From the theoretical perspective of "body fluids and blood stasis mixing"， environmental microplastics （MPs） are conceptualized as a "novel turbid-toxin". This study aims to elucidate the complete pathogenic pathway through which MPs act as a key driving force （the "crucible" of pathogenesis） in the initiation and progression of atherosclerosis （AS）. By tracing the classical theories in the Chapter The Occurrence of All Diseases of Miraculous Pivot （Ling Shu）， this paper clarifies the core connotations of "body fluids"-it not only refers to endogenous pathological fluids and lipid turbidity but also provides a theoretical basis for incorporating "exogenous turbid fluids"， thereby laying a logical foundation for conceptualizing MPs as a "novel turbid-toxin". Meanwhile， the implications of "blood" （encompassing both blood quality abnormalities and blood stasis） and the dynamic process of "mixing" are elucidated. Drawing upon modern toxicological evidence， this paper demonstrates the high homology between MPs and "exogenous turbid-fluids" from three aspects： Morphology， toxicity， and invasion routes. The micro/nano-scale particle morphology of MPs enables mobility within the bloodstream. The multiple exposure pathways of MPs correspond to the traditional Chinese medicine understanding of pathogens invading through the mouth， nose， and skin. The characteristics of accumulating in vivo while inducing oxidative stress and inflammatory responses of MPs fully embody the pathogenic features-adhesion， binding， and vessel damage-of "turbid-toxin". On this basis， the dynamic pathogenesis of MP-induced AS is systematically interpreted. Initially， MPs with the "turbid-toxin" nature impair nutrient-defense harmony and cause endothelial dysfunction. Subsequently， as the core of "mixing"， they interact with blood lipids and immune cells， generating heat and phlegm to form a major pathological hub of chronic inflammation. Ultimately， this process drives the coalescence of phlegm， stasis， and turbid-toxin into tangible plaques， evolving from stable lesions to vulnerable masses and accumulations. By integrating classical pathogenic model with contemporary environmental medicine， this study establishes an analytical framework that bridges macro-theory and micro-mechanisms for understanding the cardiovascular risks of MPs through an integrative Chinese-Western medicine lens.

Pancreatic ductal adenocarcinoma （PDAC） has an extremely poor prognosis， and resistance to gemcitabine is one of the key reasons for treatment failure， with an underlying mechanism closely associated with lipid metabolic reprogramming in tumor cells. This article aims to systematically elaborate on the multidimensional drug resistance network constructed by such reprogramming and the feasibility of targeted intervention. Lipid metabolic reprogramming comprehensively remodels the metabolic homeostasis of PDAC cells by enhancing lipid uptake， de novo synthesis， storage， and oxidative catabolism in a synergistic manner. This process alters membrane lipid composition to impede drug influx and promote efflux， thereby reducing intracellular drug concentration. Meanwhile， it activates pathways involving sterol regulatory element-binding protein and peroxisome proliferator-activated receptor δ， couples lipid synthesis with cell survival， stemness， and anti-apoptotic capacity， and synergizes with autophagy to provide survival support through “lipophagy”. In addition， it reshapes the tumor microenvironment through “lipid hijacking” and the secretion of immunosuppressive mediators. Based on the above mechanisms， targeting key lipid metabolic enzymes （such as fatty acid synthase， stearoyl-CoA desaturase， carnitine palmitoyltransferase 1） or their upstream regulators has shown certain potential in reversing such drug resistance in preclinical studies. Although clinical translation faces the challenges such as systemic toxicity， metabolic redundancy in tumors， and patient heterogeneity， the development of biomarkers， intelligent drug delivery systems， and combined therapies may provide new ideas for overcoming drug resistance.

ObjectiveTo investigate the mechanism by which Sini San （SNS） treats liver fibrosis through regulating the polarization of intrahepatic Kupffer cells. MethodsSixty SPF-grade male Balb/c mice were randomized into blank control， model， silymarin （0.2 g·kg^-1）， and low-， medium-， and high-dose （2.93， 5.85， 11.70 g·kg^-1， respectively） SNS groups. A mouse model of liver fibrosis was induced by intraperitoneal injection of CCl₄. After 5 weeks of administration， the body mass， liver pathological changes ［Hematoxylin and Eosin （HE）， Masson， and Sirius red staining］， serum biochemical indicators ［alkaline phosphatase （ALP）， aspartate aminotransferase （AST）， and alanine aminotransferase （ALT）］， liver fibrosis markers ［procollagen type Ⅲ （PCⅢ）， laminin （LN）， and hyaluronic acid （HA）］， inflammatory cytokines ［interleukin-6 （IL-6）， tumor necrosis factor-α （TNF-α）， and interleukin-10 （IL-10）］， and fibrosis-related proteins ［α-smooth muscle actin （α-SMA）， collagen type Ⅰ （Col Ⅰ）， and collagen type Ⅲ （Col Ⅲ）］ were assessed. A co-culture system of THP-1 cells （M1 macrophages） and human hepatic stellate cells （LX-2） was established. The cell experiment was designed with blank control （LX-2 alone）， model （LX-2 + M1 macrophages）， and low-， medium-， and high-dose SNS （co-culture with 5%， 10%， or 20% SNS-containing serum， respectively） groups. Cell viability， inflammatory cytokines， and macrophage phenotype were examined. Human primary hepatic Kupffer cells were allocated into blank control， M1 （LPS 100 μg·L^-1+IFN-γ 20 μg·L^-1）， M2 （IL-4 20 μg·L^-1+IL-13 20 μg·L^-1）， M1+M2， M1+SNS （supplemented with 10% SNS-containing serum for 2 h after culture under M1 conditions for 24 h）， M2+SNS （supplemented with 10% SNS-containing serum for 2 h after culture under M2 conditions for 24 h）， and M1+M2+SNS groups （supplemented with 10% SNS-containing serum for 2 h after culture under M1+M2 conditions for 24 h）， and the expression of nuclear factor-κB （NF-κB） p65 and signal transducer and activator of transcription 3 （STAT3） at protein and mRNA levels was determined. ResultsCompared with the blank group， the model group exhibited increased serum levels of ALT， AST， ALP， PCⅢ， LN， HA， IL-6， and TNF-α， upregulated protein and mRNA levels of α-SMA， Col Ⅰ， and Col Ⅲ in the liver tissue （P<0.05， P<0.01）， and decreased IL-10 level and STAT3 mRNA level （P<0.05， P<0.01）， accompanied by marked collagen deposition and inflammatory infiltration in the liver. Compared with the model group， all doses of Sini San reversed these alterations （P<0.05， P<0.01）， with the high-dose group showing the most pronounced effects. Cell experiments demonstrated that， compared with the blank control group， the model group had elevated levels of pro-inflammatory cytokines （IL-1β， IL-6， and TNF-α） and upregulated protein and mRNA levels of M1 markers ［cluster of differentiation 86 （CD86， inducible nitric oxide synthase （iNOS）， and monocyte chemoattractant protein-1 （MCP-1）］ （P<0.01）， along with declined level of IL-10 and downregulated expression of M2 markers ［（CD163， CD206， and arginase-1 （Arg-1）］ （P<0.05，P<0.01）. Compared with the model group， treatment with Sini San-containing serum at various concentrations lowered the levels of pro-inflammatory cytokines and expression of M1 markers （P<0.05， P<0.01）， while increasing the IL-10 level and M2 marker expression （P<0.05， P<0.01）. Additionally， Sini San downregulated the mRNA level of NF-κB and upregulated the mRNA level of STAT （P<0.05， P<0.01）. In the experiment with human primary Kupffer cells， compared with the blank group， the M1 group showed increased NF-κB p65 expression （P<0.01） and decreased STAT3 expression （P<0.05）， whereas the M2 group exhibited increased STAT3 expression （P<0.01）. Compared with the respective model groups， Sini San-containing serum reversed the M1-induced overexpression of NF-κB p65 （P<0.05， P<0.01） and further enhanced the M2-induced STAT3 expression （P<0.05， P<0.01）. ConclusionSini San can inhibit the NF-κB p65/STAT3 signaling pathway and repolarize intrahepatic Kupffer cells from the pro-inflammatory M1 to the anti-inflammatory M2 phenotype to attenuate inflammation and suppress hepatic stellate cell activation and collagen deposition， thereby exerting anti-fibrotic effect.

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: 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

Objective:To investigate the clinical efficacy and safety of ultrasonic bone scalpel in nasal osteotomy.Methods:A retrospective analysis was conducted on clinical data from the patients who received ultrasonic bone scalpel-assisted nasal osteotomy in the Nasal Plastic & Reconstructive Surgery Department, Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College between January 2023 and April 2024. All patients underwent open lateral approach osteotomy using an ultrasonic bone scalpel under direct vision, combined with augmentation rhinoplasty using autologous costal cartilage grafting. Intraoperatively, the nasal dorsum was fully exposed, and the lateral nasal cartilage was separated from the nasal septum, followed by precise bone tissue incision using the ultrasonic bone scalpel. Parameters recorded included operative time, and postoperative complications. Based on the standardized photographs taken before the operation and during the 6-month follow-up after the operation, the observer global aesthetic improvement scale (GAIS) was evaluated by a third-party doctor, with a score ranging from 1 to 5. The smaller the score, the more significant the improvement compared to before the operation. The satisfaction of patients with the surgical outcome was evaluated and classified into four levels: very satisfied, satisfied, dissatisfied, and very dissatisfied.Results:A total of 25 female patients were enrolled, aged 20 to 38 years, with an average age of 27.1 years. All procedures were completed successfully, with a mean operative time of (25.4±4.2) minutes. Postoperative localized swelling of varying degrees was observed. Follow-up ranged from 6 to 18 months, with nasal contour and curvature stabilizing by 6 months postoperatively. No complications, such as infection, nasolacrimal duct, lacrimal sac, medial canthal ligament, nerve injuries, or sensory disturbances, were reported. Two cases exhibited mild nasal bone widening at the 6-month follow-up, though no surgical revision was requested. Significant improvement in external nasal morphology was achieved in all patients, with high satisfaction rates. The patients satisfaction survey showed that 18 cases (72%) were very satisfied and 7 cases (28%) were satisfied with the surgical outcome. GAIS scores reflected positive evaluations [(1.24±0.51) points].Conclusion:The ultrasonic bone scalpel for nasal osteotomy offers the advantages of high-precision cutting and efficient hemostasis. It is highly effective in reshaping the nasal contour, with shorter osteotomy time, reduced intraoperative bleeding, and a lower postoperative complication rate. This study provides some insights into plastic surgeons in optimizing nasal bone modification strategies.

OBJECTIVE: To establish foot and ankle models of different lateral collateral ligament injuries of ankle joint, and conduct finite element analysis on, and to explore the force conditions of subtalar articular cartilage during foot inversion movements under different gait stages and under different loads. METHODS: A normal ankle CT scan of a 30-year-old male healthy volunteer (heighted 175 cm and weighted 60 kg) was selected. The CT images were imported into software such as Mimics 21.0, Geomajic 2017, and Solidworks 2017 respectively, extract the normal ankle bone model. Then, the foot and ankle finite element models of different lateral collateral ligament injuries of ankle joint were constructed and divided into anterior talofibular ligament(ATFL) rupture group, ATFL and calcaneo fibular ligament (CFL) rupture group, ATFL, CFL and posterior talofibular ligament (PTFL) rupture group, and control group with intact ligament function by ANSYS 2021. Corresponding horizontal and vertical loads and torques were applied respectively on tibia and talus according to the force conditions of different phases to simulate landing phase, neutral and off-ground phase in walking gait. The changes in stress distribution area and stress peak of subtalar articular cartilage in the loading phase, neutral phase and off-ground phase gaits among four groups were observed. Simulate varus sprain action, apply different loads of 600, 1, 800, and 4, 200 N respectively, and changes in stress distribution area and the stress peak of subtalar articular cartilage among four groups of models were observed. RESULTS: In the gait simulation, the stress results of loading phase in ATFL fracture group, ATFL and CFL fracture groups, ATFL, CFL and PTFL fracture groups, and control group were 0.889 54, 0.960 89, 1.139 20, and 0.722 64 MPa, respectively. The neutral response force results were 1.250 60, 1.358 50, 1.363 70, 1.246 40 MPa respectively;the results of corresponding forces off-ground phase were 1.029 90, 1.138 70, 1.145 90 and 0.832 40 MPa respectively. In the inversion simulation, the stresses of ATFL fracture group, ATFL and CFL fracture groups, ATFL, CFL and PTFL fracture groups, and control group under load of 600 N were 2.191 3, 2.208 5, 2.215 7, and 2.156 6 MPa respectively. The stresses under a load of 1 800 N were 7.134 7, 9.715 2, 10.064 0, and 7.107 0 MPa respectively;the stresses under a load of 4 200 N were 17.435 0, 25.309 0, 26.119 0 and 16.010 0 MPa respectively. CONCLUSION The lateral collateral ligament of ankle joint plays an important role in the stability of the subtalar joint, especially CFL plays an important role in restricting calcaneal varus. If these ligaments are damaged, it will cause instability of the subtalar joint and further lead to lesions in the subtalar articular cartilage. Relevant exercises should be reduced or the ligament injuries should be treated in a timely manner.
Humans ; Finite Element Analysis ; Male ; Adult ; Cartilage, Articular/physiopathology* ; Ankle Injuries/physiopathology* ; Ankle Joint/physiopathology* ; Biomechanical Phenomena ; Subtalar Joint/injuries* ; Tomography, X-Ray Computed

OBJECTIVE: To explore the clinical efficacy and safety of the "Three-Step Nine-Method Lumbar Correction" combined with physical therapy in the treatment of patients with degenerative lumbar spondylolisthesis(DLS). METHODS: From January 2021 to December 2021, 72 patients diagnosed with DLS were enrolled and divided into the Three-Step Nine-Method Lumbar Correction group and the pelvic traction group, with 36 cases in each group. In the Three-Step Nine-Method Lumbar Correction group, there were 15 males and 21 females;aged 54 to 66 years old, with an average of (59.07±5.69) years old;the course of disease was 14 to 26 years old, with an average of (20.35±5.66) years old. They were treated with the Three-Step Nine-Method Lumbar Correction combined with low-frequency physical therapy, 3 times a week, for a 4-week course. In the pelvic traction group, there were 12 males and 24 females;aged 54 to 66 years old, with an average of (59.69±5.59) years old;the course of disease was 13 to 26 years old, with an average of (19.74±5.80) years old. They were treated with pelvic traction combined with low-frequency physical therapy. Efficacy evaluation was conducted using the visual analogue scale(VAS), Oswestry disability index(ODI), Japanese Orthopaedic Association (JOA) score, and Short Form 36 Health Survey (SF-36) before treatment, after 2 and 4 weeks of treatment, and at the 8-week follow-up after the end of treatment. In addition, imaging parameters of paravertebral muscles were evaluated before treatment and at the completion of treatment. RESULTS: All 72 patients completed the follow-up for 8 weeks. At the 8-week follow-up after the end of treatment, in the Three-Step Nine-Method Lumbar Correction group, the VAS score for low back pain decreased from (6.25±1.23) points before treatment to (1.25±0.65) points, with a statistically significant difference (P<0.05);the ODI decreased from (57.17±7.13)% before treatment to (19.89±5.66)%, with a statistically significant difference (P<0.05);the JOA score and SF-36 score increased from (15.46±3.20) points and (35.25±9.28) points before treatment to (23.75±2.10) points and (62.31±13.03) points, respectively, with statistically significant differences (P<0.05). The improvement of each index in the Three-Step Nine-Method Lumbar Correction group was better than that in the pelvic traction group (P<0.05), but the change in imaging parameters was not significant (P>0.05). There was no statistically significant difference in the incidence of adverse reactions between the two groups (P>0.05), and no serious adverse events occurred. CONCLUSION The Three-Step Nine-Method Lumbar Correction combined with physical therapy has a definite efficacy in the treatment of DLS. It can significantly relieve pain symptoms, improve physical function and patients' quality of life. Its effect is better than that of pelvic traction combined with physical therapy, and it has high safety. However, its improvement on paravertebral muscles is not obvious.
Humans ; Male ; Female ; Middle Aged ; Spondylolisthesis/physiopathology* ; Aged ; Prospective Studies ; Lumbar Vertebrae/physiopathology* ; Physical Therapy Modalities ; Adult

OBJECTIVES: To study the differences in clinical characteristics of term and preterm neonates with necrotizing enterocolitis (NEC) undergoing surgical treatment. METHODS: A retrospective analysis was conducted on the clinical data of 142 NEC neonates who underwent surgery at the Children's Hospital of Chongqing Medical University from June 2017 to August 2023. The neonates were categorized into a preterm group (gestational age <37 weeks; 95 cases) and a term group (gestational age 37-42 weeks; 47 cases) to compare clinical characteristics. RESULTS: The preterm group had a higher postnatal age at both diagnosis and surgery compared to the term group (P<0.05). The preterm group also had a higher incidence of preoperative bloody stools, lower preoperative platelet counts, and higher rates of preoperative respiratory distress, apnea, reduced/absent bowel sounds, and mechanical ventilation compared to the term group (P<0.05). Postoperatively, the preterm group had higher rates of purulent meningitis, sepsis, and coagulation dysfunction, lower postoperative platelet counts, and lower intraoperative minimum body temperature than the term group (P<0.05). CONCLUSIONS There are significant differences in the clinical characteristics of preterm and term neonates with NEC undergoing surgery, suggesting the need for tailored perioperative management strategies based on these characteristics.
Humans ; Enterocolitis, Necrotizing/surgery* ; Infant, Newborn ; Retrospective Studies ; Male ; Female ; Infant, Premature ; Gestational Age

OBJECTIVES: To investigate the role and mechanism of Brahma-related gene 1 (Brg1) in regulating the Wnt/β-catenin signaling pathway in a bronchopulmonary dysplasia (BPD) model. METHODS: Wild-type C57BL/6 and Brg1^f1/f1 mice were randomly divided into four groups: wild-type control, wild-type BPD, Brg1^f1/f1 control, and Brg1^f1/f1 BPD (n=5 each). Immortalized mouse pulmonary alveolar type 2 cells (imPAC2) were cultured, and Brg1 gene was knocked down using lentivirus transfection technology. Cells were divided into three groups: control, empty vector, and Brg1 knockdown. Hematoxylin and eosin staining and immunofluorescence were used to detect pathological changes in mouse lung tissue. Western blot and real-time fluorescent quantitative PCR were used to measure Brg1 protein and mRNA expression levels in mouse lung tissue. Western blot and immunofluorescence were used to detect the expression of homeodomain-containing protein homeobox (HOPX), surfactant protein C (SPC), and Wnt/β-catenin signaling pathway proteins in mouse lung tissue and imPAC2 cells. The CCK8 assay was used to assess the proliferation of imPAC2 cells, and co-immunoprecipitation was performed to verify the interaction between Brg1 and β-catenin proteins in imPAC2 cells. RESULTS: Compared to the Brg1^f1/f1 control group and wild-type BPD group, the Brg1^f1/f1 BPD group showed increased alveolar diameter and SPC protein expression, and decreased relative density of pulmonary vasculature and HOPX protein expression (P<0.05). Compared to the control group, the Brg1 knockdown group showed increased cell proliferation ability, protein expression levels of SPC, Wnt5a and β-catenin, and β-catenin protein fluorescence intensity, along with decreased HOPX protein expression (P<0.05). An interaction between Brg1 and β-catenin proteins was confirmed. CONCLUSIONS The Brg1 gene may promote the proliferation of alveolar type 2 epithelial cells by regulating the Wnt/β-catenin signaling pathway, thus influencing the occurrence and development of BPD.
Animals ; DNA Helicases/genetics* ; Transcription Factors/genetics* ; Wnt Signaling Pathway/physiology* ; Nuclear Proteins/genetics* ; Mice ; Bronchopulmonary Dysplasia/etiology* ; Mice, Inbred C57BL ; beta Catenin/physiology* ; Disease Models, Animal ; Cell Proliferation ; Lung/pathology* ; Male