Alzheimer’s disease (AD) is a central neurodegenerative disease characterized by progressive cognitive decline and memory impairment in clinical. Currently, there are no effective treatments for AD. In recent years, a variety of therapeutic approaches from different perspectives have been explored to treat AD. Although the drug therapies targeted at the clearance of amyloid β-protein (Aβ) had made a breakthrough in clinical trials, there were associated with adverse events. Neuroinflammation plays a crucial role in the onset and progression of AD. Continuous neuroinflammatory was considered to be the third major pathological feature of AD, which could promote the formation of extracellular amyloid plaques and intracellular neurofibrillary tangles. At the same time, these toxic substances could accelerate the development of neuroinflammation, form a vicious cycle, and exacerbate disease progression. Reducing neuroinflammation could break the feedback loop pattern between neuroinflammation, Aβ plaque deposition and Tau tangles, which might be an effective therapeutic strategy for treating AD. Traditional Chinese herbs such as Polygonum multiflorum and Curcuma were utilized in the treatment of AD due to their ability to mitigate neuroinflammation. Non-steroidal anti-inflammatory drugs such as ibuprofen and indomethacin had been shown to reduce the level of inflammasomes in the body, and taking these drugs was associated with a low incidence of AD. Biosynthetic nanomaterials loaded with oxytocin were demonstrated to have the capability to anti-inflammatory and penetrate the blood-brain barrier effectively, and they played an anti-inflammatory role via sustained-releasing oxytocin in the brain. Transplantation of mesenchymal stem cells could reduce neuroinflammation and inhibit the activation of microglia. The secretion of mesenchymal stem cells could not only improve neuroinflammation, but also exert a multi-target comprehensive therapeutic effect, making it potentially more suitable for the treatment of AD. Enhancing the level of TREM2 in microglial cells using gene editing technologies, or application of TREM2 antibodies such as Ab-T1, hT2AB could improve microglial cell function and reduce the level of neuroinflammation, which might be a potential treatment for AD. Probiotic therapy, fecal flora transplantation, antibiotic therapy, and dietary intervention could reshape the composition of the gut microbiota and alleviate neuroinflammation through the gut-brain axis. However, the drugs of sodium oligomannose remain controversial. Both exercise intervention and electromagnetic intervention had the potential to attenuate neuroinflammation, thereby delaying AD process. This article focuses on the role of drug therapy, gene therapy, stem cell therapy, gut microbiota therapy, exercise intervention, and brain stimulation in improving neuroinflammation in recent years, aiming to provide a novel insight for the treatment of AD by intervening neuroinflammation in the future.

ObjectiveTo investigate the anti-Alzheimer's disease （AD） effect of Dipsacus asper（DA） in the Caenorhabditis elegans model， and decipher the underlying mechanism via the peroxisome proliferator-activated receptor α （PPARα）/transcription factor EB （TFEB） pathway. MethodsFirst， transgenic AD C. elegans individuals were assigned into the blank control， model， positive control （WY14643， 20 µmol·L^-1）， and low-， medium-， and high-dose （100， 200， and 400 mg·L^-1， respectively） DA groups. The amyloid β-42 （Aβ₄₂） formation in the muscle cells， the paralysis time， and the deposition of amyloid β-protein （Aβ） in the head were detected. The lysosomal autophagy in the BV2 cell model was examined by Rluc-LC3wt/G120A. The expression levels of lysosomal autophagy-related proteins LC3Ⅱ， LC3I， LAMP2， and TFEB were detected by Western blot. Real-time quantitative polymerase chain reaction （Real-time PCR） was employed to determine the mRNA levels of autophagy-related genes beclin1 and Atg5 and lysosome-related genes LAMP2 and CLN2 downstream of PPARα/TFEB. A reporter gene assay was used to detect the transcriptional activities of PPARα and TFEB. Immunofluorescence was used to detect the fluorescence intensity of PPARα， and the active components of the ethanol extract of DA were identified by UPLC-MS. RCSB PDB， Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform （TCMSP）， and Autodock were used to analyze the binding between the active components and PPARα-ligand-binding domain （LBD）. ResultsCompared with the model group， the positive control group and 200 and 400 mg·L^-1 DA groups showed prolonged paralysis time （P<0.05）， and all the treatment groups showed decreased Aβ deposition in the head （P<0.01）. DA within the concentration range of 50-500 mg·L^-1 did not affect the viability of BV2 cells. In addition， DA enhanced the autophagy flux （P<0.05）， up-regulated the mRNA levels of beclin1， Atg5， LAMP2， and CLN2 （P<0.05， P<0.01）， promoted the nuclear translocation of TFEB （P<0.05）， increased LAMP2 expression and autophagy flux （P<0.05， P<0.01）， and enhanced the transcriptional activities of PPARα and TFEB （P<0.01）. The positive control group and 200 and 400 mg·L^-1 DA groups showed enhanced fluorescence intensity of PPARα in the BV2 nucleus （P<0.01）. UPLC-MS detected nine known compounds of DA， from which 8 active components of DA were screened out. The docking results suggested that a variety of components in DA could bind to PPARα-LBD and form stable hydrogen bonds. ConclusionDA may reduce the pathological changes in AD by regulating the PPARα-TFEB pathway.

This article reports the clinical features and gene mutation types of a large family with Nascimento form of syndromic X-linked intellectual developmental disorder (MRXSN), involving 9 individuals across 3 generations, and a literature review was conducted. In this family, 9 individuals had similar manifestations including mental retardation and unusual facies, and 4 of them had passed away. Genetic testing showed that the proband had the deletion of exons 2-3 of the UBE2A gene, which was inherited from the mother. Fluorescent quantitative polymerase chain reaction showed that the proband and his uncle had the deletion of exons 2-3 of the UBE2A gene; the proband's mother, grandmother, and great-aunt had a heterozygous deletion of exons 2-3 of the UBE2A gene; the proband's father, sister, and aunt had a normal copy number of exons 2-3 of the UBE2A gene. The 34 patients reported in the literature had diverse clinical phenotypes, and UBE2A gene mutations (22/34, 65%) and large fragment deletions (12/34, 35%) were the main mutation types. Moderate to severe mental retardation (34/34, 100%), speech and language impairment (33/34, 97%), and unusual facies (32/34, 94%) were the main clinical manifestations of MRXSN patients. The disease has obvious phenotypic heterogeneity, and early diagnosis facilitates optimal prenatal and postnatal management to improve reproductive outcomes.
Humans ; Male ; Ubiquitin-Conjugating Enzymes/genetics* ; Female ; X-Linked Intellectual Disability/genetics* ; Gene Deletion ; Child ; Pedigree ; Child, Preschool ; Adult

OBJECTIVE: To explore the clinical and genetic characteristics of a child with intellectual development disorder and seizures due to a variant of AP2M1 gene. METHODS: Clinical data of a child with intellectual development disorder and epilepsy who was admitted to the Department of Pediatric Neurology of the Third Affiliated Hospital of Zhengzhou University in January 2021 were retrospectively analyzed. Peripheral blood samples of the child and his parents were collected for whole exome sequencing. Candidate variant was verified by Sanger sequencing and pathogenicity analysis. The three-dimensional structure of the AP2M1 protein was visualized using Chimera v1.10.1 software. Pathogenicity of candidate variant was classified according to the Standards and Guidelines for the Interpretation of Sequence Variants from the American College of Medical Genetics and Genomics American College of Medical Genetics (ACMG). With "AP2M1 gene" "epilepsy" "intellectual disability" as the keywords, relevant cases were searched from CNKI, Wanfang Data knowledge service platform and PubMed databases with the search time spanning from the establishment of the database to September 2024. This study was approved by the Medical Ethics Committee of the Third Affiliated Hospital of Zhengzhou University (Ethics No.: 2020-57). RESULTS: The child was a 8-years-and-6-months-old boy, who could raise his head at 3 months and sit alone at 8 months old. He could not walk alone at 1 year old and underwent 2 months' rehabilitation treatment, and could walk alone and call his parents at 1-and-a-half-years-old. At 4-years-and-10-months-old, he started to have frequent seizures, manifesting as low level of consciousness, body shaking, accompanied by blinking, lasting about a few seconds several times a day and could be relieved. With the treatment of sodium valproate combined with lamotrigine, the convulsions were controlled, but his movement and cognition were lagged behind. DNA sequencing revealed that he has harbored a novel variant of the AP2M1 gene (NM_004068.3) c.508C>T (p.Arg170Trp). Sanger sequencing confirmed that both of his parents were of the wild-type. According to the guidelines from the American College for Medical Genetics and Genomics (ACMG), the variant was rated as pathogenic (PS2+PS4+PM1+PM2+PP2+PP3). The difference between the wild-type and mutant AP2M1 proteins can be clearly viewed through its three-dimensional structure. Two previous reports have included 5 cases due to the same variant. Common manifestations have included seizures (100%, 5/5), motor retardation (100%, 5/5), intellectual impairment (100%, 5/5), autism spectrum disorder (60%, 3/5), ataxia (100%, 5/5), and special facial features (20%, 1/5). CONCLUSION The c.508C>T (p.Arg170Trp) variant of the AP2M1 gene may underlie the intellectual retardation and seizure in this child.
Humans ; Male ; Child ; Intellectual Disability/genetics* ; Seizures/genetics* ; Exome Sequencing ; Mutation

Objective:To study the effects of manual inspection and special equipment inspection for light guiding components of hard endoscope after cleaning and disinfection,so as to provide scientific data and evidence for the application of special inspection equipment of hard endoscope in Central Sterile Supply Department(CSSD).Methods:A total of 100 hard endoscopes after cleaning and disinfection,which were in CSSD of the Fifth Medical Center of Chinese PLA General Hospital during July and August 2024,were selected.Each light guiding components of hard endoscope was respectively inspected by manual method and special functional detector for endoscope(inspection method with equipment).The positive rates of fog,stains and glass shards,and overall failure rate of light guiding components of hard endoscope,as well as the difference with the effect of clinical use,between two kinds of inspection methods were compared.Results:In 100 hard endoscopes,the inspection method with equipment found 2 cases were overall failure,which fog,strains and glass shards were respectively 2,0 and 0.The overall failure rate,and the positive rates of fog,stains and glass shards of the inspection method with equipment were respectively 2%,2%,0 and 0,which all lower than overall failure rate(23%),and the positive rates of fog(17%),stains(2%)and glass shards(4%)of manual inspection.There was significant difference in overall failure rate and positive rat of fog between the two kinds of inspection methods(x2=18.286,11.399,P＜0.05).The overall failure rate that was reflected by clinical users was 3%,which was significant lower than 23%of manual inspection,and the difference of that between two methods was significant(x2=15.959,P＜0.05).Conclusion:The inspection for light guiding components of hard endoscopes after cleaning and disinfection can be carried out by manual inspection and special inspection equipment,and results of special inspection equipment is getting closer the usage effect of clinical users.It has a series of advantages include being intuitive,easy use,high accuracy,convenient observation,and archivable.

Objective To understand the changing composition and antibiotic resistance of bacterial species in the clinical isolates from outpatient and emergency department(hereinafter referred to as outpatients)and inpatient children over time in various hospitals,and to provide laboratory evidence for rational antibiotic use.Methods The data on clinically isolated pathogenic bacteria and antimicrobial susceptibility of isolates from outpatients and inpatient children in the CHINET program from 2015 to 2021 were collected and analyzed.Results A total of 278 471 isolates were isolated from pediatric patients in the CHINET program from 2015 to 2021.About 17.1％of the strains were isolated from outpatients,primarily group A β-hemolytic Streptococcus,Escherichia coli,and Staphylococcus aureus.Most of the strains(82.9％)were isolated from inpatients,mainly SS.aureus,E.coli,and H.influenzae.The prevalence of methicillin-resistant S.aureus(MRSA)in outpatients(24.5％)was lower than that in inpatient children(31.5％).The MRSA isolates from outpatients showed lower resistance rates to the antibiotics tested than the strains isolated from inpatient children.The prevalence of vancomycin-resistant Enterococcus faecalis or E.faecium and penicillin-resistant S.pneumoniae was low in either outpatients or inpatient children.S.pneumoniae,β-hemolytic Streptococcus and S.viridans showed high resistance rates to erythromycin.The prevalence of erythromycin-resistant group A β-hemolytic Streptococcus was higher in outpatients than that in inpatient children.The prevalence of β-lactamase-producing H.influenzae showed an overall upward trend in children,but lower in outpatients(45.1％)than in inpatient children(59.4％).The prevalence of carbapenem-resistant Klebsiella pneumoniae(CRKpn),carbapenem-resistant Pseudomonas aeruginosa(CRPae)and carbapenem-resistant Acinetobacter baumannii(CRAba)was 14％,11.7％,47.8％in outpatients,but 24.2％,20.6％,and 52.8％in inpatient children,respectively.The prevalence of multidrug-resistant E.coli,K.pneumoniae,Proteus mirabilis,P.aeruginosa and A.baumannii strains was lower in outpatients than in inpatient children.The prevalence of fluoroquinolone-resistant E.coli,ESBLs-producing K.pneumoniae,ESBLs-producing P.mirabilis,carbapenem-resistant E.coli(CREco),CRKpn,and CRPae was lower in children in outpatients than in inpatient children,but the prevalence of CRAba in 2021 was higher than in inpatient children.Conclusions The distribution of clinical isolates from children is different between outpatients and inpatients.The prevalence of MRSA,ESBL,and CRO was higher in inpatient children than in outpatients.Antibiotics should be used rationally in clinical practice based on etiological diagnosis and antimicrobial susceptibility test results.Ongoing antimicrobial resistance surveillance and prevention and control of hospital infections are crucial to curbing bacterial resistance.

Objective To investigate the changing antibiotic resistance profiles of E.coli isolated from patients in the 52 hospitals participating in the CHINET program from 2015 to 2021.Methods Antimicrobial susceptibility was tested for clinical isolates of E.coli according to the unified protocol of CHINET program.WHONET 5.6 and SPSS 20.0 software were used for data analysis.Results Atotal of 289 760 nonduplicate clinical strains ofE.coli were isolated from 2015 to 2021,mainly from urine samples(44.7±3.2)％.The proportion of E.coli strains isolated from urine samples was higher in females than in males(59.0％vs 29.5％).The proportion of E.coli strains isolated from respiratory tract and cerebrospinal fluid samples was significantly higher in children than in adults(16.7％vs 7.8％,0.8％vs 0.1％,both P＜0.05).The isolates from internal medicine department accounted for the largest proportion(28.9±2.8)％with an increasing trend over years.Overall,the prevalence of ESBLs-producing E.coli and carbapenem resistant E.coli(CREco)was 55.9％and 1.8％,respectively during the 7-year period.The prevalence of ESBLs-producing E.coli was the highest in tertiary hospitals each year from 2015 to 2021 compared to secondary hospitals.The prevalence of CREco was higher in children's hospitals compared to secondary and tertiary hospitals each year from 2015 to 2021.The prevalence of ESBLs-producing E.coli in tertiary hospitals and children's hospitals and the prevalence of CREco in children's hospitals showed a decreasing trend over the 7-year period.The prevalence of CREco in secondary and tertiary hospitals increased slowly.Antibiotic resistance rates changed slowly from 2015 to 2021.Carbapenem drugs(imipenem,meropenem)were the most active drugs amongβ-lactams against E.coli(resistance rate≤2.1％).The resistance rates of E.coli to β-lactam/β-lactam inhibitor combinations(piperacillin-tazobactam,cefoperazone-sulbactam),aminoglycosides(amikacin),nitrofurantoin and fosfomycin(for urinary isolates only)were all less than 10％.The resistance rate of E.coli strains to antibiotics varied with the level of hospitals and the departments where the strains were isolated,especially for cefazolin and ciprofloxacin,to which the resistance rate of E.coli strains from children in non-ICU departments was significantly lower than that of the strains isolated from other departments(P＜0.05).The E.coli isolates from ICU showed higher resistance rate to most antimicrobial agents tested(excluding tigecycline)than the strains isolated from other departments.The E.coli strains isolated from tertiary hospitals showed higher resistance rates to the antimicrobial agents tested(excluding tigecycline,polymyxin B,cefepime and carbapenems)than the strains from secondary hospitals and children's hospitals.Conclusions E.coli is an important pathogen causing clinical infection.More than half of the clinical isolates produced ESBL.The prevalence of CREco is increasing in secondary and tertiary hospitals over the 7-year period even though the overall prevalence is still low.This is an issue of concern.

Objective:To investigate the correlation between occupational ionizing radiation exposure and abnormal metabolic indicators, providing a basis for assessing the health risks of occupational ionizing radiation workers and establishing a risk prediction model for chronic metabolic diseases.Methods:In January 2023, 7708 individuals were randomly selected from the occupational health examination data in Zhejiang Province. After excluding 16 individuals due to record errors, 2698 on-the-job workers exposed to ionizing radiation from 2020 to 2021 were selected as the exposure group, 2027 pre-employment workers exposed to ionizing radiation from 2016 to 2022 were selected as the pre-employment control group, and 2967 non-ionizing radiation workers from 2016 to 2022 were selected as the control group. Demographic data, blood routine, urine routine, biochemical indicators, and peripheral blood lymphocyte micronucleus rate of each group were collected. One-way ANOVA and rank sum test were used for comparison of indicators. The exposure group was divided into different groups based on age, exposure duration, and body mass index (BMI), and the correlation between indicators and occupational ionizing radiation was analyzed. Lasso variable selection was conducted by constructing a penalty coefficient (λ), and a complete regression model was established.Results:There were statistically significant differences in indicators such as blood pressure, heart rate, and average hemoglobin concentration between the exposure group and the control group, as well as the pre-employment control group ( P<0.05). Through Lasso variable selection, 19 indicators including exposure length, systolic blood pressure (SBP), diastolic blood pressure (DBP), body weight, body mass index (BMI), urine pH value, red blood cell count, microscopic white blood cells, casts, absolute value of monocytes, mean corpuscular volume of red blood cells, mean hemoglobin concentration, alkaline phosphatase, albumin-to-globulin ratio, total bile acid, α-L-fucosidase, urea, creatinine, and low-density lipoprotein cholesterol (LDL-C). There were statistically significant differences in exposure length, SBP, DBP, body weight, BMI, microscopic white blood cells, casts, albumin-to-globulin ratio, total bile acid, α-L-fucosidase, urea, creatinine, LDL-C, and mean corpuscular volume of red blood cells among workers of different ages in the exposure group ( P<0.05) ; there were statistically significant differences in SBP, DBP, body weight, BMI, microscopic white blood cells, casts, albumin-to-globulin ratio, total bile acid, α-L-fucosidase, urea, creatinine, LDL-C, and mean corpuscular volume of red blood cells among workers with different exposure durations ( P<0.05) ; there were statistically significant differences in exposure length, SBP, DBP, body weight, BMI, red blood cells, microscopic white blood cells, casts, albumin-to-globulin ratio, total bile acid, α-L-fucosidase, urea, creatinine, LDL-C, absolute value of monocytes, mean corpuscular volume of red blood cells, and mean hemoglobin concentration among workers with different BMIs ( P<0.05) . Conclusion:Occupational ionizing radiation is associated with abnormal metabolic indicators such as blood pressure, heart rate, total bile acid, α-L-fucosidase, urea, and creatinine in the human body. More attention should be paid to the risk of chronic metabolic diseases among workers exposed to ionizing radiation.

Objective:To preliminarily evaluate the accuracy of a segmented rotational motion-based osteotomy module for autonomous dental implant robots in immediate implant placement in the anterior region through an in vitro model experiment, providing references for clinical practice. Methods:Twenty-three identical commercial maxillary resin models with dentition defects for immediate implant placement were divided into three groups: a fully guided static computer-assisted implant surgery (sCAIS) group ( n=5), a robotic computer-assisted implant surgery (rCAIS) group based on conventional coronal-apical linear motion osteotomy (rCAIS-C, n=9) and a rCAIS group based on segmented rotational motion osteotomy (rCAIS-S, n=9). Two implants were placed in each model using the corresponding surgical protocols. Intraoral scan data of pre-and post-operative models were imported into software to evaluate deviations between the actual and planned implant positions. Results:In the rCAIS-S group, the global deviations at the implant platform and apex were 0.50 (0.32) mm and 0.52 (0.22) mm, respectively, with an angular deviation of 1.08° (0.49°). These values were significantly smaller than those in the sCAIS group [platform: 0.88 (0.50) mm, apex: 1.44 (0.50) mm, angular deviation: 2.86° (1.76°), P<0.05]. rCAIS-S group also showed significantly smaller platform and apex deviations compared to rCAIS-C group [platform: 0.69 (0.12) mm, apex: 0.94 (0.16) mm, P<0.05], though angular deviations of rCAIS-S group did not differ significantly from rCAIS-C group [1.27° (0.56°), P>0.05]. Conclusions:Within the limitation of this study, the segmented rotational motion-based osteotomy module for dental implant robots demonstrates superior accuracy in immediate implant placement in the anterior area compared to sCAIS and rCAIS based on conventional coronal-apical linear motion osteotomy.

Objective To explore the application values of different detection methods in monitoring the decline pattern of syphilis-spe-cific antibody in the non-congenital syphilis children.Methods A total of 80 non-congenital syphilis children were included in the study.The serum specimens were collected after birth,and the syphilis-specific antibodies were detected using electrochemilumines-cence immunoassay(ECLIA),western blotting(WB),treponema pallidum particle agglutination assay(TPPA),enzyme-linked im-munosorbent assay(ELISA),and toluidine red unheated serum test(TRUST).Follow-up was conducted every three months until the positive results of ELISA and TRUST turned to negative.Results The results of ECLIA showed that the syphilis-specific antibody lev-els in the non-congenital syphilis children declined to 25％of the level at birth within 2 to 3 months,and the rate of decline was inde-pendent of the initial concentration.WB analysis indicated that the specific IgG bands in non-congenital syphilis children at birth were consistent with those of their mother,and the sequence of specific antibodies decline was as follows:TPN47,TPN15,TPN45,and TPN17.Due to methodological limitations,the absorbance values of ELISA showed no significant change during the first three months after birth when high concentrations of antibodies were present in the samples,but it showed high sensitivity in the detection for the samples with low-concentration of syphilis antibodies.The detection rates of ECLIA,TPPA,and WB were compared by using ELISA as the reference method.At birth,the detection rates of syphilis antibodies were 100％,100％,and 90％,respectively.In 3 months after birth,the detection rates were 100％,100％,and 75％.In 6 months after birth,,they were 100％,46％,and 15％.In 9 months after birth,they were 83％,33％,and 0％.The positive rate of TRUST was 17.5％at birth.and turned to negative in 3 month of follow-up.Conclusion Syphilis specific IgG antibodies may fully transferred to the fetus and decline in a predictable pattern after birth.The comprehensive analysis for the results of the four methods suggested that dynamic detection using ECLIA method could be used to pre-dict the risk of non-congenital syphilis or terminate the follow-up at 3 months,while the seroconversion detected by WB was earlier than that by TPPA,while ELISA required the longest follow-up period.