ObjectiveTo study the chemical constituents of Painong powder and the constituents absorbed into blood after oral administration to rats by ultra performance liquid chromatography-quadrupole-electrostatic field orbitrap high-resolution mass spectrometry （UPLC-Q-Orbitrap-MS）. MethodsUPLC-Q-Orbitrap-MS was employed for mass spectrometry data acquisition. The chemical constituents of Painong Powder and the constituents absorbed into blood were characterized and identified via Xcalibur 4.2 and Compound Discoverer v3.3.1 （CD） based on retention time， accurate molecular weights， secondary fragmentation ions， and comparison with reference standards and literature reports. ResultsA total of 176 chemical compounds， including 56 flavonoids， 42 triterpenoid saponins， 23 monoterpenes， 7 coumarins， 5 tannins， and other 43 compounds were identified from Painong powder. 49 components were identified in the rat plasma after oral administration of Painong powder， including 33 prototype constituents and 16 metabolites. The major metabolic pathways included hydrolysis in phase Ⅰ metabolic reactions， as well as methylation， sulfation， and glucuronidation in phase Ⅱ metabolic reaction. ConclusionThe method comprehensively identified the chemical constituents of Painong powder both in vitro and in vivo， and may provide a reference for the study of quality control and clinical applications.

Objective:To investigate the correlation between statins and contrast-induced acute kidney injury (CI-AKI) and provide a reference basis for clinical practice.Methods:It was a retrospective cohort study. The adult patients were admitted to Peking University First Hospital from January 1, 2018, to December 31, 2020, and received at least one intravascular iodinated contrast administration during hospitalization. The clinical data of the patients were collected. The enrolled patients were divided into statin group and non-statin group according to statin exposure. The exposure of statins was defined as use of any type of statins within 48 hours before iodinated contrast administration. The primary outcome was in-hospital AKI defined as AKI developed after contrast administration and before discharge, with 30 days as the endpoint observation time, and the secondary outcome was post-contrast AKI (PC-AKI) defined as AKI onset within 72 hours after contrast administration. Cox regression model was applied to investigate the correlation between statin prescription prior to contrast administration and clinical outcomes. Pre-specified interaction analysis was conducted to examine modification effect of age, gender, baseline estimated glomerular filtration rate (eGFR), diabetes and the injection method of contrast.Results:Among 10 321 enrolled patients, the age was 63 (54, 71) years old, and 6 274 (60.8%) patients were males. There were 2 372 (23.0%) patients taking statins before the use of iodinated contrast agents, and the person-time incidence rate of in-hospital AKI was 2.5 per 1 000 person-days. The person-time incidence rate of statin users and statin non-users was 3.2 and 2.4 per 1 000 person-days, respectively. Compared with the non-statin group, age, serum creatinine and the proportions of males, admitted to the intensive care unit, lipid metabolism disorder, hypertension, diabetes, cerebrovascular diseases, cardiovascular diseases, using renin-angiotensin- aldosterone inhibitors, using diuretics, using non-steroidal anti-inflammatory drugs, using proton pump inhibitors, iodinated contrast administration via artery, eGFR<60 ml·min -1·(1.73 m 2) -1 were higher, while the proportions of general anesthesia surgery, severe liver diseases and tumors, and eGFR were lower in the statin group (all P<0.05). Among 10 321 patients, 5 867 patients had serum creatinine measurement within 72 hours after iodinated contrast administration, among which 70 patients (4.0 per 1 000 person-days) developed PC-AKI. Multivariate Cox regression analysis showed that statin use was an independent protective factor for in-hospital AKI ( HR=0.65, 95% CI 0.45?0.93, P=0.017) and PC-AKI ( HR=0.44, 95% CI 0.22?0.88, P=0.020). Subgroup analysis showed the significant interaction between diabetes and statin use ( P for interaction=0.039), and the protective effect of statins against in-hospital AKI was only observed in non-diabetic group ( HR=0.45, 95% CI 0.26?0.77). There were no significant differences in subgroups stratified by age, sex, baseline eGFR and the injection method of contrast (all P for interaction>0.05). Conclusions:Statin use prior to iodinated contrast administration is correlated with reduced risks of in-hospital AKI and PC-AKI in hospitalized patients, and the correlation between statin use and in-hospital AKI is more significant in non-diabetic patients. It is suggested that statin use before the application of iodinated contrast agents in hospitalized patients may prevent the occurrence of AKI.

OBJECTIVE: To explore the genetic basis for a woman with oocyte maturation disorder during assisted reproductive treatment (ART), and to verify the source of the variant and its impact on oocyte maturation through family verification. METHODS: A 35-year-old infertile woman presented at the Reproductive Medicine Center of Gansu Provincial Maternal and Child Health Care Hospital on 20 October 2023 for a 10-year history of infertility despite unprotected intercourse was selected as study subject. Peripheral venous blood sample was collected from the proband. Next-generation sequencing (NGS) was used to detect the potential variant. Candidate variants were validated within her family by Sanger sequencing, and their deleteriousness was assessed with comprehensive bioinformatic analyses to elucidate their origin and impact on oocyte maturation. According to the Standards and Guidelines for the Interpretation of Sequence Variants (hereinafter referred to as ACMG Guidelines) formulated by the American College of Medical Genetics and Genomics (ACMG), the pathogenicity of the candidate variant was rated. This study was approved by the Medical Ethics Committee of Gansu Provincial Maternal and Child Health Care Hospital (Ethics No.: 2023GSFYLS78). RESULTS: The proband underwent three controlled ovarian-stimulation cycles as part of assisted reproductive technology, yielding a total of 29 oocytes, among which only three were mature, whilst the remainders exhibited maturation arrest. Targeted sequencing of peripheral-blood DNA revealed a heterozygous c.728C>T (p.P243L) missense variant of the TUBB8 gene. While the same variant was detected in the proband's father. Based on the ACMG guidelines, the variant was classified to be likely pathogenic (PS4_Supporting+PM2_Supporting+PP2+PP3+PP4). CONCLUSION The heterozygous c.728C>T (p.P243L) missense variant of the TUBB8 gene probably underlay the oocyte maturation disorder in the proband, which may be either autosomal dominant or autosomal recessive. For probands with oocyte maturation disorders caused by the heterozygous c.728C>T variant of the TUBB8 gene, oocyte donation may be considered.
Humans ; Female ; Adult ; Mutation, Missense ; Oocytes/metabolism* ; Heterozygote ; Tubulin/genetics* ; Infertility, Female/genetics* ; High-Throughput Nucleotide Sequencing ; Pedigree

OBJECTIVE: To investigate the clinical phenotype and genetic etiology of a patient with primary infertility accompanied by Oocyte maturation defect (OOMD). METHODS: A 24-year-old female patient who visited the Reproductive Medicine Center of Gansu Provincial Maternity and Child Care Hospital in April 2024 was selected as the study subject. Whole-exome sequencing (WES) was performed on the proband and her husband. Candidate gene variants were validated in the family using Sanger sequencing, and compound heterozygous variants were confirmed through vector construction. Candidate variants were classified for pathogenicity according to the "Standards and Guidelines for the Interpretation of Sequence Variants" established by the American College of Medical Genetics and Genomics (ACMG). This study was approved by the Medical Ethics Committee of the Hospital [Ethics No.: (2023) GSFYLS(78)]. RESULTS: The proband, a 24-year-old female, had been unable to conceive for four years without contraception after marriage. She had undergone two ovarian stimulation cycles using the antagonist protocol and the PPOS protocol, respectively. A total of 74 oocytes were retrieved, with all showing OOMD and some oocytes exhibiting abnormal morphology and poor quality. WES results revealed two heterozygous missense variants in exons 14 and 16 of the PATL2 gene: c.1127G>A (p.R376Q) and c.1388C>G (p.A463G). Family validation results indicated that the missense variant in exon 14 was inherited from the proband's father, while the variant in exon 16 was de novo. CONCLUSION The compound heterozygous variants of the PATL2 gene probably underlay the OOMD and infertility in this proband. Further analysis based on the variant sites and protein structures is needed to determine whether PATL2 gene variants can fully affect oocyte development, thereby providing a personalized treatment plan for the proband.
Female ; Humans ; Young Adult ; Exome Sequencing ; Infertility, Female/genetics* ; Oocytes/metabolism* ; Pedigree ; Phenotype

OBJECTIVE: To explore the clinical and genetic characteristics of a Chinese pedigree affected with Hypertrophic cardiomyopathy (HCM) due to a truncating variant of ALPK3 gene. METHODS: A 44-year-old male admitted to Taizhou Hospital of Zhejiang Province on December 29, 2018 was selected as the study subject. Whole-exome sequencing (WES) was carried out, and candidate variant was interpreted by following the guidelines from the American College of Medical Genetics and Genomics (ACMG). For ALPK3 was considered an autosomal recessive gene, the WES results was considered insufficient to explain his phenotype. In April 2023, the proband's WES data were re-analyzed using updated annotation pipelines, and peripheral blood samples were collected from his first-degree relatives (mother and brother) for Sanger sequencing validation. Conservation analysis and protein structural modeling were performed to assess the impact of the variant. Clinical evaluation and genetic counseling were provided to the proband's family members. Relevant literature on ALPK3tv-induced HCM patients were searched in Wanfang Data Knowledge Service Platform, CNKI, and PubMed database using "ALPK3" and "hypertrophic cardiomyopathy" as keywords. Clinical characteristics of HCM patients with heterozygous ALPK3tv variants were summarized and compared with the clinical characteristics of HCM patients with positive sarcomere-associated gene variants (SARC+). This study was approved by the Medical Ethics Committee of Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University (Ethics No.: K20230314). RESULTS: The proband was a 44-year-old male who was transferred to our institution on December 29, 2018 due to "chest tightness and pain for 6 months, exacerbated for 2 days". Emergency coronary angiography was performed, which led to a preliminary diagnosis of "acute coronary syndrome", and the patient was admitted to the Cardiology Department for treatment. Based on electrocardiogram and echocardiogram findings, the diagnosis was revised as HCM. The patient's condition has stabilized post-coronary angiography, and he was discharged with improved condition. On January 2019, WES was conducted to determine the etiology of the proband's HCM. WES results identified a novel heterozygous c.2156dupC (p.Pro720ThrfsTer53) truncating variant in the ALPK3 gene. At that time, the inheritance pattern could not explain the phenotype. In 2022, a literature indicated that heterozygous ALPK3tv could lead to autosomal dominant HCM. Consequently, in April 2023, the proband's whole-exome data were re-annotated, revealing changes in the transcript and protein versions, with the updated site annotated as ALPK3 (NM_020778.5): c.1550dupC (p.Pro518ThrfsTer53). Sanger sequencing confirmed that the proband's mother and brother also carried this variant. The mother exhibited obstructive HCM, while the brother showed no related phenotype. Bioinformatics analysis demonstrated conservation of this site across multiple species, and the variant has resulted in the loss of a protein domain. Based on ACMG guidelines, the variant was classified as likely pathogenic. Literature review and Bayesian calculation further elevated the pathogenicity rating, indicating that this variant was the cause of HCM in the patient. Literature study revealed distinctions between HCM caused by this variant type and SARC+ HCM. The age of onset among heterozygous ALPK3tv patients was delayed by approximately 10 years compared to SARC+ patients. Both forms of HCM exhibited a male predominance, which was particularly marked in individuals with ALPK3tv. Electrocardiographic left ventricular hypertrophy was more prevalent in heterozygous ALPK3tv patients than in SARC+ patients. The incidence of apical or concentric hypertrophy patterns was higher in heterozygous ALPK3tv patients compared to asymmetric septal hypertrophy, which predominated in SARC+ patients. ALPK3tv patients exhibited lower penetrance and later onset compared to SARC+ patients. A positive correlation between left ventricular wall thickness and age was noted in female patients only. CONCLUSION In this pedigree, the proband has presented with HCM, characterized by echocardiographic evidence of apical left ventricular hypertrophy without significant outflow tract obstruction or extracardiac phenotypes. Although his mother and brother had carried the same heterozygous ALPK3 (NM_020778.5) c.1550dupC (p.Pro518ThrfsTer53), the mother exhibited severe obstructive HCM, while the brother was asymptomatic, suggesting incomplete or age-dependent penetrance within the family. This study has enriched the evidence for the pathogenicity of ALPK3tv among Chinese HCM pedigrees and underscored the importance of periodic literature reviews and genetic re-analysis for unresolved genetic testing results.
Humans ; Male ; Pedigree ; Adult ; Cardiomyopathy, Hypertrophic/genetics* ; Heterozygote ; Asian People/genetics* ; Exome Sequencing ; Mutation ; China ; Female ; East Asian People

Objective To study the application of mesoporous silica nanoparticle(MSN)as drug carriers in the treatment of osteoarthritis(OA).Methods Core-cone structured MSN(MSN-CC)was synthesized by sol-gel method,modified by polyethyleneimine(PEI),and loaded with hyaluronic acid synthase 2(HAS2).Forty OA model rats were randomly assigned to OA group,MSN-CC-PEI group,hyaluronic acid(HA)group,or MSN-CC-PEI-HAS2 group.Ten healthy rats were assigned to control group.Normal saline 100 μL was injected into the knee joint in the control group and OA group.MSN-CC-PEI 100 μL,HA solution 100 μL,and MSN-CC-PEI-HAS2 100 μL were injected in MSN-CC-PEI group,HA group,and MSN-CC-PEI-HAS2 group,respectively.The levels of HA,interleukin-1β(IL-1β),and prostaglandin E2(PGE2)in the joint effusion and the foot swelling degree were measured at 1,2,and 3 weeks after injection.Results HA level in the MSN-CC-PEI-HAS2 group was significantly lower than that in the HA group at 1 week after intervention(P<0.05),while HA level in the MSN-CC-PEI-HAS2 group was significantly higher than that in the HA group at 2 and 3 weeks after intervention(P<0.05).With the time going on,HA level in the HA group was gradually decreased(P<0.05),but HA level in the MSN-CC-PEI-HAS2 group was gradually increased(P<0.05).At 1 and 2 weeks after intervention,compared with the HA group,IL-1β,PGE2 and foot swelling degree in the MSN-CC-PEI-HAS2 group were increased(P<0.05).At 3 weeks after intervention,compared with the HA group,IL-1β,PGE2 and foot swelling degree in the MSN-CC-PEI-HAS2 group were decreased(P<0.05).With the time going on,IL-1β,PGE2 and foot swelling degree in the HA group and MSN-CC-PEI-HAS2 group were gradually decreased(P<0.05).Conclusion MSN carrier can stably stimulate the secretion of endogenous HA,reduce the inflammatory response within joint cavity of OA rats,and improve the joint morphology and soft tissue pathological changes.

Objective:To investigate the expression of Artemin (ARTN) in malignant peripheral nerve sheath tumor (MPNST), its effect on the malignant behavior of MPNST cells, and its signaling pathway.Methods:Fifty-one MPNST paraffin embedded tissues through surgical resection at Tianjin Medical University Cancer Hospital from January 1995 to November 2011 were collected, the expression of the ARTN protein was detected by immunohistochemistry, and the relationship between the ARTN protein expression and the clinical pathological characteristics and prognosis were analyzed. In human MPNST cell lines ST-8814 (NF-1) and STS26T(sporadic), ARTN overexpression and low expression cell lines were constructed by transfecting ARTN overexpression plasmids and ARTN small interfering RNA (siRNA), respectively. The expression of ARTN mRNA was detected by real time quantitative polymerase chain reaction (RT-qPCR), the expression of the ARTN protein and Phosphoinositide 3-kinase(PI3K)/Akt signaling pathway related proteins were detected by Western blot. CCK-8 assay was used to detect cell proliferation ability, and cell invasion assay was used to detect cell invasion ability. The pathway proteins that interacted with ARTN were searched in the STRING database, and the functional pathways were clarified by Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. The PI3K/Akt pathway specific inhibitor LY294002 was used to block the PI3K/Akt pathway of ST-8814 and STS26T cells to observe the changes in cell proliferation and invasion.Results:Among the 51 MPNST tissue specimens, 22 cases showed a high expression of the ARTN protein and 29 cases showed a low expression of the protein. Higher expressions of the ARTN protein was associated with larger tumor diameters and disease progression (recurrence or metastasis) (both P＜0.05). The median disease-free survival (DFS) of patients with a low expression of the ARTN protein was 26.2 months, and the median overall survival (OS) was 66.9 months. The median DFS and median OS of patients with a high expression of the ARTN protein were 10.7 months and 53.8 months, respectively. The log rank test results showed that the progression free survival rate of patients with a high expression of the ARTN protein was worse than that of patients with a low expression ( P=0.027), but the difference in overall survival rate between the two groups was not statistically significant ( P=0.790), which was also confirmed by Cox regression analysis. The CCK-8 assay results showed that after 48 hours of transfection, the absorbance ( A) values of ST-8814 and STS26T cells in the ARTN overexpression group were 1.35±0.01 and 1.10±0.02, respectively, which were higher than those in the empty plasmid control group (1.05±0.01 and 0.78±0.01, both P＜0.01), while the A values of ST-8814 and STS26T cells in the ARTN siRNA group were 0.35±0.01 and 0.61±0.01, respectively, which were lower than those in the control siRNA group (0.74±0.01 and 1.10±0.04, both P＜0.01). The results of cell invasion assay showed that the number of transmembrane cells in ST-8814 and STS26T cells overexpressing ARTN was (29.67±2.08) and (31.67±2.08), respectively, which were higher than those in the empty plasmid control group [(20.00±1.00) and (24.33±1.15), both P＜0.01]. The number of transmembrane cells in ST-8814 and STS26T cells in the ARTN siRNA group were (14.00±2.00) and (19.33±1.53), respectively, which were lower than those in the control siRNA group [(19.33±2.52) and (23.33±0.58), both P＜0.05].The KEGG results showed that ARTN is associated with multiple tumor signaling pathways, especially the PI3K/Akt signaling pathway. Western blot results showed that overexpression of ARTN upregulated the expression of p-PI3K and p-Akt proteins in ST-8814 and STS26T cells (both P＜0.01).After knocking down ARTN expression, the expression of p-PI3K and p-Akt proteins was significantly down regulated (both P＜0.01). LY294002 could significantly inhibit the effect of ARTN overexpression on ST-8814 and STS26T cells after blocking the PI3K/Akt pathway. The A values of ST-8814 and STS26T cells in the ARTN overexpression+LY294002 group were 1.09±0.06 and 0.82±0.01, respectively, which were lower than those in the ARTN overexpression group (1.50±0.01 and 1.29±0.01, respectively, both P＜0.01). The numbers of transmembrane cells in the cell invasion assay were 16.67±3.21 and 19.67±2.31, respectively, which were also lower than those in the ARTN overexpression group (29.67±2.08 and 31.67±2.08, respectively, both P＜0.01). Conclusions:In MPNST, a high expression of the ARTN protein was associated with larger tumor size, disease progression, and worse DFS. ARTN promotes the proliferation and invasion of MPNST cells through the PI3K/Akt signaling pathway.

Objective:To investigate and analyze the thyroid examination results and influencing factors of interventional radiation workers in Tianjin.Methods:In February 2023, A convenient sampling method was used to select the staff engaged in interventional radiation work in an occupational health inspection institution in Tianjin from 2020 to 2022 as the study object. After excluding the incomplete data, 1080 people were included, and 363 medical staff with non-radiological work during the same period were included as the control group. To analyze the individual doses and occupational health examination data of interventional radiation workers, and to analyze the possible influencing factors of thyroid abnormalities.Results:The cumulative dose M ( Q1, Q3) of interventional radiation workers was 1.039 (0.528, 1.905) mSv. The levels of FT 3 and FT 4 in the intervention group were higher than those in the control group, while TSH levels were lower than those in the control group ( Z=4.84、6.03、-5.82, P<0.05). The levels of FT 3 and FT 4 in female interventional radiation workers were lower than those in males, while the levels of TSH were higher than those in males ( Z= -17.54、-6.65、3.61, P<0.05). There were statistically significant differences in FT 3 levels among different ages, differen tradiation exposure years, different initial age of exposure to radiation, and different cumulative doses ( H=47.22、11.33、16.70, Z=-2.48, P<0.05). There were statistically significant differences in thyroid ultrasound abnormalities among different genders, different ages, different initial age of exposure to radiation, and different cumulative doses ( χ2=28.02、61.12、17.87、11.30, P<0.05). The results of logistic regression analysis showed that the influencing factors of FT 3 distributed in the low-level group were female ( OR=10.53, 95% CI: 7.66-14.47, P<0.05), and age 40-49, ≥50 years old ( OR=2.40, 95% CI: 1.12-5.14 OR=3.79, 95% CI: 1.59-9.03, P<0.05). The influencing factors of thyroid ultrasound abnormalities were female ( OR=1.92, 95% CI: 1.48-2.50, P<0.05) and age ≥50 years old ( OR=3.93, 95% CI: 1.91-8.09, P<0.05) . Conclusion:Long term low dose ionizing radiation has a certain effect on FT 3, FT 4 and TSH levels of interventional radiation workers. Gender and increased age are possible influencing factors of the decreased FT 3 levels and thyroid ultrasound abnormalities.

As cardiac magnetic resonance imaging technology advances,T1 mapping has emerged as a non-invasive method offering visual and quantitative insights into myocardial fibrosis,edema,and infiltration associated with cardiac dis-eases.The application of T1 mapping in myocardial diseases allows for evaluating both focal and diffuse myocardial fibro-sis,playing a crucial clinical role in the differentiation,treatment,and prognostic risk assessment of diseases.This arti-cle aims to provide a thorough overview of the clinical applications of T1 mapping in patients with cardiomyopathy,summa-rizing the commonly employed scanning techniques and imaging principles.

Objective:To investigate the correlation between statins and contrast-induced acute kidney injury (CI-AKI) and provide a reference basis for clinical practice.Methods:It was a retrospective cohort study. The adult patients were admitted to Peking University First Hospital from January 1, 2018, to December 31, 2020, and received at least one intravascular iodinated contrast administration during hospitalization. The clinical data of the patients were collected. The enrolled patients were divided into statin group and non-statin group according to statin exposure. The exposure of statins was defined as use of any type of statins within 48 hours before iodinated contrast administration. The primary outcome was in-hospital AKI defined as AKI developed after contrast administration and before discharge, with 30 days as the endpoint observation time, and the secondary outcome was post-contrast AKI (PC-AKI) defined as AKI onset within 72 hours after contrast administration. Cox regression model was applied to investigate the correlation between statin prescription prior to contrast administration and clinical outcomes. Pre-specified interaction analysis was conducted to examine modification effect of age, gender, baseline estimated glomerular filtration rate (eGFR), diabetes and the injection method of contrast.Results:Among 10 321 enrolled patients, the age was 63 (54, 71) years old, and 6 274 (60.8%) patients were males. There were 2 372 (23.0%) patients taking statins before the use of iodinated contrast agents, and the person-time incidence rate of in-hospital AKI was 2.5 per 1 000 person-days. The person-time incidence rate of statin users and statin non-users was 3.2 and 2.4 per 1 000 person-days, respectively. Compared with the non-statin group, age, serum creatinine and the proportions of males, admitted to the intensive care unit, lipid metabolism disorder, hypertension, diabetes, cerebrovascular diseases, cardiovascular diseases, using renin-angiotensin- aldosterone inhibitors, using diuretics, using non-steroidal anti-inflammatory drugs, using proton pump inhibitors, iodinated contrast administration via artery, eGFR<60 ml·min -1·(1.73 m 2) -1 were higher, while the proportions of general anesthesia surgery, severe liver diseases and tumors, and eGFR were lower in the statin group (all P<0.05). Among 10 321 patients, 5 867 patients had serum creatinine measurement within 72 hours after iodinated contrast administration, among which 70 patients (4.0 per 1 000 person-days) developed PC-AKI. Multivariate Cox regression analysis showed that statin use was an independent protective factor for in-hospital AKI ( HR=0.65, 95% CI 0.45?0.93, P=0.017) and PC-AKI ( HR=0.44, 95% CI 0.22?0.88, P=0.020). Subgroup analysis showed the significant interaction between diabetes and statin use ( P for interaction=0.039), and the protective effect of statins against in-hospital AKI was only observed in non-diabetic group ( HR=0.45, 95% CI 0.26?0.77). There were no significant differences in subgroups stratified by age, sex, baseline eGFR and the injection method of contrast (all P for interaction>0.05). Conclusions:Statin use prior to iodinated contrast administration is correlated with reduced risks of in-hospital AKI and PC-AKI in hospitalized patients, and the correlation between statin use and in-hospital AKI is more significant in non-diabetic patients. It is suggested that statin use before the application of iodinated contrast agents in hospitalized patients may prevent the occurrence of AKI.