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.

[Objective] To retrospectively analyze the detection results of alanine aminotransferase (ALT) unqualified repeat blood donors in Guangzhou, so as to provide evidence for further expanding the repeat blood donor pool, reducing the rate of blood discarding and improving the qualified rate of blood test. [Methods] Blood donors with unqualified ALT in Guangzhou Blood Center from January 2018 to April 2024 were selected as the research objects. The past blood donation and population characteristics were analyzed according to the number of blood donations and ALT unqualified times. [Results] Among repeat blood donors with previous ALT disqualification, 99.5% to 99.7% did not have reactive markers for transfusion-transmitted diseases (TTD), which was higher than the rate among first-time blood donors with unqualified ALT (95.8%) (P<0.05). The rate of single-item ALT disqualification in repeat blood donors was higher in males than in females (P<0.05); it also varied by age (18-25 years > 26-35 years > 36-45 years > over 45 years) (P<0.05); and by quarter (third and fourth quarters > first and second quarters) (P<0.05). The ALT unqualified rate was significantly higher whole blood donors than that of platelet donors and returning blood donors (P<0.05). The overall ALT level (51.0 U/L), individual ALT level (56.0 U/L) and individual ALT unqualified rate (66.7%) of repeat blood donors with multiple ALT disqualifications were higher than those of repeat blood donors with single-item ALT disqualifications (26.0 U/L, 38.5 U/L, and 33.3%, respectively) (P<0.05). Moreover, as the number of ALT disqualifications increased, the overall level of ALT in repeat blood donors also increased (P<0.05), and the average level of individual ALT and individual ALT unqualified ratio tended to increase. Repeat blood donors with frequent ALT disqualifications had higher ALT levels (69.0 U/L). [Conclusion] The ALT unqualified rates of repeat blood donors were mostly non-specific elevation without TTD. Repeat blood donors with multiple ALT disqualifications tend to have continuous high ALT. Moreover, and with the increase of ALT disqualifications times, the overall ALT levels the average individual ALT levels and individual ALT unqualified rates showed an increasing trend.

OBJECTIVES: To evaluate the efficacy of molecular targeted agents in children with progressive pediatric low-grade gliomas (pLGG). METHODS: A retrospective analysis was conducted on pLGG patients treated with oral targeted therapies at the Department of Pediatrics, Beijing Shijitan Hospital, Capital Medical University, from July 2021. Treatment responses and safety profiles were assessed. RESULTS: Among the 20 enrolled patients, the trametinib group (n=12, including 11 cases with BRAF fusions and 1 case with BRAF V600E mutation) demonstrated 4 partial responses (33%) and 2 minor responses (17%), with a median time to response of 3.0 months. In the vemurafenib group (n=6, all with BRAF V600E mutation), 5 patients achieved partial responses (83%), showing a median time to response of 1.0 month. Comparative analysis revealed no statistically significant difference in progression-free survival rates between the two treatment groups (P>0.05). The median duration of clinical benefit (defined as partial response + minor response + stable disease) was 11.0 months for vemurafenib and 18.0 months for trametinib. Two additional cases, one with ATM mutation treated with olaparib for 24 months and one with NF1 mutation receiving everolimus for 21 months, discontinued treatment due to sustained disease stability. No severe adverse events were observed in any treatment group. CONCLUSIONS Molecular targeted therapy demonstrates clinical efficacy with favorable tolerability in pLGG. Vemurafenib achieves high response rates and induces early tumor shrinkage in patients with BRAF V600E mutations, supporting its utility as a first-line therapy.
Humans ; Glioma/genetics* ; Male ; Female ; Child ; Child, Preschool ; Retrospective Studies ; Brain Neoplasms/genetics* ; Molecular Targeted Therapy/adverse effects* ; Adolescent ; Infant ; Proto-Oncogene Proteins B-raf/genetics* ; Pyrimidinones/therapeutic use* ; Mutation

Debates persist regarding the efficacy and safety of azvudine, particularly its real-world outcomes. This study involved patients aged ≥60 years who were admitted to 25 hospitals in mainland China with confirmed SARS-CoV-2 infection between December 1, 2022, and February 28, 2023. Efficacy outcomes were all-cause mortality during hospitalization, the proportion of patients discharged with recovery, time to nucleic acid-negative conversion (T _NANC), time to symptom improvement (T _SI), and time of hospital stay (T _HS). Safety was also assessed. Among the 5884 participants identified, 1999 received azvudine, and 1999 matched controls were included after exclusion and propensity score matching. Azvudine recipients exhibited lower all-cause mortality compared with controls in the overall population (13.3% vs. 17.1%, RR, 0.78; 95% CI, 0.67-0.90; P = 0.001) and in the severe subgroup (25.7% vs. 33.7%; RR, 0.76; 95% CI, 0.66-0.88; P < 0.001). A higher proportion of patients discharged with recovery, and a shorter T _NANC were associated with azvudine recipients, especially in the severe subgroup. The incidence of adverse events in azvudine recipients was comparable to that in the control group (2.3% vs. 1.7%, P = 0.170). In conclusion, azvudine showed efficacy and safety in older patients hospitalized with COVID-19 during the SARS-CoV-2 omicron wave in China.

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

BACKGROUND: The available evidence regarding the benefits of percutaneous coronary intervention (PCI) on patients receiving dialysis with coronary artery disease (CAD) is limited and inconsistent. This study aimed to evaluate the association between PCI and clinical outcomes as compared with medical therapy alone in patients undergoing dialysis with CAD in China. METHODS: This multicenter, retrospective study was conducted in 30 tertiary medical centers across 12 provinces in China from January 2015 to June 2021 to include patients on dialysis with CAD. The primary outcome was major adverse cardiovascular events (MACE), defined as a composite of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke. Secondary outcomes included all-cause death, the individual components of MACE, and Bleeding Academic Research Consortium criteria types 2, 3, or 5 bleeding. Multivariable Cox proportional hazard models were used to assess the association between PCI and outcomes. Inverse probability of treatment weighting (IPTW) and propensity score matching (PSM) were performed to account for potential between-group differences. RESULTS: Of the 1146 patients on dialysis with significant CAD, 821 (71.6%) underwent PCI. After a median follow-up of 23.0 months, PCI was associated with a 43.0% significantly lower risk for MACE (33.9% [ n  = 278] vs . 43.7% [ n  = 142]; adjusted hazards ratio 0.57, 95% confidence interval 0.45-0.71), along with a slightly increased risk for bleeding outcomes that did not reach statistical significance (11.1% vs . 8.3%; adjusted hazards ratio 1.31, 95% confidence interval, 0.82-2.11). Furthermore, PCI was associated with a significant reduction in all-cause and cardiovascular mortalities. Subgroup analysis did not modify the association of PCI with patient outcomes. These primary findings were consistent across IPTW, PSM, and competing risk analyses. CONCLUSION This study indicated that PCI in patients on dialysis with CAD was significantly associated with lower MACE and mortality when comparing with those with medical therapy alone, albeit with a slightly increased risk for bleeding events that did not reach statistical significance.
Humans ; Percutaneous Coronary Intervention/methods* ; Male ; Female ; Coronary Artery Disease/drug therapy* ; Retrospective Studies ; Renal Dialysis/methods* ; Middle Aged ; Aged ; China ; Proportional Hazards Models ; Treatment Outcome

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

PURPOSE: Assessing fluid responsiveness relying on central venous oxygen saturation (ScvO₂) yields varied outcomes across several studies. This study aimed to determine the ability of the change in ScvO₂ (ΔScvO₂) to detect fluid responsiveness in ventilated septic shock patients and potential influencing factors. METHODS: In this prospective, single-center study, all patients conducted from February 2023 to January 2024 received fluid challenge. Oxygen consumption was measured by indirect calorimetry, and fluid responsiveness was defined as an increase in cardiac index (CI) ≥ 10% measured by transthoracic echocardiography. Multivariate linear regression analysis was conducted to evaluate the impact of oxygen consumption, arterial oxygen saturation, CI, and hemoglobin on ScvO₂ and its change before and after fluid challenge. The Shapiro-Wilk test was used for the normality of continuous data. Data comparison between fluid responders and non-responders was conducted using a two-tailed Student t-test, Mann Whitney U test, and Chi-square test. Paired t-tests were used for normally distributed data, while the Wilcoxon signed-rank test was used for skewed data, to compare data before and after fluid challenge. RESULTS: Among 49 patients (31 men, aged (59 ± 18) years), 27 were responders. The patients had an acute physiology and chronic health evaluation II score of 24 ± 8, a sequential organ failure assessment score of 11 ± 4, and a blood lactate level of (3.2 ± 3.1) mmol/L at enrollment. After the fluid challenge, the ΔScvO₂ (mmHg) in the responders was greater than that in the non-responders (4 ± 6 vs. 1 ± 3, p = 0.019). Multivariate linear regression analysis suggested that CI was the only independent influencing factor of ScvO₂, with R² = 0.063, p = 0.008. After the fluid challenge, the change in CI became the only contributing factor to ΔScvO₂ (R² = 0.245, p < 0.001). ΔScvO₂ had a good discriminatory ability for the responders and non-responders with a threshold of 4.4% (area under the curve = 0.732, p = 0.006). CONCLUSION ΔScvO₂ served as a reliable surrogate marker for ΔCI and could be utilized to assess fluid responsiveness, given that the change in CI was the sole contributing factor to the ΔScvO₂. In stable hemoglobin conditions, the absolute value of ScvO₂ could serve as a monitoring indicator for adequate oxygen delivery independent of oxygen consumption.
Humans ; Shock, Septic/blood* ; Male ; Female ; Middle Aged ; Prospective Studies ; Oxygen Saturation ; Aged ; Fluid Therapy ; Oxygen/blood* ; Oxygen Consumption ; Adult

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.