ObjectiveCerebrospinal fluid (CSF) plays a crucial role in maintaining the homeostasis of the central nervous system (CNS). CSF rapidly exchanges with interstitial fluid (ISF) via the glymphatic system within the brain parenchyma. CSF-ISF circulation and its associated mechanisms are often referred to as the brain lymphatic system. This system is connected directly to meningeal lymphatic vessels (mLVs), jointly performing the function of clearing metabolic waste from the CNS. Emerging evidence indicates that this system is closely associated with the onset and progression of neurodegenerative diseases (NDs) such as Alzheimer’s disease (AD). Importantly, abnormal CSF circulation is not only a downstream consequence of AD pathology, but also a risk factor. In AD, the dynamics of CSF flow within the CNS are diminished, immune dysregulation occurs, and this may increase the risk of AD by exacerbating the burden of amyloid β-protein (Aβ). In the mouse model of AD, impaired CSF flow compromises this clearance function, leading to cognitive deficits. Clinically, acupuncture at cognition-related acupoints is commonly used for the prevention and treatment of AD. However, whether its therapeutic effects are mediated through the modulation of CSF dynamics remains unclear. This study aimed to evaluate the impact of acupuncture on CSF flow and investigate its acupoint specificity. MethodsMice were randomly assigned to experimental groups for the different electroacupuncture groups with the following acupoints: Baihui point (GV 20), Ear point, Neiguan point (PC 6), and Tianshu point (ST 25). Wild-type mice on a C57BL/6J background were used as controls. Fluorescent tracer was injected into the cisterna magna to label CSF flow. Fluorescence imaging was employed to assess the distribution of CSF within the brain before and after acupuncture stimulation. ResultsFollowing tracer injection into the cisterna magna, fluorescence signals rapidly reached the cerebellum and medulla—the regions closest to the injection site. Fluorescence intensity was higher in ventral brain regions compared to dorsal regions, likely due to greater vascular density in ventral areas facilitating CSF-ISF exchange. Electroacupuncture at the GV 20 produced the most pronounced enhancement of CSF across the whole brain, while stimulation at the ST 25 primarily augmented flow within subcortical regions. In contrast, electroacupuncture at the Ear point or the PC 6 had no observable effect on CSF in mice. ConclusionElectroacupuncture promotes CSF flow into the brain parenchyma in an acupoint-specific manner, with GV 20 exhibiting the most pronounced enhancement of CSF dynamics. These findings suggest that acupuncture-mediated facilitation of CSF flow may represent a potential therapeutic strategy for preventing or delaying age-related cognitive decline.

ObjectiveCerebrospinal fluid (CSF) plays a crucial role in maintaining the homeostasis of the central nervous system (CNS). CSF rapidly exchanges with interstitial fluid (ISF) via the glymphatic system within the brain parenchyma. CSF-ISF circulation and its associated mechanisms are often referred to as the brain lymphatic system. This system is connected directly to meningeal lymphatic vessels (mLVs), jointly performing the function of clearing metabolic waste from the CNS. Emerging evidence indicates that this system is closely associated with the onset and progression of neurodegenerative diseases (NDs) such as Alzheimer’s disease (AD). Importantly, abnormal CSF circulation is not only a downstream consequence of AD pathology, but also a risk factor. In AD, the dynamics of CSF flow within the CNS are diminished, immune dysregulation occurs, and this may increase the risk of AD by exacerbating the burden of amyloid β-protein (Aβ). In the mouse model of AD, impaired CSF flow compromises this clearance function, leading to cognitive deficits. Clinically, acupuncture at cognition-related acupoints is commonly used for the prevention and treatment of AD. However, whether its therapeutic effects are mediated through the modulation of CSF dynamics remains unclear. This study aimed to evaluate the impact of acupuncture on CSF flow and investigate its acupoint specificity. MethodsMice were randomly assigned to experimental groups for the different electroacupuncture groups with the following acupoints: Baihui point (GV 20), Ear point, Neiguan point (PC 6), and Tianshu point (ST 25). Wild-type mice on a C57BL/6J background were used as controls. Fluorescent tracer was injected into the cisterna magna to label CSF flow. Fluorescence imaging was employed to assess the distribution of CSF within the brain before and after acupuncture stimulation. ResultsFollowing tracer injection into the cisterna magna, fluorescence signals rapidly reached the cerebellum and medulla—the regions closest to the injection site. Fluorescence intensity was higher in ventral brain regions compared to dorsal regions, likely due to greater vascular density in ventral areas facilitating CSF-ISF exchange. Electroacupuncture at the GV 20 produced the most pronounced enhancement of CSF across the whole brain, while stimulation at the ST 25 primarily augmented flow within subcortical regions. In contrast, electroacupuncture at the Ear point or the PC 6 had no observable effect on CSF in mice. ConclusionElectroacupuncture promotes CSF flow into the brain parenchyma in an acupoint-specific manner, with GV 20 exhibiting the most pronounced enhancement of CSF dynamics. These findings suggest that acupuncture-mediated facilitation of CSF flow may represent a potential therapeutic strategy for preventing or delaying age-related cognitive decline.

ObjectiveTo evaluate the efficacy of Shexiang Baoxinwan in treating stable angina pectoris with Qi stagnation and blood stasis syndrome in patients with coronary artery disease （CAD） complicated with anxiety and depression and explore its underlying mechanisms. MethodsThis study employed a randomized， double-blind， and placebo-controlled clinical trial design. Patients admitted to the hospital were randomly assigned to the observation group and the control group， with 52 patients in each group. Patients in the observation and control groups received Shexiang Baoxinwan and placebo， respectively， both in combination with conventional Western medication. The dose was 45.0 mg， three times daily， for a total duration of eight weeks. The primary outcome was the Seattle Angina Questionnaire （SAQ） scores before and after treatment. Secondary outcomes included changes in traditional Chinese medicine （TCM） syndrome score， the patient health questionnaire-9 （PHQ-9）， generalized anxiety disorder-7 （GAD-7）， inflammatory markers ［interleukin-18 （IL-18）， interleukin-10 （IL-10）， tumor necrosis factor-alpha （TNF-α）， CD40， etc.］， monoamine neurotransmitters ［e.g.， dopamine （DA）］， vascular endothelial function markers ［e.g.， endothelin-1（ET-1）］， adipokines， and ischemia-modified albumin （IMA）. Adverse reactions were also recorded. ResultsA total of 92 patients completed the study， with 44 in the observation group and 48 in the control group. Compared with baseline， both groups showed significant decreases in PHQ-9， GAD-7， and TCM syndrome scores following treatment （P<0.05）， along with a significant increase in SAQ scores （P<0.05）. In the observation group， DA levels were significantly increased （P<0.05）， while levels of IL-18， TNF-α， CD40， ET-1， and IMA were decreased （P<0.05）. In contrast， the control group exhibited significantly increased CD40 levels （P<0.05）. Compared with the control group after treatment， the observation group showed significant improvements in the SAQ dimensions of physical limitation， angina stability， treatment satisfaction， and disease perception， as well as in TCM syndrome score， PHQ-9 score， IL-18， CD40， ET-1， and IMA （P<0.05）. No adverse reactions were observed in either group during treatment. ConclusionShexiang Baoxinwan can improve anxiety and depression， alleviate angina symptoms， and reduce TCM symptoms of Qi stagnation and blood stasis in CAD patients. The mechanism may involve anti-inflammation， improvement of vascular endothelial function， reduction of IMA， and increase of monoamine neurotransmitter levels.

ObjectiveTo evaluate the efficacy of Shexiang Baoxinwan in treating stable angina pectoris with Qi stagnation and blood stasis syndrome in patients with coronary artery disease （CAD） complicated with anxiety and depression and explore its underlying mechanisms. MethodsThis study employed a randomized， double-blind， and placebo-controlled clinical trial design. Patients admitted to the hospital were randomly assigned to the observation group and the control group， with 52 patients in each group. Patients in the observation and control groups received Shexiang Baoxinwan and placebo， respectively， both in combination with conventional Western medication. The dose was 45.0 mg， three times daily， for a total duration of eight weeks. The primary outcome was the Seattle Angina Questionnaire （SAQ） scores before and after treatment. Secondary outcomes included changes in traditional Chinese medicine （TCM） syndrome score， the patient health questionnaire-9 （PHQ-9）， generalized anxiety disorder-7 （GAD-7）， inflammatory markers ［interleukin-18 （IL-18）， interleukin-10 （IL-10）， tumor necrosis factor-alpha （TNF-α）， CD40， etc.］， monoamine neurotransmitters ［e.g.， dopamine （DA）］， vascular endothelial function markers ［e.g.， endothelin-1（ET-1）］， adipokines， and ischemia-modified albumin （IMA）. Adverse reactions were also recorded. ResultsA total of 92 patients completed the study， with 44 in the observation group and 48 in the control group. Compared with baseline， both groups showed significant decreases in PHQ-9， GAD-7， and TCM syndrome scores following treatment （P<0.05）， along with a significant increase in SAQ scores （P<0.05）. In the observation group， DA levels were significantly increased （P<0.05）， while levels of IL-18， TNF-α， CD40， ET-1， and IMA were decreased （P<0.05）. In contrast， the control group exhibited significantly increased CD40 levels （P<0.05）. Compared with the control group after treatment， the observation group showed significant improvements in the SAQ dimensions of physical limitation， angina stability， treatment satisfaction， and disease perception， as well as in TCM syndrome score， PHQ-9 score， IL-18， CD40， ET-1， and IMA （P<0.05）. No adverse reactions were observed in either group during treatment. ConclusionShexiang Baoxinwan can improve anxiety and depression， alleviate angina symptoms， and reduce TCM symptoms of Qi stagnation and blood stasis in CAD patients. The mechanism may involve anti-inflammation， improvement of vascular endothelial function， reduction of IMA， and increase of monoamine neurotransmitter levels.

Objective: To explore glymphatic impairment in pediatric refractory epilepsy (RE) using multi-parameter magnetic resonance imaging (MRI), assess its relationship with white-matter (WM) abnormalities and clinical indicators, and preliminarily evaluate the performance of multi-parameter MRI in discriminating RE from drug-sensitive epilepsy (DSE). Materials and Methods: We retrospectively included 70 patients with DSE (mean age, 9.7 ± 3.5 years; male:female, 37:33) and 26 patients with RE (9.0 ± 2.9 years; male:female, 12:14). The diffusion tensor imaging analysis along the perivascular space (DTI-ALPS) index as well as fractional anisotropy (FA), mean diffusivity (MD), and nodal efficiency values were measured and compared between patients with RE and DSE. With sex and age as covariables, differences in the FA and MD values were analyzed using tract-based spatial statistics, and nodal efficiency was analyzed using a linear model. Pearson’s partial correlation was analyzed. Receiver operating characteristic (ROC) curves were used to evaluate the discrimination performance of the MRI-based machine-learning models through five-fold cross-validation. Results: In the RE group, FA decreased and MD increased in comparison with the corresponding values in the DSE group, and these differences mainly involved the callosum, right and left corona radiata, inferior and superior longitudinal fasciculus, and posterior thalamic radiation (threshold-free cluster enhancement, P < 0.05). The RE group also showed reduced nodal efficiency, which mainly involved the limbic system, default mode network, and visual network (false discovery rate, P < 0.05), and significantly lower DTI-ALPS index (F = 2.0, P = 0.049). The DTI-ALPS index was positively correlated with FA (0.25 ≤ r ≤ 0.32) and nodal efficiency (0.22 ≤ r ≤ 0.37), and was negatively correlated with the MD (-0.24 ≤ r≤ -0.34) and seizure frequency (r = -0.47). A machine-learning model combining DTI-ALPS, FA, MD, and nodal efficiency achieved a cross-validated ROC curve area of 0.83 (sensitivity, 78.2%; specificity, 84.8%). Conclusion Pediatric patients with RE showed impaired glymphatic function in comparison with patients with DSE, which was correlated with WM abnormalities and seizure frequency. Multi-parameter MRI may be feasible for distinguishing RE from DSE.

Objective: To explore glymphatic impairment in pediatric refractory epilepsy (RE) using multi-parameter magnetic resonance imaging (MRI), assess its relationship with white-matter (WM) abnormalities and clinical indicators, and preliminarily evaluate the performance of multi-parameter MRI in discriminating RE from drug-sensitive epilepsy (DSE). Materials and Methods: We retrospectively included 70 patients with DSE (mean age, 9.7 ± 3.5 years; male:female, 37:33) and 26 patients with RE (9.0 ± 2.9 years; male:female, 12:14). The diffusion tensor imaging analysis along the perivascular space (DTI-ALPS) index as well as fractional anisotropy (FA), mean diffusivity (MD), and nodal efficiency values were measured and compared between patients with RE and DSE. With sex and age as covariables, differences in the FA and MD values were analyzed using tract-based spatial statistics, and nodal efficiency was analyzed using a linear model. Pearson’s partial correlation was analyzed. Receiver operating characteristic (ROC) curves were used to evaluate the discrimination performance of the MRI-based machine-learning models through five-fold cross-validation. Results: In the RE group, FA decreased and MD increased in comparison with the corresponding values in the DSE group, and these differences mainly involved the callosum, right and left corona radiata, inferior and superior longitudinal fasciculus, and posterior thalamic radiation (threshold-free cluster enhancement, P < 0.05). The RE group also showed reduced nodal efficiency, which mainly involved the limbic system, default mode network, and visual network (false discovery rate, P < 0.05), and significantly lower DTI-ALPS index (F = 2.0, P = 0.049). The DTI-ALPS index was positively correlated with FA (0.25 ≤ r ≤ 0.32) and nodal efficiency (0.22 ≤ r ≤ 0.37), and was negatively correlated with the MD (-0.24 ≤ r≤ -0.34) and seizure frequency (r = -0.47). A machine-learning model combining DTI-ALPS, FA, MD, and nodal efficiency achieved a cross-validated ROC curve area of 0.83 (sensitivity, 78.2%; specificity, 84.8%). Conclusion Pediatric patients with RE showed impaired glymphatic function in comparison with patients with DSE, which was correlated with WM abnormalities and seizure frequency. Multi-parameter MRI may be feasible for distinguishing RE from DSE.

Acute burns and chronic wounds frequently fail to heal owing to various reasons. Most drugs currently used for wound therapy in clinical practice have notable drawbacks, making their application a substantial concern. For instance, anti-inflammatory drugs can exert multisystem toxicity, and cellular therapies are costly and difficult to retain. In recent years, natural functional proteins derived from animals and plants have gained increasing attention owing to their unique biological activities, low cost, and broad application prospects in wound therapy. Herein, we isolated a new protein (JH015Y) from amphibians and demonstrated its excellent wound repair and regeneration properties compared with those of epidermal growth factor, both in vitro and in vivo. JH015 protein increased the proliferative ability of human keratinocytes and skin fibroblasts by 47.73 and 41.40%, respectively. In vivo, the medium-dose (0.5 mg/dose) groups of JH015Y protein demonstrated accelerated wound healing from day 4, with wound healing rates 1.26, 1.27, and 1.14 times that of the blank group in acute wounds, burn wounds, and diabetic ulcer, respectively. Histological analysis of Masson-stained sections indicated that the JH015Y protein contributed to collagen deposition on the wound surface, markedly reduced inflammatory cell infiltration, and exhibited low biological toxicity. Accordingly, the JH015Y protein is a promising biotherapeutic agent for accelerated wound repair and regeneration.

Schizophrenia (SZ) stands as a severe psychiatric disorder. This study applied diffusion tensor imaging (DTI) data in conjunction with graph neural networks to distinguish SZ patients from normal controls (NCs) and showcases the superior performance of a graph neural network integrating combined fractional anisotropy and fiber number brain network features, achieving an accuracy of 73.79% in distinguishing SZ patients from NCs. Beyond mere discrimination, our study delved deeper into the advantages of utilizing white matter brain network features for identifying SZ patients through interpretable model analysis and gene expression analysis. These analyses uncovered intricate interrelationships between brain imaging markers and genetic biomarkers, providing novel insights into the neuropathological basis of SZ. In summary, our findings underscore the potential of graph neural networks applied to multimodal DTI data for enhancing SZ detection through an integrated analysis of neuroimaging and genetic features.
Humans ; Schizophrenia/pathology* ; Diffusion Tensor Imaging/methods* ; Male ; Female ; Adult ; Brain/metabolism* ; Young Adult ; Middle Aged ; White Matter/pathology* ; Gene Expression ; Nerve Net/diagnostic imaging* ; Graph Neural Networks

OBJECTIVE: To analyze the prevalence and burden of headache disorders in China and its provinces from 1990 to 2021. METHODS: Using data from the Global Burden of Disease Study (GBD) 2021, the number of prevalent cases, prevalence rate, disability-adjusted life years (DALYs), and age-standardized DALY rates were analyzed by sex, age group, and province for headache disorders and their subtypes (migraine and tension-type headache [TTH]) between 1990 and 2021. Percentage changes during this period were also estimated. RESULTS: In 2021, approximately 426 million individuals in China were affected by headache disorders, with an age-standardized prevalence rate of 27,582.61/100,000. The age-standardized DALY rate for all headache disorders was 487.15/100,000. Between 1990 and 2021, the number of prevalent cases increased by 37.78%, while the prevalence of all headache disorders, migraine, and TTH increased by 6.92%, 7.57%, and 7.86%, respectively. The highest prevalence was observed in the 30-34 age group (39,520.60/100,000). Migraine accounted for a larger proportion of DALYs attributable to headache disorders, whereas TTH has a greater impact on its prevalence. In 2021, the highest age-standardized DALY rates for headache disorders were observed in Heilongjiang (617.85/100,000) and Shanghai (542.86/100,000). CONCLUSION The prevalence of headache disorders is increasing in China. Effective health education, improve diagnosis and treatment are essential, particularly for middle-aged working populations and women of childbearing age.
Humans ; China/epidemiology* ; Female ; Male ; Adult ; Middle Aged ; Prevalence ; Young Adult ; Adolescent ; Aged ; Child ; Headache Disorders/epidemiology* ; Disability-Adjusted Life Years ; Child, Preschool ; Cost of Illness ; Infant ; Aged, 80 and over

OBJECTIVE: Humans are exposed to complex mixtures of environmental chemicals and other factors that can affect their health. Analysis of these mixture exposures presents several key challenges for environmental epidemiology and risk assessment, including high dimensionality, correlated exposure, and subtle individual effects. METHODS: We proposed a novel statistical approach, the generalized functional linear model (GFLM), to analyze the health effects of exposure mixtures. GFLM treats the effect of mixture exposures as a smooth function by reordering exposures based on specific mechanisms and capturing internal correlations to provide a meaningful estimation and interpretation. The robustness and efficiency was evaluated under various scenarios through extensive simulation studies. RESULTS: We applied the GFLM to two datasets from the National Health and Nutrition Examination Survey (NHANES). In the first application, we examined the effects of 37 nutrients on BMI (2011-2016 cycles). The GFLM identified a significant mixture effect, with fiber and fat emerging as the nutrients with the greatest negative and positive effects on BMI, respectively. For the second application, we investigated the association between four pre- and perfluoroalkyl substances (PFAS) and gout risk (2007-2018 cycles). Unlike traditional methods, the GFLM indicated no significant association, demonstrating its robustness to multicollinearity. CONCLUSION GFLM framework is a powerful tool for mixture exposure analysis, offering improved handling of correlated exposures and interpretable results. It demonstrates robust performance across various scenarios and real-world applications, advancing our understanding of complex environmental exposures and their health impacts on environmental epidemiology and toxicology.
Humans ; Environmental Exposure/analysis* ; Linear Models ; Nutrition Surveys ; Environmental Pollutants ; Body Mass Index