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 To explore the molecular mechanism by which SOS Ras/Rac guanine nucleotide exchange factor 1-intronic transcript 1(SOS1-IT1)affects enhancer of zeste homolog 2(EZH2)protein expression in endometrial cancer cells Ishikawa and RL95-2.Methods Lentiviral transfection of short hairpin RNA(shRNA)and overexpression plasmid were used in Ishikawa and RL95-2 cell lines to knock down and overexpress SOS1-IT1.The mechanism of EZH2 expression regulation was studied using Real-time PCR,Western blotting,and chromatin immunoprecipitation.Results The expression of SOS1-IT1 and EZH2 genes was positively correlated in endometrial cancer tissues.Knocking down SOS1-IT1 significantly reduces the expression of EZH2,inhibited the proliferation and migration of Ishikawa and RL95-2 cells,and could reduced the acetylation of histone H3 at position 27(H3K27)and the enrichment of CREB binding protein(CBP)in the EZH2 gene promoter region.Overexpression of SOS1-IT1 could increased the expression of EZH2 and enhance the acetylation of H3K27 and the enrichment of CBP.CBP could bind to SOS1-IT1 RNA,and this binding ability was weakened when CBP was knocked down.Conclusion SOS1-IT1 can promote the expression level of EZH2 in endometrial cancer cells Ishikawa and RL95-2 by regulating the acetylation modification level of the EZH2 gene promoter region,thereby affecting the proliferation and migration ability of endometrial cancer cells.

Objective To establish a high performance liquid chromatography(HPLC)aging characteristic chromatogram of Guangdong Citri Reticulatae Pericarpium.Methods HPLC-diode array detector(DAD)was used to analyze the composition differences between different years of Guangdong Citri Reticulatae Pericarpium,and the relative peak area of each differential chromatographic peak was determined.The aging grade was classified by cluster analysis,and evaluated by the similarity evaluation system for chromatographic fingerprint of TCM(2012A edition).Results The different years of Guangdong Citri Reticulatae Pericarpium was clustered into two different aging grades of classⅠ and class Ⅱ.The similarity of class Ⅰ(low aging grade)Guangdong Citri Reticulatae Pericarpium was 0.708-0.957,and the similarity of class Ⅱ(high aging grade)Guangdong Citri Reticulatae Pericarpium was 0.734-0.976,and the similarity between the two was lower than 0.6.There were 9 different chromatographic peaks in the established characteristic chromatogram.The control characteristic spectrum T2 of typeⅡ Guangdong Citri Reticulatae Pericarpium can be regarded as its aging characteristic spectrum,among which peaks 1-4 and 9 are aging characteristic peaks.Conclusion The established aging characteristic chromatogram of Guangdong Citri Reticulatae Pericarpium is simple in operation,with good repeatability and reliability,and can be used for quality evaluation of different years of Guangdong Citri Reticulatae Pericarpium.

This study investigated the clinical and epidemiological characteristics of patients with monkeypox in the Chang-sha City,and analyzed the results of laboratory and ultrasound examinations,to provide a basis for monkeypox epidemic pre-vention and control.Epidemiological characteristics,clinical manifestations,laboratory tests,and ultrasound examinations for 44 patients with monkeypox hospitalized at the First Hospital of Changsha between June 29,2023,and December 15,2023,were analyzed.Differences in laboratory results were compared between patients with monkeypox with versus without HIV in-fection.The median age of the 44 patients with monkeypox was 33 years.All patients were men who had sex with men within 21 days before the diagnosis of monkeypox.A total of 81.82％patients were unmarried,and 38.64％were unemployed.Moreo-ver,40.91％of patients were infected with Treponema pallidum,and 61.36％patients were infected with HIV,of whom 88.89％received ART.The median incubation period was 5 days.The median time from onset to hospitalization was 6.88 days.The median hospitalization time was 10.51 days.All patients presented with skin rash,distributed primarily in the repro-ductive organs,limbs,facial features,trunk,and perianal area.Most patients had fever.Lymph node enlargement oc-curred mainly in the groin.Compared with patients who were co-infected with HIV,the other patients had lower levels of neutrophils,and higher levels of red blood cells,albumin,aspartate aminotransferase,total bilirubin,and creatine kinase isoenzymes.Most patients with monkeypox in the Changsha City were middle-aged or young men who had sex with men.The main manifestations included rash,fever,and enlarged lymph nodes.

For the past 30 years,percutaneous balloon mitral valve dilatation has been performed under the guidance of X-rays and bedside ultrasound.However,there are still some cases of mitral valve stenosis in the large atrium where balloon dilation failed.Intraperitoneal ultrasound-guided percutaneous balloon mitral valve plasty is accurate and feasible,which can reduce the occurrence of complications and improve the success rate of such elderly complex cases.Two patients with severe mitral stenosis underwent percutaneous balloon mitral valve plasty guided by intracardiac ultrasound.The operations were successful without any complications,which can provide reference for clinical treatment of mitral stenosis.

Objective: To analyze the prevalence and the risk factors of fungal sepsis in 25 neonatal intensive care units (NICU) among preterm infants in China, and to provide a basis for preventive strategies of fungal sepsis. Methods: This was a second-analysis of the data from the "reduction of infection in neonatal intensive care units using the evidence-based practice for improving quality" study. The current status of fungal sepsis of the 24 731 preterm infants with the gestational age of <34⁺⁰ weeks, who were admitted to 25 participating NICU within 7 days of birth between May 2015 and April 2018 were retrospectively analyzed. These preterm infants were divided into the fungal sepsis group and the without fungal sepsis group according to whether they developed fungal sepsis to analyze the incidences and the microbiology of fungal sepsis. Chi-square test was used to compare the incidences of fungal sepsis in preterm infants with different gestational ages and birth weights and in different NICU. Multivariate Logistic regression analysis was used to study the outcomes of preterm infants with fungal sepsis, which were further compared with those of preterm infants without fungal sepsis. The 144 preterm infants in the fungal sepsis group were matched with 288 preterm infants in the non-fungal sepsis group by propensity score-matched method. Univariate and multivariate Logistic regression analysis were used to analyze the risk factors of fungal sepsis. Results: In all, 166 (0.7%) of the 24 731 preterm infants developed fungal sepsis, with the gestational age of (29.7±2.0) weeks and the birth weight of (1 300±293) g. The incidence of fungal sepsis increased with decreasing gestational age and birth weight (both P<0.001). The preterm infants with gestational age of <32 weeks accounted for 87.3% (145/166). The incidence of fungal sepsis was 1.0% (117/11 438) in very preterm infants and 2.0% (28/1 401) in extremely preterm infants, and was 1.3% (103/8 060) in very low birth weight infants and 1.7% (21/1 211) in extremely low birth weight infants, respectively. There was no fungal sepsis in 3 NICU, and the incidences in the other 22 NICU ranged from 0.7% (10/1 397) to 2.9% (21/724), with significant statistical difference (P<0.001). The pathogens were mainly Candida (150/166, 90.4%), including 59 cases of Candida albicans and 91 cases of non-Candida albicans, of which Candida parapsilosis was the most common (41 cases). Fungal sepsis was independently associated with increased risk of moderate to severe bronchopulmonary dysplasia (BPD) (adjusted OR 1.52, 95%CI 1.04-2.22, P=0.030) and severe retinopathy of prematurity (ROP) (adjusted OR 2.55, 95%CI 1.12-5.80, P=0.025). Previous broad spectrum antibiotics exposure (adjusted OR=2.50, 95%CI 1.50-4.17, P<0.001), prolonged use of central line (adjusted OR=1.05, 95%CI 1.03-1.08, P<0.001) and previous total parenteral nutrition (TPN) duration (adjusted OR=1.04, 95%CI 1.02-1.06, P<0.001) were all independently associated with increasing risk of fungal sepsis. Conclusions: Candida albicans and Candida parapsilosis are the main pathogens of fungal sepsis among preterm infants in Chinese NICU. Preterm infants with fungal sepsis are at increased risk of moderate to severe BPD and severe ROP. Previous broad spectrum antibiotics exposure, prolonged use of central line and prolonged duration of TPN will increase the risk of fungal sepsis. Ongoing initiatives are needed to reduce fungal sepsis based on these risk factors.
Infant ; Infant, Newborn ; Humans ; Birth Weight ; Intensive Care Units, Neonatal ; Retrospective Studies ; Tertiary Care Centers ; Infant, Extremely Low Birth Weight ; Gestational Age ; Infant, Extremely Premature ; Sepsis/epidemiology* ; Retinopathy of Prematurity/epidemiology* ; Bronchopulmonary Dysplasia/epidemiology*

OBJECTIVE: Exposure to high intensity, low frequency noise (HI-LFN) causes vibroacoustic disease (VAD), with memory deficit as a primary non-auditory symptomatic effect of VAD. However, the underlying mechanism of the memory deficit is unknown. This study aimed to characterize potential mechanisms involving morphological changes of neurons and nerve fibers in the hippocampus, after exposure to HI-LFN. METHODS: Adult wild-type and transient receptor potential vanilloid subtype 4 knockout (TRPV4^-/-) mice were used for construction of the HI-LFN injury model. The new object recognition task and the Morris water maze test were used to measure the memory of these animals. Hemoxylin and eosin and immunofluorescence staining were used to examine morphological changes of the hippocampus after exposure to HI-LFN. RESULTS: The expression of TRPV4 was significantly upregulated in the hippocampus after HI-LFN exposure. Furthermore, memory deficits correlated with lower densities of neurons and neurofilament-positive nerve fibers in the cornu ammonis 1 (CA1) and dentate gyrus (DG) hippocampal areas in wild-type mice. However, TRPV4^-/- mice showed better performance in memory tests and more integrated neurofilament-positive nerve fibers in the CA1 and DG areas after HI-LFN exposure. CONCLUSION TRPV4 up-regulation induced neurofilament positive nerve fiber injury in the hippocampus, which was a possible mechanism for memory impairment and cognitive decline resulting from HI-LFN exposure. Together, these results identified a promising therapeutic target for treating cognitive dysfunction in VAD patients.
Animals ; Mice ; TRPV Cation Channels/metabolism* ; Intermediate Filaments/metabolism* ; Hippocampus/metabolism* ; Neurons/metabolism* ; Memory Disorders/metabolism*

This study explored a new model of Prostate Imaging Reporting and Data System (PIRADS) and adjusted prostate-specific antigen density of peripheral zone (aPSADPZ) for predicting the occurrence of prostate cancer (PCa) and clinically significant prostate cancer (csPCa). The demographic and clinical characteristics of 853 patients were recorded. Prostate-specific antigen (PSA), PSA density (PSAD), PSAD of peripheral zone (PSADPZ), aPSADPZ, and peripheral zone volume ratio (PZ-ratio) were calculated and subjected to receiver operating characteristic (ROC) curve analysis. The calibration and discrimination abilities of new nomograms were verified with the calibration curve and area under the ROC curve (AUC). The clinical benefits of these models were evaluated by decision curve analysis and clinical impact curves. The AUCs of PSA, PSAD, PSADPZ, aPSADPZ, and PZ-ratio were 0.669, 0.762, 0.659, 0.812, and 0.748 for PCa diagnosis, while 0.713, 0.788, 0.694, 0.828, and 0.735 for csPCa diagnosis, respectively. All nomograms displayed higher net benefit and better overall calibration than the scenarios for predicting the occurrence of PCa or csPCa. The new model significantly improved the diagnostic accuracy of PCa (0.945 vs 0.830, P < 0.01) and csPCa (0.937 vs 0.845, P < 0.01) compared with the base model. In addition, the number of patients with PCa and csPCa predicted by the new model was in good agreement with the actual number of patients with PCa and csPCa in high-risk threshold. This study demonstrates that aPSADPZ has a higher predictive accuracy for PCa diagnosis than the conventional indicators. Combining aPSADPZ with PIRADS can improve PCa diagnosis and avoid unnecessary biopsies.
Male ; Humans ; Prostate/pathology* ; Prostate-Specific Antigen/analysis* ; Prostatic Neoplasms/diagnostic imaging* ; Biopsy ; Nomograms ; Retrospective Studies

This study aims to prepare vitexin albumin nanoparticles(VT-BSA-NPs) to alleviate the low bioavailability of vitexin(VT) in vivo due to its poor water solubility. VT micro powders were prepared by the antisolvent crystallization method, and the morphology, size, and physicochemical properties of VT micro powders were studied. The results showed that the VT micro powder had a particle size of(187.13±7.15) nm, an approximate spherical morphology, and a uniform size distribution. Compared with VT, the chemical structure of VT micro powders has not changed. VT-BSA-NPs were prepared from VT micro powders by desolvation-crosslinking curing method. The preparation process was screened by single factor test and orthogonal test, and the quality evaluation of the optimal prescription particle size, PDI, Zeta potential, EE, and morphology was performed. The results showed that the average particle size of VT-BSA-NPs was(124.33±0.47) nm; the PDI was 0.184±0.012; the Zeta potential was(-48.83±2.20) mV, and the encapsulation rate was 83.43%±0.39%, all of which met the formulation-related requirements. The morphological results showed that the VT-BSA-NPs were approximately spherical in appearance, regular in shape, and without adhesion on the surface. In vitro release results showed a significantly reduced release rate of VT-BSA-NPs compared with VT, indicating a good sustained release effect. LC-MS/MS was used to establish an analytical method for in vivo analysis of VT and study the plasma pharmacokinetics of VT-BSA-NPs in rats. The results showed that the specificity of the analytical method was good, and the extraction recovery was more than 90%. Compared with VT and VT micro powders, VT-BSA-NPs could significantly increase AUC, MRT, and t_(1/2), which was beneficial to improve the bioavailability of VT.
Rats ; Animals ; Serum Albumin, Bovine/chemistry* ; Chromatography, Liquid ; Tandem Mass Spectrometry ; Nanoparticles/chemistry* ; Particle Size ; Drug Carriers/chemistry*

OBJECTIVE: To derive the Chinese medicine (CM) syndrome classification and subgroup syndrome characteristics of ischemic stroke patients. METHODS: By extracting the CM clinical electronic medical records (EMRs) of 7,170 hospitalized patients with ischemic stroke from 2016 to 2018 at Weifang Hospital of Traditional Chinese Medicine, Shandong Province, China, a patient similarity network (PSN) was constructed based on the symptomatic phenotype of the patients. Thereafter the efficient community detection method BGLL was used to identify subgroups of patients. Finally, subgroups with a large number of cases were selected to analyze the specific manifestations of clinical symptoms and CM syndromes in each subgroup. RESULTS: Seven main subgroups of patients with specific symptom characteristics were identified, including M3, M2, M1, M5, M0, M29 and M4. M3 and M0 subgroups had prominent posterior circulatory symptoms, while M3 was associated with autonomic disorders, and M4 manifested as anxiety; M2 and M4 had motor and motor coordination disorders; M1 had sensory disorders; M5 had more obvious lung infections; M29 had a disorder of consciousness. The specificity of CM syndromes of each subgroup was as follows. M3, M2, M1, M0, M29 and M4 all had the same syndrome as wind phlegm pattern; M3 and M0 both showed hyperactivity of Gan (Liver) yang pattern; M2 and M29 had similar syndromes, which corresponded to intertwined phlegm and blood stasis pattern and phlegm-stasis obstructing meridians pattern, respectively. The manifestations of CM syndromes often appeared in a combination of 2 or more syndrome elements. The most common combination of these 7 subgroups was wind-phlegm. The 7 subgroups of CM syndrome elements were specifically manifested as pathogenic wind, pathogenic phlegm, and deficiency pathogens. CONCLUSIONS There were 7 main symptom similarity-based subgroups in ischemic stroke patients, and their specific characteristics were obvious. The main syndromes were wind phlegm pattern and hyperactivity of Gan yang pattern.
Humans ; Syndrome ; Ischemic Stroke ; Medicine, Chinese Traditional ; Liver ; Phenotype