OBJECTIVE: To explore the genetic etiology of 46 Chinese pedigrees affected with Hereditary multiple exostoses (HME) and provide genetic counseling and reproductive intervention. METHODS: Whole-exome sequencing and Sanger sequencing were carried out on 87 patients from the 46 pedigrees to analyze the variants of EXT1 and EXT2 genes. Pathogenicity of the variants was assessed based on the guidelines from the American College of Medical Genetics and Genomics and Association for Molecular Pathology (ACMG/AMP). Prenatal diagnosis and preimplantation genetic testing (PGT) were provided for couples with identified pathogenic mutations. This study was approved by the Medical Ethics Committee of the hospital (Ethics No.: LL-SC-SG-2014-010). RESULTS: In total 17 and 22 pathogenic variants were respectively identified in the EXT1 and EXT2 genes, among which 5 EXT1 and 12 EXT2 variants were unreported previously. Three patients with no family history were found to harbor de novo variants of the EXT1 gene. Twenty nine couples had opted for PGT or underwent prenatal diagnosis following natural conception, and 17 healthy babies were born. CONCLUSION This study has clarified the genetic etiology of 45 HME pedigrees and identified 17 novel variants, which has enriched the mutational spectrum of the EXT1 and EXT2 genes. Reproductive intervention through PGT and prenatal diagnosis have prevented the recurrence of HME in these families.
Humans ; Female ; Male ; Pedigree ; Exostoses, Multiple Hereditary/diagnosis* ; N-Acetylglucosaminyltransferases/genetics* ; Adult ; Exostosin 1 ; Asian People/genetics* ; Genetic Testing ; Exostosin 2 ; Mutation ; China ; Prenatal Diagnosis ; Pregnancy ; Genetic Counseling ; Preimplantation Diagnosis ; Exome Sequencing ; East Asian People

Diabetic retinopathy (DR) is one of the most prevalent and vision-threatening microvascular complications of diabetes mellitus, yet its pathogenesis extends far beyond vascular injury alone. As the retina is among the most energy-demanding tissues in the body, its neurons, glial cells, pigment epithelial cells, pericytes, and endothelial cells are highly dependent on mitochondrial oxidative phosphorylation to maintain visual signal transduction, ionic homeostasis, and neurovascular integrity. This review summarizes current evidence indicating that mitochondrial dysfunction is not merely a downstream consequence of chronic hyperglycemia, but a central pathogenic hub that initiates, amplifies, and perpetuates retinal neurovascular degeneration in DR. Persistent hyperglycemia activates multiple abnormal metabolic pathways, including the polyol pathway, hexosamine pathway, protein kinase C signaling, advanced glycation end-product formation, and angiotensin II-related responses. Although these pathways differ mechanistically, they converge on excessive reactive oxygen species (ROS) generation, antioxidant depletion, and mitochondrial injury. Under diabetic stress, electron transport chain overload promotes mitochondrial ROS leakage, damages mitochondrial DNA, disrupts membrane potential, and impairs the transcription of key respiratory chain components. In parallel, mitochondrial quality-control systems become progressively compromised. The balance between fusion and fission shifts toward pathological fragmentation through reduced MFN1/2 and OPA1 activity and enhanced DRP1-mediated fission. Mitochondrial biogenesis is suppressed through inhibition of the AMPK/SIRT1/PGC-1α/NRF1/TFAM axis, while mitophagy changes from an early compensatory response to a later state of autophagic flux blockade and accumulation of dysfunctional mitochondria. Importantly, damaged mitochondria serve as signal amplifiers linking metabolic stress to inflammation and programmed cell death. Mitochondrial ROS, oxidized mitochondrial DNA, calcium overload, cardiolipin exposure, and membrane permeabilization activate interrelated death pathways, including intrinsic apoptosis, ferroptosis, and pyroptosis. Cytochrome C and apoptosis-inducing factor promote caspase-dependent and caspase-independent apoptosis; iron dyshomeostasis, glutathione depletion, GPX4 dysfunction, and lipid peroxidation drive ferroptosis; and mitochondrial danger signals activate the NLRP3 inflammasome and gasdermin-dependent pyroptosis. These pathways jointly damage the retinal neurovascular unit and contribute to pericyte loss, endothelial barrier breakdown, Müller cell dysfunction, retinal ganglion cell apoptosis, retinal pigment epithelial injury, and photoreceptor degeneration. This review also emphasizes the role of epigenetic regulation in stabilizing mitochondrial pathology. DNA methylation, histone modifications, and non-coding RNAs interact to silence mitochondrial protective genes, alter antioxidant responses, and maintain the “metabolic memory” of DR even after glycemic normalization. Therefore, mitochondrial dysfunction should be understood as a dynamic, multidimensional network rather than a single pathological event. Current clinical approaches, such as laser photocoagulation, intravitreal anti-VEGF therapy, and vitrectomy, mainly target advanced vascular lesions and are limited by invasiveness, incomplete responsiveness, recurrence, and potential adverse effects. Therapeutically, strategies targeting mitochondrial ROS, restoring mitochondrial dynamics, enhancing biogenesis, regulating mitophagy, inhibiting inflammasome activation, correcting epigenetic abnormalities, and improving targeted delivery systems show promising potential. However, major translational barriers remain, including retinal cell heterogeneity, stage-specific mitochondrial responses, insufficient organelle-specific drug delivery, and long-term safety concerns. A deeper understanding of mitochondrial regulatory networks may support earlier, more precise, and multi-target interventions for preventing or slowing DR progression.

Neuraxial opioids, widely used in obstetric and perioperative pain management, often lead to unwanted itch, reducing patient satisfaction. While the μ-opioid receptor has been implicated in opioid-induced itch, the genetic basis for variable itch incidence remains unknown. This study examined 3616 patients receiving epidural opioids, revealing an itch occurrence of 26.55%, with variations among opioid types and gender. Analysis of the OPRM1 gene identified six single-nucleotide polymorphisms, notably rs1799971 (A118G), that correlated with opioid-induced itch. Mouse models with an equivalent A112G mutation showed reduced neuraxial opioid-induced itch and light touch-evoked itch, mirroring human findings. The 118G allele demonstrated an anti-itch effect without impacting analgesia, addiction, or tolerance, offering insights for risk stratification and potential anti-itch pretreatment strategies.
Receptors, Opioid, mu/genetics* ; Pruritus/chemically induced* ; Humans ; Analgesics, Opioid/administration & dosage* ; Female ; Male ; Animals ; Polymorphism, Single Nucleotide/genetics* ; Adult ; Mice ; Middle Aged

OBJECTIVE: EPF3 is a fibrinolysin monomer isolated and purified from Pheretima vulgaris Chen, an earthworm used in traditional Chinese medicine as Dilong for treating blood stasis syndrome. Its composition, anticoagulant and fibrinolytic activities, and relevant mechanisms have been confirmed through in vitro experiments. However, whether it has antithrombotic effects in vivo and can be absorbed by the gastrointestinal tract is unknown. This study evaluates the antithrombotic effect in zebrafish and investigates the gastrointestinal stability and intestinal absorption mechanism of this protein in vitro. METHODS: The antithrombotic effect of EPF3 in vivo was verified using the zebrafish thrombus model induced by arachidonic acid and FeCl₃. Then, the protein bands of EPF3 incubated with simulated gastric fluid (SGF), simulated intestinal fluid (SIF), and homogenate of Caco-2 cells (HC2C) were analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis to evaluate its gastrointestinal stability. Finally, the transport behavior and absorption mechanism of EPF3 were studied using Caco-2 cell monolayer. RESULTS: EPF3 could significantly enhance the returned blood volume and blood flow velocity in zebrafish with platelet aggregation thrombus induced by arachidonic acid. It could also prolong the formation time of tail artery thrombus and increase the blood flow velocity in zebrafish with vessel injury thrombus induced by FeCl₃. EPF3 was stable in SIF and HC2C and unstable in SGF. The permeability of EPF3 in Caco-2 monolayer was time-dependent and concentration-dependent. The efflux ratio was less than 1.2 during transport, and the transport behavior was not affected by inhibitors. EPF3 could reversibly reduce the expression of tight junction-related proteins, including zonula occludens-1, occludin, and claudin-1 in Caco-2 cells. CONCLUSION EPF3 could play a thrombolytic and antithrombotic role in zebrafish. It could be transported and absorbed into the intestine through cellular bypass pathway by opening the intestinal epithelium tight junction. This study provides a scientific explanation for the antithrombotic effect of earthworm and provides a basis for the feasibility of subsequent development of EPF3 as an antithrombotic enteric-soluble preparation. Please cite this article as: Zhong WL, Yang JQ, Liu H, Wu YL, Shen HJ, Li PY, Du SY. Antithrombotic effect in zebrafish of a fibrinolytic protein EPF3 from Dilong (Pheretima vulgaris Chen) and its transport mechanism in Caco-2 monolayer through cell bypass pathway. J Integr Med. 2025; 23(4): 415-428.
Animals ; Zebrafish ; Humans ; Caco-2 Cells ; Fibrinolytic Agents/pharmacology* ; Thrombosis/drug therapy* ; Intestinal Absorption

In February 2025, a local cluster outbreak caused by the D8 genotype Measles virus (MV) was first discovered in Henan Province. Epidemiological investigations and laboratory testing were conducted, including the collection of serum and throat swabs for MV IgM antibody and nucleic acid detection, virus isolation and genetic homology analysis. Measures such as close contact tracing, vaccination rate assessment and supplementary immunization activities were implemented, successfully preventing broader community transmission. A total of three cases were reported during the outbreak, including one imported-related adolescent and two secondary local adult cases. All cases presented with typical symptoms such as fever and rash. Both adult cases were complicated by pneumonia, with one case developing into severe pneumonia. MV genotyping showed that the two secondary cases were both the D8 genotype, with the viral sequences being completely homologous to the Kazakhstan strain. Among the close contacts, 98.2% were adults, and 142 individuals received emergency vaccination.

Objective To explore the changes of durability properties of reusable surgical gowns when used in dry and wet conditions.Methods Reusable surgical gowns made of single-layer polyester fiber or 3-layer composite material were selected as test samples,and a Martindale abrasion and pilling tester was used as the basic test platform and modified to form fixtures suitable for the wet state environment.The reusable surgical gowns underwent abrasion experiments in wet and dry conditions to observe the changes in their fiber structure,and were subjected to water penetration resistance and swelling strength tests.Results Visually the reusable surgical gowns had few changes of the microscopic textile fiber structure in dry and wet conditions,and the gowns made of single-layer polyster fiber gained advantages over the outer layers of those of 3-layer composite material in abrasion resistance with the same friction cycles.In dry and wet conditions,the hydrostatic pressure values of the gowns of single-layer polyster fiber gradually decreased with the increase of the degree of abrasion,which were always lower than those of the gowns of 3-layer composite material;the swelling strength of the gowns of single-layer polyster fiber was always greater than that of the gowns of 3-layer composite material,which decreased with the deterioration of the wear more significantly than that of the gowns of 3-layer composite material.Conclusion The reusable surgical gowns made of single-layer polyester fiber or 3-layer composite material have few differences in durability and protective properties at the early stages of ablation in dry and wet conditions.The durability of the gowns decreases as the degree of wear increases,while the trend of the decrease is slowing down until the fabric breaks down and completely loses its barrier effect.[Chinese Medical Equipment Journal,2025,46(6):28-33]

Objective:To analyze the correlation between serum uric acid-to-high-density lipoprotein cholesterol ratio (UHR) and risk of all-cause death or cardiovascular disease (CVD) death among urban and rural elderly in Beijing.Methods:Based on the Beijing Healthy Aging Cohort Study, 9 022 participants with complete baseline data were enrolled, and their survival and death outcomes were followed up. Multivariable Cox proportional hazard regression model were used to analyze the associations between the UHR level and the risks of all-cause mortality and CVD mortality.Results:As of March 31, 2021, the median follow-up time M( Q1, Q3) was 6.18 (5.36, 6.75) years. There were 1 166 all-deaths, with a death density of 19.26 per 1 000 person-years, and 562 CVD deaths, with a death density of 9.28 per 1 000 person-years. After adjusting sociodemographic characteristics and lifestyle factors, multivariable Cox proportional hazard regression model showed that the risk of all-cause mortality increased by 3% ( HR=1.03, 95% CI: 1.02-1.04) and the risk of CVD mortality increased by 4% ( HR=1.04, 95% CI: 1.02-1.06) for every 1% increase in UHR. Compared with the T1 group of UHR tertiles, the T3 group had a 42% increase in the risk of all-cause death ( HR=1.42, 95% CI: 1.22-1.66) and a 53% increase in the risk of CVD death ( HR=1.53, 95% CI: 1.21-1.94). Conclusions:The UHR level is significantly associated with the risks of all-cause mortality and CVD mortality among urban and rural older adults in Beijing. The UHR level may be one of the potential predictors of death risk in community-dwelling older adults.

Objective:To analyze the correlation between serum uric acid-to-high-density lipoprotein cholesterol ratio (UHR) and risk of all-cause death or cardiovascular disease (CVD) death among urban and rural elderly in Beijing.Methods:Based on the Beijing Healthy Aging Cohort Study, 9 022 participants with complete baseline data were enrolled, and their survival and death outcomes were followed up. Multivariable Cox proportional hazard regression model were used to analyze the associations between the UHR level and the risks of all-cause mortality and CVD mortality.Results:As of March 31, 2021, the median follow-up time M( Q1, Q3) was 6.18 (5.36, 6.75) years. There were 1 166 all-deaths, with a death density of 19.26 per 1 000 person-years, and 562 CVD deaths, with a death density of 9.28 per 1 000 person-years. After adjusting sociodemographic characteristics and lifestyle factors, multivariable Cox proportional hazard regression model showed that the risk of all-cause mortality increased by 3% ( HR=1.03, 95% CI: 1.02-1.04) and the risk of CVD mortality increased by 4% ( HR=1.04, 95% CI: 1.02-1.06) for every 1% increase in UHR. Compared with the T1 group of UHR tertiles, the T3 group had a 42% increase in the risk of all-cause death ( HR=1.42, 95% CI: 1.22-1.66) and a 53% increase in the risk of CVD death ( HR=1.53, 95% CI: 1.21-1.94). Conclusions:The UHR level is significantly associated with the risks of all-cause mortality and CVD mortality among urban and rural older adults in Beijing. The UHR level may be one of the potential predictors of death risk in community-dwelling older adults.

Objective:To construct a questionnaire to measure parents′ behavioral and social drivers (BeSD) in administering rotavirus vaccine to their children, and to test the reliability and validity of the questionnaire.Methods:A questionnaire was constructed to investigate the BeSD of rotavirus vaccination among parents based on the WHO BeSD questionnaire. A survey was conducted among parents of children aged 0-3 years old in vaccination clinics from 15 community health service centers in Nanjing City of Jiangsu Province, Yuhuan and Kaihua Counties of Zhejiang Province, Anqing City of Anhui Province, and Yangpu District of Shanghai City from April to May in 2024. Exploratory factor analysis (EFA) and confirmatory factor analysis (CFA) were used to analyze the reliability (internal consistency reliability, combination reliability and split half reliability) and validity (structural validity, convergence validity and discriminative validity) of the questionnaire.Results:A total of 850 questionnaires were collected, of which 614 were valid, with an effective response rate of 72.20%. The EFA resulted in the refinement of the rotavirus vaccine BeSD questionnaire from 37 to 35 items (including 24 core items), and suggested a five-factor structure including the perceptions of vaccine, confidence in vaccine, social process of vaccination, motivation for vaccination, and practical problems of vaccination. The cumulative variance contribution rate reached 56.27%. The CFA confirmed an ideal five-factor model fit (GFI=0.82,CFI=0.86,PNFI=0.67,RMSEA=0.07). The AVE of each dimension was greater than 0.50. The AVE square root of each dimension of the questionnaire was greater than its correlation coefficient. The Cronbach′s α coefficient of the total questionnaire was 0.79.Conclusion:The developed BeSD questionnaire of rotavirus vaccine has good reliability and validity, and can be used to measure parents′ behavioral and social factors in administering rotavirus vaccine to their children.

Objective:To explore the value of neutrophil extracellular traps (NETs) and interleukin (IL)-33 in the early diagnosis of contrast-induced acute kidney injury (CIAKI).Methods:It was a prospective cohort study. The clinical data of patients who underwent coronary angiography (CAG) in Sir Run Run Hospital, Nanjing Medical University from December 2022 to December 2023 were collected. The main indicators of NETs included myeloperoxidase (MPO), neutrophil elastase (NE), citrullinated histone H3 (H3Cit) and antimicrobial peptide LL-37 amide (LL-37). Serum samples were collected before CAG, and 2 hours and 12 hours after CAG, and the levels of MPO, NE, H3Cit, LL-37, IL-33 and neutrophil gelatinase-associated lipocalin (NGAL) were detected. The differences of clinical data between CIAKI group and non-CIAKI group were compared. Multivariate logistic regression model was applied to analyze the risk factors of CIAKI. The receiver- operating characteristic curve was used to evaluate the predictive performance of biomarkers. Spearman correlation analysis was used to analyze the correlations among those biomarkers.Results:A total of 280 eligible patients with CAG were included in this study, with age of (65±13) years and 203 males (72.5%). The incidence rate of CIAKI was 11.8% (33/280). Compared with non-CIAKI group, the proportions of diabetes ( χ2=5.302, P=0.021), preoperative positive urine protein ( χ2=6.871, P=0.009), taking beta-blockers ( χ2=4.580, P=0.032), diuretics ( χ2=21.987, P<0.001) and calcium channel blocker ( χ2=10.424, P=0.001), preoperative blood glucose ( Z=2.807, P=0.005), preoperative blood urea nitrogen ( Z=2.504, P=0.012), neutrophil at 24 hours after CAG ( Z=2.173, P=0.030), serum creatinine at 24 hours after CAG ( Z=4.000, P<0.001), and blood urea nitrogen at 24 hours after CAG ( Z=4.459, P<0.001) were higher, while the preoperative hemoglobin ( Z=-2.380, P=0.017) and serum albumin ( Z=-2.556, P=0.011) were lower in CIAKI group. Multivariate logistic regression analysis showed that increasing neutrophil at 24 hours after CAG ( OR=1.180，95% CI 1.037-1.341), diuretics ( OR=5.615，95% CI 2.294-13.745) and calcium channel blockers ( OR=3.141，95% CI 1.374-7.182) were independent influencing factors of CIAKI. There were statistically significant differences in the levels of serum NE, MPO, H3Cit, LL-37, NGAL and IL-33 among before CAG, 2 hours after CAG and 12 hours after CAG in the overall population, CIAKI group and non-CIAKI group (all P<0.05). In addition, the changes of IL-33 before CAG and 12 hours after CAG was positively correlated with the changes of MPO, NE, H3Cit, LL-37, NGAL, serum creatinine and blood urea nitrogen before CAG and 12 hours after CAG (all P<0.05). The levels of NE ( Z=3.435, P=0.001; Z=6.164， P<0.001), MPO ( Z=3.627, P<0.001; Z=4.729, P<0.001), H3Cit ( Z=5.174, P<0.001; Z=6.241, P<0.001), LL-37 ( Z=4.986, P<0.001; Z=6.346, P<0.001), NGAL ( Z=2.956, P=0.003; Z=4.263, P<0.001) and IL-33 ( Z=5.056, P<0.001; Z=6.240, P<0.001) in CIAKI group at 2 h and 12 h after CAG were significantly higher than those in non-CIAKI group. The receiver-operating characteristic curve indicated that the combined AUC of neutrophil 24 hours after CAG, diuretics and calcium channel blockers in predicting CIAKI was 0.791. NE ( AUC=0.701), MPO ( AUC=0.712), H3Cit ( AUC=0.777), LL-37 ( AUC=0.767) and IL-33 ( AUC=0.795) at 2 hours after CAG predicted CIAKI relatively well. NE ( AUC=0.865), MPO ( AUC=0.758), H3Cit ( AUC=0.834), LL-37 ( AUC=0.840) and IL-33 ( AUC=0.867) at 12 hours after CAG had better prediction effect for CIAKI. The AUC of NETs combined with IL-33 in predicting CIAKI at 2 hours and 12 hours after CAG was 0.874 and 0.956, respectively. Conclusions:CIAKI patients exhibit elevated levels of NETs and IL-33. Serum MPO, NE, H3Cit, LL-37 and IL-33 at 12 hours after CAG can predict the occurrence of CIAKI. The combination of NETs and IL-33 is more effective in predicting CIAKI.