particle size of (98.03±0.22) nm. The IR780 encapsulation efficiency was 74.15%, with a drug loading content of 2.07%. After 7 days at 4 ℃, there was no significant change in hydrated particle size ( P=0.062). The 24-hour release rates of the micelles in PBS at pH 7.4 and 6.5 were (2.41±0.21)% and (43.69±2.09)%, respectively, showing a significant difference ( P＜0.000 1). The cytotoxicity assay revealed that the cell viability in the micelles group without light exposure was significantly higer than that in the micelles group under light exposure [(97.00±5.38)% vs. (53.27±9.00)%, P=0.000 2]. The micelles were able to target and accumulate in the tumor tissue, and this accumulation increased significantly with HAase treatment. CD31 and HIF-1α immunofluorescence staining indicated that the CD31 signal was enhanced [(0.27±0.05)% vs. (4.57±0.27)%, P＜0.000 1] and the HIF-1α signal was reduced [(5.14±0.38)% vs. (0.08±0.04)%, P＜0.000 1] in the HAase-treated group compared to that in the micelle-only group. After 11 days of treatment with HAase combined with photosensitive micelles, there was no statistically significant difference in mouse body weight ( P＞0.05). However, the tumor volume inhibition rate in the HAase-micelle-mediated PDT group was significantly higher than that in the micelle-mediated PDT group [(87.66±6.37)% vs. (25.34±12.63)%, P=0.002]. Histological staining showed a significant increase in tumor cell necrosis and apoptosis in the HAase-micelle-mediated PDT group. Conclusion:HAase enhances the deep tumor penetration and targeted accumulation of pH-responsive IR780-loaded photosensitive micelles, significantly improves the efficacy of photodynamic therapy in triple-negative breast cancer.