Mining pharmacovigilance signals for asthma adverse events in underage population based on the FAERS database / 药物流行病学杂志

Objective To conduct data mining of asthma-inducing medications in underage populations based on the U.S.Food and Drug Administration Adverse Event Reporting System(FAERS)database,so as to provide reference for the clinical application of related medications.Methods Adverse drug event(ADE)reports from the first quarter of 2013 to the fourth quarter of 2022 in the FAERS database were collected and screened for reports of asthma adverse events in the this population(under 18 years old),which were categorized into infants,toddlers,children,and adolescents according to different age groups,and were subjected to medication signal mining by using the reporting odds ratio method,the composite standardized method,and the information component method.Results A total of 1 915 reports were obtained after screening,involving 1 042(54.41％)males and 831(43.39％)females;the highest percentage of the reporting population was between 12 and under 18 years old,with a total of 762(39.79％);60.78％of the reports were reported by health professionals;and the results of the clinical referrals showed that serious adverse events occurred in 85.90％of the cases.306 suspected drugs were screened,52 drugs were determined to be valid signals,and 1 044 adverse events were reported,of which 16 drug inserts did not mention the risk of asthma,in order of elosulfatase alpha,canakinumab,tobramycin,vancomycin,ceftriaxone,cetirizine,phenylephrine,imiglucerase,cefuroxime,betamethasone,atropine,tadalafil,riscovastatin,cyclophosphamide,octreotide,and omeprazole.Conclusion The FAERS database was mined for adverse drug event signals and evaluated using the proportional disequilibrium method to identify 16 medicines that may trigger pharmacogenetic asthma and are not documented in the specification,which can be used to provide a good early warning for the clinic.At the same time,focusing on special populations,strengthening the assessment of lung function before medication and monitoring during and after medication,timely interventions were taken to reduce the harm of drug-derived adverse reactions and ensure the safe use of medication.

Establishment and validation of a dose-response curve for semi-automatic analysis of dicentric chromosomes / 中国职业医学

ObjectiveTo establish a dose-effect curve for semi-automatic analysis of dicentric chromosomes(DC) based on an automatic chromosome analysis system. Methods A total of three healthy volunteers were recruited as the study subjects, and their peripheral blood was collected and stimulated by X-ray at doses of 0.00, 0.10, 0.25, 0.50, 0.75, 1.00, 2.00, 3.00, 4.00, and 5.00 Gy, with the absorbed dose rate of 1.0 Gy/min. Images of DC in the mid-stage of cell division were collected using a high-throughput automatic chromosome analysis system. The DCScore software was used to automatically analyze DC aberrations, and a dose-effect curve for semi-automatic analysis of DC was fitted after manual confirmation. The fitted dose-effect curve for semi-automatic analysis of DC was validated for accuracy using three proficiency test samples from the national quality assessment of biological dose. Results The incidence of DC increased with increasing irradiation doses in the range of 0.00-5.00 Gy (P<0.01). The dose-effect curve for the fitted semi-automatic analysis of DC was ŷ =0.000 8 (±0.000 2) +0.009 2(±0.000 9) D+0.014 2(±0.000 4) D2 (R2= 0.999 8). The relative deviation between the estimated dose and the actual dose of the three test samples was about 20.00%, indicating curve applicability for biological dose estimation. Moreover, excluding the time spent on manual analysis, the semi-automatic analysis method increased the analysis efficiency by 26.0 times. Conclusion The semi-automatic analysis dose-effect curve for DC stimulated by X-ray is constructed for biological dose estimation, which can reduce the manual analysis time, and holds great potential for application in nuclear emergency response to large-scale radiation accidents.

Evaluation of influencing factors for the severity of cerebral microbleed and its relationship with cognitive impairment in end-stage renal disease using MRI semi-automatic quantitative susceptibility imaging / 中华放射学杂志

Objective:To investigate the influencing factors for total number, total volume, and total iron burden of cerebral microbleeds (CMBs) and the relationship between CMBs with cognitive impairment in end-stage renal disease (ESRD) using semi-automatic quantitative susceptibility mapping (QSM).Methods:The study was a cross-sectional study. Clinical and imaging data of 46 ESRD patients with≥1 CMBs who attended Tianjin First Central Hospital from November 2018 to August 2022 were retrospectively analyzed. There were 26 males and 20 females, aged 42-75 years. All patients underwent susceptibility-weighted imaging (SWI) scanning, then SWI data was post-processed to obtain QSM. The semi-automatic dynamic programming algorithm was used to get the volume and mean susceptibility value of each CMB by sketching the boundary of CMBs. The CMBs iron load total volume were calculated. Stepwise linear regression analysis was used to explore independent influencing factors for the number, total volume, and total iron burden of CMBs in ESRD patients. Partial correlation analysis was used to explore the relationship between CMBs and cognitive impairment with the other signs of cerebral small vessel diseases as covariates.Results:In patients with ESRD, CMBs were located in the frontal lobe in 19 cases, parietal lobe in 9 cases, temporal lobe in 19 cases, occipital lobe in 14 cases, basal ganglia in 27 cases, dorsal thalamus in 15 cases, centrum semiovale in 14 cases, cerebellum in 14 cases, and brainstem in 13 cases. C-reactive protein levels (95% CI 101.81-157.85, r=0.96, P=0.001) and creatinine levels (95% CI 5.32-29.61, r=0.71, P=0.010) were influencing factors for the total iron burden of CMBs. C-reactive protein levels (95% CI 0.72-1.15, r=0.99, P=0.001) and creatinine levels (95% CI 0.03-0.22, r=0.89, P=0.014) were influencing factors for the total volume of CMBs. C-reactive protein levels (95% CI 0.10-0.12, r=0.96, P=0.001) and alkaline phosphatase levels (95% CI 0.16-0.38, r=0.59, P=0.001) were influencing factors for the number of CMBs. The total volume ( r=-0.61, P=0.009) and total iron burden ( r=-0.71, P=0.002) of CMBs in the frontal lobe were negatively correlated with cognitive function. However, although the number of CMBs in the frontal lobe was negatively correlated with cognitive function, the statistics analysis was insignificant ( r=-0.53, P=0.063). Conclusions:C-reactive protein and creatinine are influencing factors for CMBs′ total volume and total iron burden; C-reactive protein levels and alkaline phosphatase are influencing factors for the number of CMBs. The total iron burden and total volume of CMBs in the frontal lobe may be the biomarkers of cognitive impairment in patients with end-stage renal disease.

Clinical efficacy and prognosis analysis of different treatment regimens in patients with uncomplicated brucellosis / 中华传染病杂志

Objective:To analyze the efficacy and prognosis of different treatment regimens in patients with uncomplicated brucellosis, and to provide guidance for clinical treatment.Methods:The patients diagnosed with brucellosis in the Sixth People′s Hospital of Shenyang from September 2014 to June 2019 were enrolled. The clinical data of patients with uncomplicated brucellosis were collected. The two most frequent treatment regimens were screened, after conducting propensity score matching with 1∶4, and the clinical characteristics, prognosis, and adverse reactions in patients with two regimens were retrospectively analyzed. The primary outcome was clinical cure. The secondary outcomes were disease progression and relapse. Statistical analysis was performed using chi-square test, Wilcoxon rank sum test and log-rank method.Results:A total of 1 570 patients clinically diagnosed with brucellosis were included, and 939(59.8%) showed uncomplicated infection. There were 608(38.7%) patients who received doxycycline and rifampicin treatment, and 65(4.1%) received doxycycline and levofloxacin treatment. By propensity score matching, 223 patients (DR group) who used doxycycline and rifampicin were included, while 65 patients (DL group) who used doxycycline and levofloxacin were included. The cure rate, progression rate, symptom persistence rate and recurrence rate of DR group were 94.6%(211/223), 1.8%(4/223), 2.2%(5/223) and 1.3%(3/223), respectively. In DL group, those were 95.4%(62/65), 3.1%(2/65), 1.5%(1/65) and 0(0/65), respectively. And there was no significant difference between the two groups ( χ2=0.18, P=0.632). No significant difference of symptom durations between the two groups was observed (29.0(28.0, 30.0) d vs 28.0(26.1, 29.9) d, hazard ratio ( HR)=0.966, 95% confidence interval ( CI) 0.723 to 1.290, χ2=1.01, P=0.315), while treatment course of DR group was statistically longer than DL group (90.0(84.1, 95.9) d vs 44.0(37.3, 50.7) d, HR=0.489, 95% CI 0.361 to 0.662, χ2=14.18, P<0.001). Procalcitonin (0.02(0.02, 0.05) μg/L and 0.02(0.02, 0.04) μg/L) and C-reactive protein (8(3, 17) mg/L and 18(7, 55) mg/L) levels in DR group and DL group had decreased significantly after treatment than before treatment (0.09(0.04, 0.16) μg/L and 0.19(0.08, 0.25) μg/L, 106(19, 274) mg/L and 255(50, 494) mg/L), and the differences were statistically significant ( W=2.55, 2.04, 3.66 and 2.19, respectively, all P<0.05). The adverse reaction (ADR) rate in DR group was 4.2%(8/191), and five patients showed liver function injury. The ADR rate in DL group was 2.0%(1/51), which showed liver function injury. There was no significant difference of ADR between the two groups ( P>0.05). Conclusions:Doxycycline combined with rifampicin and doxycycline combined with levofloxacin have similar efficacy and adverse reaction rates for treating uncomplicated brucellosis.

Analysis of GNAS gene variant in a Chinese pedigree affected with pseudohypoparathyroidism / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic etiology of a Chinese pedigree affected with pseudohypoparathyroidism.@*METHODS@#Peripheral blood samples of the proband and his parents were collected and subjected to trio-whole exome sequencing (trio-WES). Candidate variants were verified among the pedigree and 50 randomly selected healthy individuals through analysis of restriction fragment length polymorphism. Short tandem repeat (STR) linkage analysis was used to verify the parental origin of the pathogenic variants.@*RESULTS@#Trio-WES and Sanger sequencing showed that the proband and his mother had both harbored a c.121C>G (p.His41Asp) variant of the GNAS gene, which was not found in other family members and the 50 healthy controls. The variant was not found in international databases. Based on guidelines from the American College of Medical Genetics and Genomics, the variant was predicted to be likely pathogenic.@*CONCLUSION@#The novel c.121C>G variant of the GNAS gene probably underlay the disease in this pedigree. Above finding has enriched the spectrum of GNAS gene variants.

Early prenatal exposure to air pollutants and congenital heart disease: a nested case-control study

BACKGROUND@#Congenital heart disease (CHD) is one of the most common congenital malformations in humans. Inconsistent results emerged in the existed studies on associations between air pollution and congenital heart disease. The purpose of this study was to evaluate the association of gestational exposure to air pollutants with congenital heart disease, and to explore the critical exposure windows for congenital heart disease.@*METHODS@#The nested case-control study collected birth records and the following health data in Tianjin Women and Children's Health Center, China. All of the cases of congenital heart disease from 2013 to 2015 were selected matching five healthy controls for each case. Inverse distance weighting was used to estimate individual exposure based on daily air pollution data. Furthermore, the conditional logistic regression with distributed lag non-linear model was performed to identify the association between gestational exposure to air pollution and congenital heart disease.@*RESULTS@#A total of 8,748 mother-infant pairs were entered into the analysis, of which 1,458 infants suffered from congenital heart disease. For each 10 µg/m3 increase of gestational exposure to PM2.5, the ORs (95% confidence interval, 95%CI) ranged from 1.008 (1.001-1.016) to 1.013 (1.001-1.024) during the 1st-2nd gestation weeks. Similar weak but increased risks of congenital heart disease were associated with O3 exposure during the 1st week and SO2 exposure during 6th-7th weeks in the first trimester, while no significant findings for other air pollutants.@*CONCLUSIONS@#This study highlighted that gestational exposure to PM2.5, O3, and SO2 had lag effects on congenital heart disease. Our results support potential benefits for pregnancy women to the mitigation of air pollution exposure in the early stage, especially when a critical exposure time window of air pollutants may precede heart development.

Clinical laboratory genetic diagnosis of Marfan syndrome / 中华检验医学杂志

Objective:To establish the clinical laboratory genetic diagnosis procedures for Marfan syndrome (MFS) and carry out clinical laboratory genetic diagnosis for MFS families.Methods:The second generation high-throughput sequencing was used to sequence and analyze the FBN1 gene of two MFS families who visited to Fuwai Central China Cardiovascular Hospital (Heart Center of Henan People′s Hospital) from January to December 2020, and then Sanger sequencing was used to verify the second generation high-throughput sequencing results. At the same time, the sanger sequencing of mutation sites was performed on normal family members and 100 healthy people to identify the pathogenic mutations of FBN1 gene in the MFS families. The pregnant women of two families were guided for prenatal diagnosis in the second trimester of pregnancy.Results:The clinical laboratory diagnosis of MFS showed that two MFS patients had the pathogenic mutation of c.2560T>C heterozygous mutation and c.6772T>C heterozygous mutation in FBN1 gene, respectively. The mutation was not observed in 100 healthy people and normal members in two families. The prenatal diagnosis showed that there was a heterozygous mutation of FBN1 gene c.2560T>C in the first fetus of the MFS family, which was MFS. There was no mutation in the FBN1 gene in the second fetus of the MFS family, so it was recommended to continue the pregnancy. The results of postpartum follow-up were consistent with the results of clinical laboratory diagnosis.Conclusion:The clinical laboratory genetic diagnosis procedures for MFS have been established successfully, which provides an important reference for clarifying the clinical diagnosis of MFS.

Copy number variation analysis and outcomes of 1 658 fetuses with increased nuchal translucency / 中华围产医学杂志

Objective:To analyze the genetic etiology and prognosis in fetuses with increased nuchal translucency (NT) in order to assist in the clinical prenatal genetic counseling and diagnosis.Methods:This study retrospectively enrolled 1 658 cases of singleton pregnancy (<35 years old) receiving invasive prenatal diagnosis, including karyotype analysis and/or chromosome microarray analysis or copy number variation (CNV) sequencing, due to NT value ≥2.5 mm in the first trimester in Henan Provincial People's Hospital from August 2014 to December 2021. They were divided into different groups according to the thickness of NT (≥2.5-<3.0, ≥3.0-<3.5, ≥3.5-<4.5, ≥4.5-<5.5, ≥5.5-<6.5 and ≥6.5 mm groups) and abnormal ultrasound findings (isolated increased NT group, increased NT complicated by soft markers/non-severe structural abnormality group and increased NT complicated by severe structural abnormality group). The results of invasive prenatal diagnosis and pregnancy outcomes were compared between different groups using Chi-square test and trend Chi-square test. Results:The detection rates of numerical abnormalities of chromosomes were 15.8% (262/1 658) and 17.6% (252/1 431) when the NT thickness cut-off value were 2.5 mm or 3.0 mm, respectively. Overall, the detection rate of numerical abnormalities of chromosomes increased with thickness of NT ( χ2trend=180.75, P<0.001), ranging from 6.6% (44/671) in the NT≥2.5-<3.5 mm group to 45.6% (113/248) in the NT≥5.5 mm group. The incidence of pathogenic/likely pathogenic CNV(P/LP CNV) did not increased with NT thickness ( χ2trend=3.26, P=0.071), and the highest detection rate was observed in the NT≥4.5-<5.5 mm group (9.0%, 19/211). The detection rate of numerical abnormalities of chromosomes plus P/LP CNV in the isolated NT≥2.5-<3.0 mm group and NT≥3.0-<3.5 mm group were 5.3% (10/188) and 9.6% (36/375), respectively, however, the difference was not statistically significant ( χ2=3.06, P=0.080). The detection rates of numerical abnormalities of chromosomes plus P/LP CNV in the isolated NT≥3.5-<4.5 mm group and NT≥2.5-<3.0 mm complicated by soft markers/ non-severe structural abnormality group were 12.7% (52/410) and 24.1% (7/29), respectively, and the risk were 2.6 times (95% CI: 1.3-5.2) and 5.7 times (95% CI: 2.0-16.4) of the isolated NT≥2.5-<3.0 mm group, respectively. The pregnancy termination rate increased with the NT thickness ( χ2trend=304.42, P<0.001), ranging from 10.8% (23/212) in the NT≥2.5-<3.0 mm group to 90.7% (117/129) in the NT≥6.5 mm group. After exclusion of the pregnancies terminated due to numerical abnormalities of chromosomes and P/LP CNV, 87.6% (862/984) of the fetus with increased NT were born alive. Conclusions:The detection rate of numerical abnormalities of chromosomes increases with the thickness of NT. Invasive prenatal diagnosis is required for non-advance aged singleton pregnant women when fetuses present with isolated NT≥2.5 mm with or without soft markers/structural abnormalities.

Effect of long non-coding RNA LNC 01309 on proliferation and migration abilities of human hepatoma cells and its mechanism of action / 临床肝胆病杂志

Objective To investigate the effect of long non-coding RNA (lncRNA) LNC01309 on the proliferation and migration abilities of human hepatocellular carcinoma (HCC) cells and its mechanism of action. Methods HCC samples and corresponding adjacent tissue samples were collected from 12 patients with HCC who underwent surgical treatment in The Sixth Medical Center of PLA General Hospital from February 2018 to June 2019, and quantitative real-time PCR was used to measure the relative expression level of LNC01309. Quantitative real-time PCR was also used to measure the expression level of LNC01309 in human hepatoma cell lines (HepG2, SNU-398, and Hep3B) and the human immortalized normal liver cell line THLE-2. After LNC01309 was overexpressed in HepG2 cells, the cells were divided into plasmid control group (pEXP-control) and overexpression group (pEXP-LNC01309). CCK-8 assay was used to observe the change in cell proliferation, and wound healing assay and Transwell assay were used to observe migration ability. RNA co-immunoprecipitation was used to detect the interaction between LNC01309 with RBM38, with cells divided into IgG group and RBM38 antibody group, and cycloheximide chase assay was used to analyze the effect of LNC01309 on the stability of RBM38 protein. RBM38 was overexpressed in HepG2 cells to conduct the recovery experiment, and CCK-8 assay, wound healing assay, and Transwell assay were used to observe the changes in cell proliferation and migration abilities. The t -test was used for comparison of continuous data between two groups. Results The mean expression level of LNC01309 in HCC tissue was significantly higher than that in adjacent tissue (4.225±2.285 vs 1.541±0.530, t =3.618, P =0.004), and the relative expression level of LNC01309 in hepatoma cells (HepG2, SNU-398, and Hep3B) was also significantly higher than that in normal hepatocytes (THLE-2) ( t =4.231、6.489、14.480, all P < 0.05). Compared with the control group, HepG2 cells with the overexpression of LNC01309 had significant increases in growth rate (OD 450 value at 96 hours: 1.885±0.107 vs 2.527±0.234, t =4.330, P =0.012) and migration ability (11.65%±2.40% vs 35.66%±4.90%, t =9.837, P < 0.001; 100.00%±3.11% vs 161.00%±35.93%, t =4.399, P =0.005); however, the upregulated proliferation and migration abilities of hepatoma cells induced by LNC01309 overexpression were partially inhibited by RBM38 (OD 450 value at 96 hours: 2.500±0.227 vs 1.913±0.282, t =2.812, P =0.048; 168.00%±9.43% vs 117.20%±18.03%, t =6.622, P < 0.001). Compared with the IgG control group, RBM38 antibody significantly enriched the precipitation of LNC01309 ( t =3.846, P =0.031). The results of cycloheximide chase assay showed that the LNC01309 overexpression group had a significant reduction in the stability of RBM38 protein ( t =8.038, P =0.001). Conclusion The newly identified LNC01309 reduces the stability of RBM38 protein through interaction with RBM38 and promotes the proliferation and migration of HCC cells.

Early warning of low maternal unconjugated estriol level by prenatal screening for fetus with X-linked ichthyosis / 中华妇产科杂志

Objective:To analyze the characteristic of prenatal serological screening in fetus with X-linked ichthyosis (XLI), and to explore the relationship between unconjugated estriol (uE 3) levels and XLI. Methods:A total of 56 fetuses with Xp22.31 microdeletion indicated by prenatal diagnosis and 70 fetuses diagnosed with trisomy 21 and 26 fetuses with trisomy 18 in Henan Provincial People's Hospital and Affiliated Hospital of Weifang Medical College from September 2016 to June 2021 were collected. The multiples of median (MoM) values of uE 3, alpha-fetoprotein (AFP), and human chorionic gonadotropin (hCG) during the second trimester of pregnancy were retrospectively analyzed. Prenatal diagnosis was made by amniotic fluid karyotype analysis and genome copy number variant analysis, parent genetic verification and pathogenicity analysis were performed, and maternal and infant outcomes were followed up. Results:Of 56 pregnant women with fetal Xp22.31 microdeletion, 43 underwent serological screening during the second trimester of pregnancy, of which 42 were abnormal (39 male fetuses and 3 female fetuses). The median uE 3 MoM value of 39 male fetuses [0.06 (0.00-0.21)] was lower than the normal value and significantly lower than that of fetuses with trisomy 21 [0.71 (0.26-1.27)] and fetuses with trisomy 18 [0.36 (0.15-0.84)], the difference was statistically significant ( Z=99.96, P<0.001). While the MoM values of AFP and hCG were all within the normal range. Among the 56 fetuses carrying Xp22.31 microdeletion, 45 were male fetuses and 11 were female fetuses, and the deletion fragments all involved STS gene. Eighty-nine percent (50/56) were inherited from mother (49 cases) or father (1 case), and 11% (6/56) were de novo mutations. Follow-up showed 48 live births (38 males and 10 females) and 8 chose to terminate pregnancy (7 males and 1 female). Among the 38 male newborns, 37 presented with scaly skin changes from 1 to 3 months of age, and one had no clinical manifestations until 4 months after birth. Ten female newborns had no obvious clinical manifestations. Conclusions:The decrease levels of uE 3 MoM on maternal serological screening is closely related to the higher risk of XLI in male fetuses. For pregnant women with low uE 3 in serological screening or with family history of ichthyosis, in addition to chromosomal karyotype analysis, joint detection of genomic copy number variant analysis should be recommended.

Clinicopathological analysis of lung transplantation in the treatment of end-stage lung disease complicated with neuroendocrine carcinoma / 中华器官移植杂志

Objective:To explore the clinicopathological features of end-stage lung disease complicated with neuroendocrine carcinoma after lung transplantation (LT).Methods:From April 2017 to December 2021, 5 cases of neuroendocrine cancer were diagnosed as end-stage lung disease by hematoxylin-eosin (HE) and immunohistochemical stain.Clinical follow-up data, histological characteristics and immunophenotyping were analyzed retrospectively.Results:The ratio of male-to-female in five recipients was 4: 1 and the average age 64(56-73) years.Three cases were idiopathic pulmonary fibrosis concomitant with small cell carcinoma (including 1 case of combined small cell carcinoma), bronchiectasis plus carcinoid carcinoma (n=1) and connective tissue disease-related fibrosis plus carcinoid carcinoma (n=1). HE stain indicated that morphological spectrum changed from neuroendocrine cell hyperplasia to carcinoid in transplanted lung of bronchiectasis.Immunohistochemical stain indicated that neuroendocrine markers CgA, Syn, CD56 and epithelial markers AE1/AE3, TTF-1 were positive for small cell carcinoma and carcinoid.Ki-67 index of small cell carcinoma (n=2) and combined small cell carcinoma (n=1) was 80% and Ki-67 index of carcinoid (n=2) was ≤1%.Until the last follow-up, 3/5 patients survived and the remaining 2 died of Klebsiella pneumoniae, Corynebacterium striatus and Acinetobacter baumannii infections at Days 33 and 196 post-transplantation.Conclusions:Neuroendocrine carcinoma in transplanted lung is more common in elderly males and end-stage lung disease is mostly idiopathic pulmonary fibrosis.Small cell carcinoma is a major type of neuroendocrine carcinoma.Specific neuroendocrine markers and TTF-1 aid in a definite diagnosis of neuroendocrine carcinoma.Postoperative infection is an important prognostic factor.

Correlation between serum BDNF，Val66Met gene polymorphism and clinical symptoms in early Parkinson’s disease / 中风与神经疾病杂志

@#To investigate the correlation between serum Brain-derived neurotrophic factor （BDNF），Val66Met gene polymorphism and clinical symptoms in patients with newly diagnosed Parkinson’s disease （PD）. Methods A total of 62 early PD patients and 46 healthy controls were collected from Ningbo First Hospital. General demographics，Hamilton Anxiety Scale （HAMA），Hamilton Depression Scale （HAMD），Orthostatic Hypotension （OH） or not，serum BDNF levels，Val66Met genotype were examined in all subjects，duration of disease，Hoehn-Yahr （HY） Rating Scale，Unified Parkinson’s Disease Rating Scale motor scores （UPDRS-Ⅲ），symptom classification （tremor type，rigid type or mixed type） were also assessed in patients. Results PD patients had significantly higher HAMA，HAMD scores，incidence of OH and lower BDNF levels than controls，there was no significant difference in the distribution of Val66Met gene polymorphism between the two groups. Multiple linear regression revealed that BDNF levels were negatively associated with HAMA （P=0.014） and HAMD （P=0.013） scores in PD patients，however，no significant correlation were found between Val66Met polymorphism and clinical symptoms. Conclusion Evident non-motor symptoms can occur in early PD patients，serum BNDF levels were correlated with the degree of anxiety and depression in patients，and Val66Met gene polymorphism may not play an important role in the course of disease.

Collection of autologous peripheral hematopoietic stem cells in patients with sequential double transplantation of solid tumors and effect analysis / 中国输血杂志

【Objective】 To explore the methods and safety of autologous peripheral hematopoietic stem cells collection in patients with sequential double transplantation of solid tumors and conduct efficacy analysis. 【Methods】 Peripheral blood stem cells were collected from 27 patients with solid tumors after routine mobilization of rhG-CSF and rhGM-CSF.A specific program was made for the patients.The condition and cooperation degree of children were comprehensively evaluated before cell collection, and a femoral venous catheterization was inserted to ensure the cells collected smoothly.A mononuclear cell collection(MNC) program was selected, and machine parameters were set based on the patient's low body weight.The number of mononuclear cell (MNC) and the CD34+ cell was detected by flow cytometry for retrospective analysis. 【Results】 A total of 73 cell collections were performed in 27 patients, and the number of mononuclear cells and CD34+ cells was 12.586(10.22~19.586)×108/kg and 13.575(7.275~23.825)×106/kg, respectively, which can meet the requirement of sequential double transplantation. No intoxication of citrate and other serious adverse reactions occurred, and the follow-up was generally in good condition. 【Conclusion】 The method is effective and safe for pediatric patients, even for pediatric patients with low weight. Sufficient stem cells can be collected for patients with solid tumors by this method to meet the requirement of sequential double transplantation.

Identification and analysis of anovel variant of TRAPPC2 in a X-linked spondyloepiphyseal dysplasia tarda pedigree / 中华骨科杂志

Objective:To provide experimental evidence for genetic counseling and prenatal diagnosis by analyzing the clinical characteristics, screening and identification of the function of suspicious variants in a X-1inked spondyloepiphyseal dysplasia tarda (SEDT) family.Methods:The family members' medical history, general physical examination, femur, spine X-ray examination were collected. Peripheral blood samples of the family members were collected and DNA was extracted from these samples. Sequencing clinical whole exons of proband DNA by targeted gene high-throughput sequencing method, then analysis sequencing data. The suspicious mutation was confirmed in pedigree members by PCR and Sanger sequencing. Reverse transcription polymerase chain reaction (RT-PCR) experiments of total RNA from blood lymphocytes were performed. The amplification of exons 3 and 4 of the pathogenic gene were amplified and identified by agarose gel. The expression of the pathogenic gene was also detected.Results:Three affected males of the family were diagnosed with SEDT according to their clinical and radiological features. A nonsense mutation in the transport protein particle complex subunit 2 ( TRAPPC2) gene NM_001011658: c.91A>T (p.K31*) was found in the proband using whole exome sequencing. This variation was also detected in his cousin, but not in non-phenotypic members of the family. The RT-PCR result for amplification of exon 3 and 4 of peripheral blood lymphocytes was the same as those of normal controls, indicating that the mutation did not affect the splicing of transcripts. qPCR results showed that the transcriptional expression of TRAPPC2 in patients was significantly lower than that in family normal controls and normal people controls. Conclusion:Identification of the novel nonsense mutation (c.91A>T) in the SEDT family enables early patients screening, carrier detection, genetic counseling, prenatal diagnosis, and clinical prevention and treatment. The detailed genotype/phenotype descriptions contribute to the SEDT mutation spectrum. The study of the function of TRAPPC2 mutation will help to further elucidate the role of sedlin in cartilage.

Pedigree analysis and prenatal diagnosis of intellectual disability caused by synonymous mutations of p.S434S in DLG3 gene / 中华围产医学杂志

Objective:To analyze the pathogenic gene and prenatal diagnosis of a family with intellectual disability.Methods:Out of this family consisting of 17 members in three generations, four males had intellectual disability. The proband's elder sister (Ⅱ-7) visited Henan Provincial People's Hospital in Oct 2019 for genetic counseling at 8 weeks of gestation. After informed consent was obtained, peripheral blood samples of the family members were collected. The whole exome sequencing was performed on the genome DNA of the proband (Ⅱ-9, male) and his parents to screen the candidate variants for phenotype co-segregated analysis by Sanger sequencing. The expression vectors were constructed by homologous recombination and the splicing experiments were performed in vitro. Reverse transcription polymerase chain reaction, Sanger sequencing, and TA clone sequencing were used to analyze the effect of candidate variants on splicing. After the pathogenic variant was determined the proband's elder sister underwent prenatal diagnosis (Ⅲ-7) using goldeneyeTM20A genotyping system and Sanger sequencing. Results:A hemizygous synonymous variant of c.1302G>A (p. S434S) in DLG3 gene was found in the proband by whole exome sequencing, which was carried by his mother (Ⅰ-1) and co-segregated with the phenotype in other family patients. In vitro splicing experiment showed that c.1302G>A variant led to abnormal splicing of 88.24% transcripts, which further resulted in the reading frame shift and protein function impairment. The mutation was not detected in the fetus (Ⅲ-7), who was born alive later and showed no abnormal mental or behavioral development at the age of one and a half year and is still being followed up. Conclusions:The synonymous mutation c.1302G>A in DLG3 gene was the etiopathogenesis of X-linked intellectual disability in this family.

Genetic analysis and prenatal diagnosis of intellectual disability caused by Xq25 microduplication in a pedigree / 中华围产医学杂志

Objective:To analyze the clinical and genetic characteristics of a 27-year-old male patient with intellectual disability and his pedigree to provide a reference for genetic counseling and prenatal diagnosis.Methods:G-banding and array comparative genomic hybridization (aCGH) were performed to analyze the karyotypes and genomic copy number variations of the proband (Ⅲ-1) and his family members. Based on the results, prenatal diagnosis was performed for one pregnant woman (Ⅲ-2) in the pedigree who is the sister of the proband.Results:All karyotyping were normal in the family members, while aCGH results showed a 1 533 kb microduplication in the Xq25 region of the proband, his mother (Ⅱ-3), his uncle (Ⅱ-2), and his sister (Ⅲ-2), which was confirmed to be pathogenic. The proband and his uncle presented with intellectual disability, bradylalia, and facial dysmorphism. In contrast, his mother and sister showed normal phenotypes. His sister's fetal karyotype and aCGH results were normal, and the pregnancy continued. A male baby (Ⅳ-1) was delivered vaginally at term and showed no physical or intellectual abnormalities during a 46-month follow-up.Conclusions:Xq25 microduplication might be the cause of intellectual disability in the proband. STAG2 is probably the essential gene in Xq25 region.

Application of genomic copy number variation detection technology in prenatal diagnosis of 7617 pregnant women with serological screening abnormalities during the second trimester of pregnancy / 中华医学遗传学杂志

OBJECTIVE@#To analyze the genomic variation characteristics of fetal with abnormal serological screening, and to further explore the value of copy number variation (CNV) detection technology in prenatal diagnosis of fetal with abnormal serological screening.@*METHODS@#7617 singleton pregnant women who underwent amniocentesis for prenatal diagnosis solely due to abnormal Down's serological screening were selected. According to the results of serological screening, the patients were divided into high risk group, borderline risk group and single abnormal multiple of median (MOM) group. CMA and CNV-Seq were used to detect the copy number variation of amniotic fluid cell genomic DNA and combined with amniotic fluid cell karyotype analysis for prenatal diagnosis. Outpatient revisit combined with telephone inquiry was used for postnatal follow-up.@*RESULTS@#Among 7617 amniotic fluid samples, aneuploidy was detected in 138cases (1.81%) by CMA and CNV-Seq, 9 cases of aneuploid chimerism were detected by amniotic fluid cell karyotype analysis, and 203 cases of fetus carrying pathogenic and likely pathogenic CNV (P/LP CNV) were detected, the variant of uncertain significance (VUS) was detected in 437 cases (5.7%), the overall abnormal detection rate was 10.33%. The detection rate of aneuploidy by CMA and CNV-Seq in three group were 123 cases (2.9%), 13 cases (1.3%) and 2 cases (0.4%), respectively,and showing no significant difference (χ 2=7.469, P=0.024). The detection rate of pathogenic and likely pathogenic CNV in three group were 163cases (2.6%); 24 cases (2.6%) and 16 cases (3.3%), respectively, and showing no significant difference (χ 2=0.764, P=0.682). The CMA reported 2.9% (108/3729)P/LP CNV, and CNV-seq reported 2.4% (95/3888)P/LP CNV, both tests showed similar detective capabilities (χ 2=1.504, P=0.22).The most popular P/LP CNV in this cohort were Xp22.31 microdeletion, 16p13.11 microduplication /microdeletion, 22q11.21 microduplication /microdeletion. In fetuses with P/LP CNV CNV, 59 fetuses were terminated pregnancy, and 32 of 112 fetuses born had abnormal clinical manifestations. Non-medically necessary termination of pregnancy occurred in 11 fetuses carrying VUS CNV, 322 fetuses carrying VUS CNV were born, 4 of them presented abnormal clinical manifestations.@*CONCLUSION@#Compared with the traditional chromosome karyotype, CMA and CNV-Seq can improve the detection rate of pathogenic and likely pathogenic CNV. CMA and CNV-seq can be used for first tier diagnosis of pregnant women in the general population with abnormal Down's serological screening.

Canagliflozin alleviates renal fat deposition and improves renal oxygenation levels in patients with newly-diagnosed type 2 diabetes mellitus / 中华内分泌代谢杂志

Objective:To evaluate the effect of canagliflozin on intrarenal fat content and oxygenation in newly-diagnosed type 2 diabetes patients.Methods:Twenty-three newly-diagnosed type 2 diabetes patients were divided into canagliflozin( n=11) and glimepiride control( n=12) groups .Both groups received MRI scanning with Dixon MRI and BOLD MRI sequence to assess patients′ intrarenal fat content, oxygenation level before treatment and 24 weeks after treatment. Fasting blood glucose, glycosylated hemoglobin, blood uric acid, blood lipids, blood pressure, weight, and other metabolic index were also tested before and after treatment. Furthermore, the relationship between body mass index(BMI) and intrarenal fat content and the correlation between changes in intrarenal fat content and improvement in renal hypoxia were analyzed. Results:No significant differences were found in baseline age, body weight, fasting blood glucose, glycosylated hemoglobin, blood lipid, and serum uric acid between the two groups. There was no significant difference in fasting blood glucose, glycosylated hemoglobin, cholesterol(CHO), low-density lipoprotein-cholesterol(LDL-C), and triglycerides(TG) levels in both groups after 12 and 24 weeks of treatment. The decrease in body weight, blood uric acid level, and diastolic blood pressure from baseline in the canagliflozin group was greater than those in the control group( P<0.05). Two groups of patients with type 2 diabetes at baseline had no obvious difference in intrarenal fat content, and the patients′ BMI showed no obvious correlation with degree of intrarenal fat accumulation. Canagliflozin treatment for 24 weeks could reduce intrarenal fat content, which was higher than that of control group. The R2 * values of renal cortex and medulla in the canagliflozin group decreased from baseline by 19.22% and 22.63% respectively( P<0.05), whereas no significant difference was seen in the glimepiride control group. The decrease of intrarenal fat content in the canagliflozin group was related to the improvement of renal cortex and medulla oxygenation. Conclusion:Canagliflozin can reduce intrarenal fat accumulation and improve renal cortical hypoxia in newly diagnosed type 2 diabetes patients with normal renal function.

Genetic mutation analysis in three pedigrees with hereditary multiple exostosis / 中华检验医学杂志

Objective:To detect the pathogenic gene of the three pedigrees with hereditary multiple exostosis, and to provide evidences for genetic counselling and prenatal diagnosis.Methods:The three families were admitted to the Institute of Medical Genetics of Henan Provincial People′s Hospital due to hereditary multiple exostosis from January 2018 to December 2020. Detail medical history and the blood samples of the family members were collected after they signed the informed consent forms. The pathological mutations were selected from the proband using whole exome sequencing (WES). Sanger sequencing was used to conduct the co-segregation analysis of the family members. The pathogenicity of the mutation was analyzed in combination with ACMG guidelines.Results:The EXT1 gene c.1056+2T>C mutation, c.369dupA (p.G124fs) mutation and the EXT2 gene c.1171C>T (p.Q391*) mutation were detected in the probands through whole exome sequencing. The same mutations were found in the patients from these three families, while the mutation was not detected among the healthy family members. These variations have co-segregated with the disease phenotype. According to ACMG guidelines, all mutations in these three families meet the criteria of pathogenic variations. Conclusion:The EXT1 gene c.1056+2T>C mutation, c.369dupA (p.G124fs) mutation and the EXT2 gene c.1171C>T (p.Q391*) mutation were identified to be responsible for hereditary multiple exostosis in these families.

Risk analysis of recurrence of women with DMD birth history in families with new mutations in DMD gene / 中华检验医学杂志

Objective:To summarize and analyze the risk of pregnancy recurrence of women with Duchenne muscular dystrophy (DMD) birth history in families with new DMD gene mutations, clarify the laws of DMD gene mutations and discuss the mode of genetic counseling in such families.Methods:Collected DMD families from January 2013 to December 2017 in Henan Provincial People′s Hospital. Firstly, the 79 exons of DMD gene were analyzed by multiplex ligation-dependent probe amplification (MLPA) in DMD patients and their mothers. The families that DMD patients with DMD gene mutations but no mutations in their mothers were selected for this study, and then MLPA combined with STR-gene linkage analysis were used to perform prenatal diagnosis for females in these DMD gene new mutation families.Results:A total of 64 families with new DMD gene mutations were included in this study. All mutations were DMD gene exon deletion mutations. A total of 65 fetuses were conducted prenatal diagnosis, included 26 SRY negative, 39 SRY positive; 63 fetuses′ DMD gene normal and 2 fetues′ DMD gene with exon deletion mutations. The results of postpartum follow-up and prenatal diagnosis were consistent.Conclusions:Exon mutations in newly mutated DMD families were mainly manifested as exon deletion, mainly presented in the 45-55 exon region. For families with new DMD mutations, even if there is no DMD gene mutation in women which had reproductive history of DMD, prenatal diagnosis for DMD during pregnancy was still recommended.