Pain is one of the common non-motor symptoms in patients with Parkinson disease and is characterized by early onset， a high incidence rate， and diverse types of discomfort， which seriously affects the quality of life of patients. Based on the related concepts of pain in Parkinson disease and the current status of research in China， this article reviews the commonly used non-pharmaceutical interventions for alleviating pain in patients and their mechanisms， in order to provide a basis for developing pain management regimens.
Parkinson Disease ; Pain

Intervention in chronically activated microglia-mediated neuroinflammation is a novel approach to treat Alzheimer's disease (AD). The low permeability of the blood‒brain barrier (BBB) and non-selective distribution in the brain severely restrict AD drugs' disease-modifying efficacy. Here, an immunosuppressant TREM2-lowing antisense oligonucleotides (ASOs) and resveratrol co-loaded cationic liposome is developed as an immune reprogramming nanomodulator modified by acid-cleavable BBB-targeting peptide and microglia-targeting peptide (Res@TcMNP/ASO) for AD management. Res@TcMNP/ASO can enter brain endothelial cells via D-T7 peptides. Then D-T7 undergoes an acid-responsive cleavage, facilitating the escape of Res@MNP/ASO from endo/lysosomes to cross the BBB. The detached Res@MNP/ASO specifically targets M1-phenotype microglia via exposed MG1 peptides to prompt the simultaneous delivery of two drugs into activated microglia. This nanomodulator can not only restore the immune function of microglia through TREM2-lowing ASO but also mitigate the immune stimulation to microglia caused by reactive oxygen species (ROS) through resveratrol, thereby synergistically inhibiting the chronic activation of microglia to alleviate neuroinflammation in AD. Our results indicate that this combination treatment can achieve significant behavioral and cognitive improvements in late APP/PS1 mice.

Objective:To establish a mouse model of spinal cord injury(SCI),and to investigate the effect of electroacupuncture(EA)intervention on cell apoptosis after acute SCI and its mechanism.Methods:Female C57BL/6 mice were used to establish a model of SCI,and after successful modeling,the mice were randomly divided into SCI group,EA group,and Rosiglitazone group(R group);a sham-operation group(Sham group)was also established.After successful modeling,the mice in the EA group were given EA at bilat-eral Jiaji points and Zusanli once a day for 14 days,those in the R ture,and the number of surviving cells.The EA group and the R group had a significant reduction in the expression of caspase-3 and significant increases in the expression of PPARγ and CD36,and the EA group had significant reductions in the expression of Hba-a1 and Hbb-bt.In addition,RNA-Seq and TMT/iTRAQ techniques,significant analysis,Venn analysis,and dual-omics analysis identi-fied Hba-a1 and Hbb-bt as the target genes of EA.The KEGG pathway enrichment analysis showed that EA had a significant effect on the PPAR signaling pathway.Conclusion:By regulating the PPARγ-CD36 signaling pathway,EA can promote the clearance of Hba-a1 and Hbb-bt after SCI,reduce the expression level of caspase-3,alleviate cell apoptosis,and facilitate the recovery of spinal cord nerve function.

A major challenge facing photodynamic therapy (PDT) is that the activity of the immune-induced infiltrating CD8⁺ T cells is subject to the regulatory T lymphocytes (Tregs), leaving the tumor at risk of recurrence and metastasis after the initial ablation. To augment the antitumor response and reprogram the immunosuppressive tumor microenvironment (TME), a supramolecular photodynamic nanoparticle (DACss) is constructed by the host-guest interaction between demethylcantharidin-conjugated β-cyclodextrin (DMC-CD) and amantadine-terminated disulfide-conjugated FFVLGGGC peptide with chlorin e6 decoration (Ad-ss-pep-Ce6) to achieve intelligent delivery of photosensitizer and immunomodulator for breast cancer treatment. The acid-labile β-carboxamide bond of DMC-CD is hydrolyzed in response to the acidic TME, resulting in the localized release of DMC and subsequent inhibition of Tregs. The guest molecule Ad-ss-pep-Ce6 can be cleaved by a high level of intracellular GSH, reducing photosensitizer toxicity and increasing photosensitizer retention in the tumor. With a significant increase in the CTL/Treg ratio, the combination of Ce6-based PDT and DMC-mediated immunomodulation adequately achieved spatiotemporal regulation and remodeling of the TME, as well as improved primary tumor and in situ lung metastasis suppression with the aid of PD-1 antibody.

Objective To discuss the morphological characteristics of three types of clinically rare cerebral aneurysms and arterial bifurcations.Methods A total of 17 patients with clinically rare cerebral aneurysms,including anterior cerebral artery-pericallosal artery aneurysms(ACA-PA aneurysms,n=8),internal carotid artery-anterior choroidal artery bifurcation aneurysms(ICA-AChA aneurysms,n=5)and vertebral artery-posterior inferior cerebellar artery bifurcation aneurysms(VA-PICA aneurysms,n=4),who received treatment in the Shijiazhuang People's Hospital between January 2017 and April 2020 were enrolled in this study.The clinical baseline data were recorded,and the morphological parameters of the aneurysms were determined.The bifurcation angle,small lateral angle and large lateral angle were defined as φ1,φ2 and φ3,respectively.D1,S1 and T1 represented the diameter,cross-sectional area and tortuosity of the main blood vessel,respectively.D2,S2 and T2 were defined as the corresponding parameters of the branch vessel forming small lateral angle with the main vessel.D3,S3 and T3 were the corresponding morphological parameters of the contralateral branch vessel.Results All of the ICA-AChA and VA-PICA bifurcation aneurysms were type D aneurysms and oriented towards the small lateral angle.Six ACA-PA bifurcation aneurysms were type C aneurysm,and 5 of them were oriented toward the small lateral angle.The S2 and φ2 of the ACA-PA and ICA-AChA bifurcations harboring aneurysms were significantly smaller than S3 and φ3(P＜0.05),while T2 was remarkably largerthan T3(P＜0.05).The VA-PICA bifurcations also showed a similar manifestations.Conclusion These three types of clinically rare cerebral aneurysms are mostly oriented towards the small lateral angle,and the diameter and cross-section area of the branch forming small lateral angle with parent artery were smaller than those of the contralateral branch vessel,while the tortuosity was greater than that of the contralateral branch.

Objective To investigate the efficacy and safety of Yushi Huayu Zhixue prescription (Huayu prescription) combined with levonorgestrel-releasing intrauterine system (LNG-IUS) in the treatment of adenomyosis (AM). Methods A prospective,randomized,double-blind,placebo-controlled trial was designed and 102 patients with AM admitted to the outpatient department of International Peace Maternal & Child Health Hospital and The First Affiliated Hospital of Naval Medical University (Second Military Medical University) from Dec. 2019 to Dec. 2022 were enrolled. The patients were randomly divided into Huayu prescription group and placebo group for double-blind clinical trial. The Huayu prescription group was treated with Huayu prescription 1 month after LNG-IUS placement,while the placebo group was treated with placebo 1 month after LNG-IUS placement,and both Huayu prescription and placebo were taken for 3 months. A total of 95 patients completed the follow-up,including 47 in the Huayu prescription group and 48 in the placebo group;and 7 were shed,with a shedding rate of 6.86％. The pictorial blood loss assessment chart (PBAC) score,uterine spotting days,visual analogue scale (VAS) score,uterine volume,serum carbohydrate antigen 125 (CA125) level and traditional Chinese medicine (TCM) syndrome quantitative score were compared between the 2 groups,and the safety was evaluated. Results After 3 months of treatment,compared with the placebo group,the PBAC score,spotting days,uterine volume,serum CA125 level and TCM syndrome quantitative score of patients in the Huayu prescription group were all decreased (all P<0.05),but there was no significant difference in the VAS score of dysmenorrhea (P>0.05). During the follow-up,no patients in the Huayu prescription group but 2 patients in the placebo group received surgical treatment (including 1 case of laparoscopic hysterectomy and 1 case of laparoscopic adenomyomectomy),and there was no significant difference in the surgical rate between the 2 groups (P>0.05). Meanwhile,no obvious adverse reactions were found in both groups. Conclusion Huayu prescription can significantly improve the spotting of patients with AM,promote uterine volume reduction,reduce serum CA125 level,and significantly improve the TCM syndrome of AM. It is suggest that AM patients should take Huayu prescription after placing LNG-IUS,so as to reduce the adverse reactions of LNG-IUS.

Objective:To investigate the relationship between lifestyle factors and stroke in the elderly.Methods:Data were obtained from a natural cohort of the Multimodal Intervention to Delay Dementia and Disability in Rural China(MIND-China)study.A total of 5 009 participants aged 60 years and above were enrolled, of whom 954(19.05%)had experienced a stroke.Logistic regression analyses were conducted to assess the association between five lifestyle factors(smoking, drinking, physical exercise, social activity and sleep quality)and the incidence of stroke.Results:In model 1, after adjusting for age, sex and education, only social activity( OR=0.783, 95% CI: 0.668-0.917)and good sleep quality( OR=0.731, 95% CI: 0.621-0.860)emerged as protective factors against stroke(both P<0.05).No statistically significant associations were found between other lifestyle factors and stroke.Analysis of a variety of healthy lifestyle practice combinations showed that having 3( OR=0.639, 95% CI: 0.433-0.944), 4( OR=0.620, 95% CI: 0.409-0.941)and 5( OR=0.397, 95% CI: 0.197-0.799)healthy lifestyle practices were protective factors against stroke(all P<0.05).In model 2, after adjusting for age, sex, education, body mass index, diabetes, hyperlipidemia, hypertension, and the APOE genotype, the results were consistent with those of Model 1. Conclusions:Lifestyle factors are significantly associated with the risk of stroke in the elderly population.The healthier lifestyle practices are adopted, the lower the risk of stroke will be.

Purpose: Higher neutrophil-lymphocyte ratio (NLRs) indicate a pro-inflammatory state and are associated with poor survival. Conversely, higher albumin-globulin ratio (AGRs) may be associated with improved prognosis. We aimed to investigate the association between NLR and AGR and prognosis and survival in patients with breast cancer. Methods: This retrospective study included all patients with stage I–III breast cancer between 2011 and 2017 in Singapore General Hospital and National Cancer Center Singapore.Multivariate logistic regression analysis of NLR, AGR, age, stage, grade, and subtype was performed. Survival data between groups were compared using Cox regression analysis and log-rank tests. Results: A total of 1,188 patients were included, of whom 323 received neoadjuvant chemotherapy (NACT) and 865 underwent upfront surgery. In patients who underwent NACT, a higher AGR was significantly associated with a higher pCR rate (cut-off > 1.28; odds ratio [OR], 2.03; 95% confidence interval [CI], 1.13–3.74; p = 0.020), better DFS (cut off > 1.55; hazard ratio [HR], 0.37; 95% CI, 0.16–0.85; p = 0.019), and better CSS (cut off > 1.46; HR, 0.39; 95% CI, 0.17–0.92; p = 0.031). Higher NLR was significantly associated with worse DFS (cut off > 4.09; HR, 1.77; 95% CI, 1.07–2.91; p = 0.026) and worse CSS (cut off > 4.09; HR, 1.98; 95% CI, 1.11–3.53; p = 0.021). In patients who underwent upfront surgery, higher AGR correlated with significantly better OS (cut off > 1.17; HR, 0.54; 95% CI, 0.36–0.82; p = 0.004) and higher NLR correlated with worse OS (cut off > 2.38; HR, 1.63; 95% CI, 1.09–2.44; p = 0.018). Conclusion NLR and AGR are useful in predicting the response to NACT as well as prognosis of patients with breast cancer. Further studies are needed to explore their value in clinical decision making.

Intelligent responsive drug delivery system opens up new avenues for realizing safer and more effective combination immunotherapy. Herein, a kind of tumor cascade-targeted responsive liposome (NLG919@Lip-pep1) is developed by conjugating polypeptide inhibitor of PD-1 signal pathway (AUNP-12), which is also a targeted peptide that conjugated with liposome carrier through matrix metalloproteinase-2 (MMP-2) cleavable peptide (GPLGVRGD). This targeted liposome is prepared through a mature preparation process, and indoleamine-2,3-dioxygenase (IDO) inhibitor NLG919 was encapsulated into it. Moreover, mediated by the enhanced permeability and retention effect (EPR effect) and AUNP-12, NLG919@Lip-pep1 first targets the cells that highly express PD-L1 in tumor tissues. At the same time, the over-expressed MMP-2 in the tumor site triggers the dissociation of AUNP-12, thus realizing the precise block of PD-1 signal pathway, and restoring the activity of T cells. The exposure of secondary targeting module II VRGDC-NLG919@Lip mediated tumor cells targeting, and further relieved the immunosuppressive microenvironment. Overall, this study offers a potentially appealing paradigm of a high efficiency, low toxicity, and simple intelligent responsive drug delivery system for targeted drug delivery in breast cancer, which can effectively rescue and activate the body's anti-tumor immune response and furthermore achieve effective treatment of metastatic breast cancer.

As known, the benefits of photothermal therapy (PTT) are greatly limited by the heat tolerance of cancer cells resulting from overexpressed heat shock proteins (HSPs). Then HSPs further trigger the formation of stress granules (SGs) that regulate protein expression and cell viability under various stress conditions. Inhibition of SG formation can sensitize tumor cells to PTT. Herein, we developed PEGylated pH (low) insertion peptide (PEG-pHLIP)-modified hollow copper sulfide nanoparticles (HCuS NPs) encapsulating the SG inhibitor ISRIB, with the phase-change material lauric acid (LA) as a gate-keeper, to construct a pH-driven and NIR photo-responsive controlled smart drug delivery system (IL@H-PP). The nanomedicine could specifically target slightly acidic tumor sites. Upon irradiation, IL@H-PP realized PTT, and the light-controlled release of ISRIB could effectively inhibit the formation of PTT-induced SG to sensitize tumor cells to PTT, thereby increasing the antitumor effect and inducing potent immunogenic cell death (ICD). Moreover, IL@H-PP could promote the production of reactive oxygen species (ROS) by tumor-associated macrophages (TAMs), repolarizing them towards the M1 phenotype and remodeling the immunosuppressive microenvironment. In vitro/vivo results revealed the potential of PTT combined with SG inhibitors, which provides a new paradigm for antitumor and anti-metastases.