Objective:To explore the distribution and clearance of 99mTc labeled diethylenetriamine pentaacetic acid(99mTc-DTPA)in different brain regions of adult rats after administration through brain extracellular space(ECS)pathway.Methods:After the injection of a volume of 2 μL and radioactive activity of about 3.7 MBq(100 μCi)of 99mTc-DTPA into the caudate nucleus and thalamus of SD rats through stereotactic positioning of rat brain,the single photon emission computed tomography/computed tomography(SPECT/CT)for small animals was used for imaging at different time points,and the dyna-mic distribution and clearance of the tracer in the whole body were observed continuously.The SD rats were injected with 99mTc-DTPA into thalamus and caudate nucleus respectively for biological distribution in vivo.They were put to death 4 h later.Their blood and urine were collected.The brain,cerebellum,heart,liver,spleen,lung,and kidney were taken and weighed by γ counter to measure its radioactivity.Results:SPECT/CT imaging results showed that after 99mTc-DTPA was administered through brain ECS,the radioactivity was concentrated in the brain,kidney and bladder.The tracer administered to the left caudate nucleus was preferentially drained to the right cerebellum,while the tracer administered to the right caudate nucleus was preferentially drained to the left cerebellum.There was a phenomenon of"con-tralateral cerebellar dominant drainage"in the caudate nucleus.The thalamic area preferentially drained to the ipsilateral cerebellum after administration.Four hours after administration via ECS,high radioac-tive uptake appeared in urine,cerebellum and brain,followed by blood and kidney.The radioactive up-take values of heart,liver,spleen and lung were low,which were mainly excreted through urinary sys-tem.Conclusion:Intracerebral ECS administration is a promising method of administration,but there are significant differences in distribution and clearance in different brain regions.This study further ex-pands the content and significance of"ECS regions",and also provides an important theoretical founda-tion for the treatment of encephalopathy and the research of new drugs through brain ECS in the future.

Objective:To explore the distribution and clearance of 99mTc labeled diethylenetriamine pentaacetic acid(99mTc-DTPA)in different brain regions of adult rats after administration through brain extracellular space(ECS)pathway.Methods:After the injection of a volume of 2 μL and radioactive activity of about 3.7 MBq(100 μCi)of 99mTc-DTPA into the caudate nucleus and thalamus of SD rats through stereotactic positioning of rat brain,the single photon emission computed tomography/computed tomography(SPECT/CT)for small animals was used for imaging at different time points,and the dyna-mic distribution and clearance of the tracer in the whole body were observed continuously.The SD rats were injected with 99mTc-DTPA into thalamus and caudate nucleus respectively for biological distribution in vivo.They were put to death 4 h later.Their blood and urine were collected.The brain,cerebellum,heart,liver,spleen,lung,and kidney were taken and weighed by γ counter to measure its radioactivity.Results:SPECT/CT imaging results showed that after 99mTc-DTPA was administered through brain ECS,the radioactivity was concentrated in the brain,kidney and bladder.The tracer administered to the left caudate nucleus was preferentially drained to the right cerebellum,while the tracer administered to the right caudate nucleus was preferentially drained to the left cerebellum.There was a phenomenon of"con-tralateral cerebellar dominant drainage"in the caudate nucleus.The thalamic area preferentially drained to the ipsilateral cerebellum after administration.Four hours after administration via ECS,high radioac-tive uptake appeared in urine,cerebellum and brain,followed by blood and kidney.The radioactive up-take values of heart,liver,spleen and lung were low,which were mainly excreted through urinary sys-tem.Conclusion:Intracerebral ECS administration is a promising method of administration,but there are significant differences in distribution and clearance in different brain regions.This study further ex-pands the content and significance of"ECS regions",and also provides an important theoretical founda-tion for the treatment of encephalopathy and the research of new drugs through brain ECS in the future.

Objective:To unveil the pathological changes associated with demyelination in schizophre-nia(SZ)and its consequential impact on interstitial fluid(ISF)drainage,and to investigate the thera-peutic efficacy of ursolic acid(UA)in treating demyelination and the ensuing abnormalities in ISF drainage in SZ.Methods:Female C57BL/6J mice,aged 6-8 weeks and weighing(20±2)g,were randomly divided into three groups:control,SZ model,and UA treatment.The control group received intraperitoneal injection(ip)of physiological saline and intragastric administration(ig)of 1％carboxy-methylcellulose sodium(CMC-Na).The SZ model group was subjected to ip injection of 2 mg/kg dizo-cilpine maleate(MK-801)and ig administration of 1％CMC-Na.The UA treatment group underwent ig administration of 25 mg/kg UA and ip injection of 2 mg/kg MK-801.The treatment group received UA pretreatment via ig administration for one week,followed by a two-week drug intervention for all the three groups.Behavioral assessments,including the open field test and prepulse inhibition experiment,were conducted post-modeling.Subsequently,changes in the ISF partition drainage were investigated through fluorescent tracer injection into specific brain regions.Immunofluorescence analysis was employed to examine alterations in aquaporin 4(AQP4)polarity distribution in the brain and changes in protein expres-sion.Myelin reflex imaging using Laser Scanning Confocal Microscopy(LSCM)was utilized to study modifications in myelin within the mouse brain.Quantitative data underwent one-way ANOVA,followed by TukeyHSD for post hoc pairwise comparisons between the groups.Results:The open field test re-vealed a significantly longer total distance[(7 949.39±1 140.55)cm vs.(2 831.01±1 212.72)cm,P＜0.001]and increased central area duration[(88.43±22.06)s vs.(56.85±18.58)s,P=0.011]for the SZ model group compared with the controls.The UA treatment group exhibited signifi-cantly reduced total distance[(2 415.80±646.95)cm vs.(7 949.39±1 140.55)cm,P＜0.001]and increased central area duration[(54.78±11.66)s vs.(88.43±22.06)s,P=0.007]compared with the model group.Prepulse inhibition test results demonstrated a markedly lower inhibition rate of the star-tle reflex in the model group relative to the controls(P＜0.001 for both),with the treatment group dis-playing significant improvement(P＜0.001 for both).Myelin sheath analysis indicated significant demy-elination in the model group,while UA treatment reversed this effect.Fluorescence tracing exhibited a significantly larger tracer diffusion area towards the rostral cortex and reflux area towards the caudal thala-mus in the model group relative to the controls[(13.93±3.35)mm2 vs.(2.79±0.94)mm2,P＜0.001 for diffusion area;(2.48±0.38)mm2 vs.(0.05±0.12)mm2,P＜0.001 for reflux area],with sig-nificant impairment of drainage in brain regions.The treatment group demonstrated significantly reduced tracer diffusion and reflux areas[(7.93±2.48)mm2 vs.(13.93±3.35)mm2,P＜0.001 for diffusion area;(0.50±0.30)mm2 vs.(2.48±0.38)mm2,P＜0.001 for reflux area].Immunofluorescence staining revealed disrupted AQP4 polarity distribution and reduced AQP4 protein expression in the model group compared with the controls[(3 663.88±733.77)μm2 vs.(13 354.92±4 054.05)μm2,P＜0.001].The treatment group exhibited restored AQP4 polarity distribution and elevated AQP4 protein expression[(11 104.68±3 200.04)μm2 vs.(3 663.88±733.77)μm2,P＜0.001].Conclusion:UA intervention ameliorates behavioral performance in SZ mice,Thus alleviating hyperactivity and anxiety symptoms and restoring sensorimotor gating function.The underlying mechanism may involve the improve-ment of demyelination and ISF drainage dysregulation in SZ mice.

Objective:To explore the efficacy and safety of endoscopic radial incision (ERI) for congenital membranous duodenal stenosis (MDS).Methods:The clinical data of 13 children with MDS receiving ERI in the Department of Gastroenterology of Xi'an Children's Hospital from May 2017 to December 2021 were reviewed and analyzed. The perioperative management, surgical procedures, postoperative complications and follow-up were summarized.Results:There were 5 boys and 8 girls with a median disease duration of 8 (2-20) months, and the median age of diagnosis was 13 months (5-30 months). The septum of 10 cases (10/13) was located in the descending part of the duodenum, and that of 3 cases (3/13) in the horizontal part. The papilla of 1 case (1/13) opened on the septum, that of 3 cases (3/13) within 5 cm of the mouth side of the septum, and that of 9 cases (9/13) within 5 cm of the anal side of the septum. The median diameter of the septal aperture was 3 mm (2-6 mm). All 13 children successfully underwent ERI with a median operation time of 20 min (15-32 min). The average surgical incision was 3 strokes (2-4 strokes), and the endoscope with outer diameter 9.9 mm could pass stenosis after ERI. The median incision diameter was 10 mm (10-12 mm). All patients achieved relief of clinical symptoms after ERI. One patient (1/13) suffered from the postoperative delayed bleeding, which was stopped by endoscopic titanium clamping. No intestinal perforation or duodenal papilla injury occurred, and median postoperative hospital stay was 6 days (5-10 days). The upper gastrointestinal angiogram and gastroscopy were repeated 3 months after ERI, and the median diameter of stenosis was 12 mm (10-15 mm), which was significantly dilated compared with before. The mean body weight increase at 1 month after ERI was 1.20 kg (0.50-1.80 kg), and the mean body weight increase at 3 months was 3.50 kg (2.50-4.00 kg), which reached the normal body weight of the same age.Conclusion:ERI is safe and effective for the treatment of MDS in children, and shows good clinical application and promotion value.

Objective:To compare the antiplatelet effects of vicagrel and clopidogrel in patients with different cytochrome P450 (CYP) 2C19 genotypes.Methods:This is a post-hoc analysis of a phase Ⅱ clinical trial of vicagrel, which included patients with coronary heart disease who underwent percutaneous coronary intervention from August 2018 to June 2019 in 18 centers. Patients were categorized based on the presence of CYP 2C19 *2 or *3 loss-of-function (LOF) alleles into LOF carrier group ( n=111) and non-LOF carrier group ( n=90). Each group included patients received vicagrel 5 mg, 6 mg, 7.5 mg, or clopidogrel 75 mg for 28 days per study protocol. P2Y 12 reaction units (PRU) were measured using VerifyNow at baseline, 6 to 8 hours after loading dose, 7 to 10 days after randomization, and 28 days after randomization and the percentage inhibition of platelet aggregation (%IPA) was calculated. The primary endpoint was %IPA on day 28. Within the patients from the General Hospital of Northern Theater Command, 8 to 12 patients in each study arms were enrolled in a prespecified pharmacokinetic sub-study, measuring the time to reach maximum plasma concentration (T max), peak plasma concentration (C max), and area under the plasma concentration-time curve (AUC). Results:Among 201 patients, the age was (58.8±8.5) years, and 139 (69.2%) were male. In non-LOF carriers, there was no significant differences in PRU values and %IPA between the vicagrel 5 mg, 6 mg, 7 mg, and clopidogrel groups at all time points (all P>0.05). In LOF carriers, %IPA was significantly higher in the vicagrel-treated groups than in the clopidogrel group at 6-8 hours after loading dose (22.9 (14.2, 31.5)% vs. 19.8 (11.0, 28.6)% vs. 29.5 (20.9, 38.0)% vs. 12.9 (3.9, 21.9)%, P=0.038) and 7-10 days after randomization (22.4 (14.2, 30.5)% vs. 34.4 (26.1, 42.6)% vs. 39.8 (31.8, 47.9)% vs. 24.7 (16.3, 33.2)%, P=0.001), with a trend towards higher %IPA in the vicagrel-treated groups at day 28 (30.4 (21.3, 39.6)% vs. 36.5 (27.2, 45.7)% vs. 40.8 (31.8, 49.8)% vs. 30.7(21.2, 40.2)%, P=0.056). Pharmacokinetic results of 35 patients showed that the C max and AUC of the active metabolite M15-2 of vicagrel was similar to that of clopidogrel in non-LOF carriers, but AUC between vicagrel 5 mg, 6 mg, 7 mg and clopidogrel were significantly different in LOF carriers ((5.6±0.6) h·μg -1·L -1 vs. (6.8±2.7) h·μg -1·L -1 vs. (9.2±3.3) h·μg -1·L -1 vs. (4.2±1.9) h·μg -1·ml -1, P=0.020). Conclusion:Vicagrel and clopidogrel have similar antiplatelet effects in non-LOF carriers, but vicagrel exhibits superior antiplatelet effects in LOF carriers.

Objective To comprehensively analyze the epidemiological characteristics and resistance mechanisms of New Delhi metallo-β-lactamase(NDM)-positive multidrug-resistant bacteria in China.Methods Relevant literatures on NDM-positive multidrug-resistant bacteria discovered in China were searched in the CNKI and PubMed databases(publications from January 1,2017 to December 31,2023).The epidemiological analysis was conducted on the types of NDM-positive bacterial strains,their regional distribution,infection sources,resistance profiles,and transfer mechanisms.Results A total of 118 eligible articles were collected,reporting 1627 NDM-positive bacterial strains.The number of reports increased annually from 2011 to 2019,but began to decline annually from 2020 onwards.NDM-1 and NDM-5 were the most commonly reported variants.The highest number of reports came from Eastern China,followed by Central China and North China.The primary pathogens were Klebsiella pneumoniae,Escherichia coli,and Enterobacter cloacae.The age distribution of patients with NDM-positive infections showed distinct patterns,with neonates and children accounting for 27.25％and patients over 50 years old accounting for 49.57％.The majority of positive bacterial infections came from sputum(38.28％),urine(28.94％),and blood(23.28％).The main departments reporting NDM-positive bacteria were the ICU(39.93％)and pediatrics(20.14％).These resistant bacteria exhibited resistance to more than 50.00％of antibiotics,with lower resistance to colistin and tigecycline(below 30.00％).The predominant plasmid type carrying the blaNDMwas IncX3,and the insertion sequences upstream and downstream of the blaNDM showed diversity.Conclusion NDM-positive multidrug-resistant bacteria are widely prevalent across regions in China,exhibiting multidrug-resistance.This poses significant challenges to clinical antibiotic selection and necessitates the development of effective countermeasures.

Interstitial lung disease is a common lung disease of connective tissue disease,which seriously affects the survival rate and quality of life of patients with connective tissue disease.Interstitial lung disease may occur in the whole course of connective tissue disease.Therefore,imaging plays an important role in the whole disease cycle of connective tissue-associated interstitial lung disease.At present,high-resolution computed tomography is the cornerstone of screening,diagnosis and follow-up of connective tissue-associated interstitial lung disease,but ionizing radiation is a potential limiting factor in its clinical application.In recent years,new imaging techniques have developed rapidly,and some promising research results have been achieved in the early screening,diagnosis and efficacy evaluation of connective tissue-associated interstitial lung disease,and they are gradually moving towards non-invasive,low-radiation and accurate imaging analysis techniques.This article reviews the advances in imaging research of connective tissue-associated interstitial lung disease,and analyzes the advantages and disadvantages of various new imaging techniques,as well as the challenges and prospects.

Approximately 140 million people worldwide are homozygous carriers of APOE4 (ε4), a strong genetic risk factor for late onset familial and sporadic Alzheimer's disease (AD), 91% of whom will develop AD at earlier age than heterozygous carriers and noncarriers. Susceptibility to AD could be reduced by targeted editing of APOE4, but a technical basis for controlling the off-target effects of base editors is necessary to develop low-risk personalized gene therapies. Here, we first screened eight cytosine base editor variants at four injection stages (from 1- to 8-cell stage), and found that FNLS-YE1 variant in 8-cell embryos achieved the comparable base conversion rate (up to 100%) with the lowest bystander effects. In particular, 80% of AD-susceptible ε4 allele copies were converted to the AD-neutral ε3 allele in human ε4-carrying embryos. Stringent control measures combined with targeted deep sequencing, whole genome sequencing, and RNA sequencing showed no DNA or RNA off-target events in FNLS-YE1-treated human embryos or their derived stem cells. Furthermore, base editing with FNLS-YE1 showed no effects on embryo development to the blastocyst stage. Finally, we also demonstrated FNLS-YE1 could introduce known protective variants in human embryos to potentially reduce human susceptivity to systemic lupus erythematosus and familial hypercholesterolemia. Our study therefore suggests that base editing with FNLS-YE1 can efficiently and safely introduce known preventive variants in 8-cell human embryos, a potential approach for reducing human susceptibility to AD or other genetic diseases.
Humans ; Apolipoprotein E4/genetics* ; Cytosine ; Mutation ; Blastocyst ; Heterozygote ; Gene Editing ; CRISPR-Cas Systems

Objective:To compare the clinical features between inflammatory bowel disease (IBD) and Clostridium difficile infection (CDI) in children. Methods:A cross-sectional study was conducted. Clinical data of patients initially diagnosed IBD and CDI in the Affiliated Children′s Hospital of Xi′an Jiaotong University from August 2017 to August 2022 were collected retrospectively. The age, gender, symptom, laboratory test indexes of children in the two groups were analyzed and compared.Results:A total of 44 children [24 males, 20 females; median age, 9.04 (5.34, 12.50) years] were included in IBD group and there were 30 patients with Crohn′s disease (CD), 12 with ulcerative colitis (UC) and 2 with IBD unclassified (IBDU). A total of 45 children [28 males, 17 females; median age, 4.00 (2.38, 6.00) years] were included in CDI group. There was no significant difference in gender between the two groups (χ 2 = 0.54, P = 0.4625). The age of the CDI group was younger than that of the IBD group, and the difference was statistically significant ( U = 568.50, P = 0.0004). The incidences of diarrhea, hematochezia, abdominal pain and fever were high both in patients with IBD and CDI. The more common symptom in IBD group was abdominal pain, and its ratio was significantly higher than that of CDI group (61.36% vs. 40.00%, χ 2 = 4.06, P = 0.0439). The common clinical manifestations in CDI group were diarrhea and hematochezia, with a significantly higher proportion compared to the IBD group (diarrhea: 71.11% vs. 47.73%, χ 2 = 6.48, P = 0.0109; hematochezia: 75.56% vs. 50.00%, χ 2 = 6.23, P = 0.0126). The duration of symptoms in the IBD group was significantly longer than that in the CDI group ( U = 437.50, P<0.01). Compared with the CDI group, IBD patients had higher level of white blood cell count, neutrophil ratio, platelet count, C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR), while lower level of hemoglobin and albumin, and all the differences were statistically significant (all P<0.05) . Conclusions:IBD and CDI have similar symptoms, however abdominal pain is more common in the patients with IBD, diarrhea and hematochezia are more common in patients with CDI. The duration of symptoms in IBD patients is longer, and the level of CRP and ESR is higher. These clinical features can be used to differentiate the patients with initially diagnosed IBD from CDI.

Objective: To investigate abnormal spinal curvature among primary and secondary school students in Sichuan Province, so as to provide evidence for scientific prevention. Methods: Using a stratified cluster random sampling method, a total of 210 713 students of grade 4 to grade 12 from 21 cities (prefectures) in Sichuan Province were selected for spinal curvature screening and questionnaire survey from September to November 2022. Chi-square test and multivariate Logistic regression model were used to analyze the influencing factors of abnormal spinal curvature. Results: The detection rate of abnormal spinal curvature was 3.42%, with urban areas (4.54%) higher than that in suburban areas(2.57%), girls (3.86%) higher than that in boys(2.98%), high school students (4.70%) higher than that in middle school students (3.80%) and elementary school students(2.21%), the differences were statistically significant ( χ 2=606.96, 123.81, 645.24, P <0.01). Multivariate Logistic regression analysis showed that urban area, junior and senior high school, girl, carrying backpack on one shoulder, desks and chairs adjusted for student height less than ≤1 time every school year, moderate-to-vigorous physical activity less than 1 h per week, and indoors sedentary time more than 10 h/d were positively associated with abnormal spinal curvature ( OR=1.72, 1.75, 1.87, 1.26, 1.09, 1.07, 1.10, 1.25 , P <0.05). Conclusion The detection rate of abnormal spinal curvature of primary and secondary school students may be affected by the urbanicity, educational stage as well as gender in Sichuan Province. More attention should be paid to urban high school girls, and targeted strategies should be explored to reduce the incidence of abnormal spinal curvature.