Here, we report a previously unrecognized syndromic neurodevelopmental disorder associated with biallelic loss-of-function variants in the RBM42 gene. The patient is a 2-year-old female with severe central nervous system (CNS) abnormalities, hypotonia, hearing loss, congenital heart defects, and dysmorphic facial features. Familial whole-exome sequencing (WES) reveals that the patient has two compound heterozygous variants, c.304C>T (p.R102*) and c.1312G>A (p.A438T), in the RBM42 gene which encodes an integral component of splicing complex in the RNA-binding motif protein family. The p.A438T variant is in the RRM domain which impairs RBM42 protein stability in vivo. Additionally, p.A438T disrupts the interaction of RBM42 with hnRNP K, which is the causative gene for Au-Kline syndrome with overlapping disease characteristics seen in the index patient. The human R102* or A438T mutant protein failed to fully rescue the growth defects of RBM42 ortholog knockout ΔFgRbp1 in Fusarium while it was rescued by the wild-type (WT) human RBM42. A mouse model carrying Rbm42 compound heterozygous variants, c.280C>T (p.Q94*) and c.1306_1308delinsACA (p.A436T), demonstrated gross fetal developmental defects and most of the double mutant animals died by E13.5. RNA-seq data confirmed that Rbm42 was involved in neurological and myocardial functions with an essential role in alternative splicing (AS). Overall, we present clinical, genetic, and functional data to demonstrate that defects in RBM42 constitute the underlying etiology of a new neurodevelopmental disease which links the dysregulation of global AS to abnormal embryonic development.
Female ; Animals ; Mice ; Humans ; Child, Preschool ; Intellectual Disability/genetics* ; Heart Defects, Congenital/genetics* ; Facies ; Cleft Palate ; Muscle Hypotonia

Objective:To retrospectively analyze the bone marrow characteristics of methimazole-induced agranulocytosis and other hematologic damage, and to explore its correlation with clinical features and prognosis.Methods:The bone marrow and clinical parameters of 20 patients of Graves′ disease diagnosed with methimazole-induced agranulocytosis at the First Affiliated Hospital of Xi′an Jiaotong University from January 2000 to December 2022 were collected. The intergroup differences in bone marrow characteristics and granulocyte recovery time were analyzed. Differences in peripheral blood and bone marrow characteristics between patients with single agranulocytosis and pancytopenia were compared. Besides, literature review of the bone marrow characteristics of methimazole-induced hematologic diseases was conducted.Results:Compared to patients with bone marrow characteristics of granulocyte and precursor maturation disorders(Type Ⅱ), patients with aplastic marrow(Type Ⅰ) had significant decreases in the proportions of granulocytes in all phases( P<0.05). Patients with bone marrow characteristics of Type Ⅰ had a significant increase in the proportion of the lymphocyte system [51.00%(41.50%, 75.50%) vs 22.00%(14.00%, 35.00%), P=0.002], and got a longer to recovery time [(6.58±1.68)d vs(3.71±1.60)d, P=0.003]; Correlation analysis suggested the granulocyte to erythrocyte ratio was negatively correlated with the granulocyte recovery time( r=-0.520, P=0.023), and the proportion of the bone marrow lymphocyte was positively correlated with granulocyte recovery time( r=0.622, P=0.004). Compared to patients with single agranulocytosis, patients with pancytopenia had a markedly longer hospital stay duration [(27.14±5.27)d vs(14.15±7.36)d, P=0.001]. Literature review suggestsed that methimazole may cause various degrees of damage to blood system and bone marrow. Conclusion:Methimazole can induce a variety of hematologic damages. Analysis of bone marrow characteristics can aid in further prognosis assessment. Clinicians should be vigilant about potential hematologic adverse reactions when using methimazole and promptly diagnose and treat them to prevent serious consequences.

Objective:To observe any effect of exercise preconditioning on the levels of hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) in the brain tissue of rats after induced cerebral ischemia and reperfusion, and how it might promote angiogenesis.Methods:Thirty-six male Sprague-Dawley rats were randomly divided into a sham-operation group, a model group and an exercise preconditioning group, each of 12. After adaptive running training for 3 days, the exercise preconditioning group ran daily for 30 minutes at 15m/min for 14 days, while the other two groups did not exercise. Middle cerebral artery occlusion and reperfusion were then induced in the model and exercise preconditioning groups using the modified Zea-Longa suture method. Rats in the sham-operation group were only cut open to expose the right carotid artery. Right after the modeling, and again 24 hours later neurological deficit was evaluated using the Zea-Longa score and modified neurological severity scoring (mNSS). Infarct sizes were measured using 2, 3, 5-triphenyl tetrazolium chloride staining. Any morphological changes were noted using hematoxylin and eosin (HE) staining, and the expression of CD31 protein, hypoxia-inducible factor-1α and vascular endothelial growth factor in the ischemic cerebral cortex were quantified immunohistochemically.Results:Right after the modelling, compared with the sham-operation group, the average Zea-Longa scores of the model and exercise groups had increased significantly, but were not significantly different from each other. Twenty-four hours later the average Zea-Longa score, mNSS score and relative cerebral infarction area of the model group had increased significantly compared with the sham-operation group, while the exercise preconditioning group′s averages had decreased significantly. The HE staining showed that compared with the sham-operation group, pathological changes such as loose tissue, reduced number of nerve cells, nucleolysis, and vacuolization of the cerebral cortex on the ischemic side were found in the model group. Compared with the model group, the pathological changes in the exercise preconditioning group were less serious. The levels of CD31 protein, HIF-1α and VEGF in the ischemic cerebral cortexes of the model group had by then increased significantly. But compared with the model group, those levels had increased more in the exercise preconditioning group.Conclusion:Exercise preconditioning can effectively promote angiogenesis after cerebral ischemia and reduce chronic injury. That may be related to the activation of the HIF-1α and/or VEGF signaling pathways.

OBJECTIVES: Uterine fluid RNA can be used as a test for endometrial receptivity, but there is still no noninvasive sampling method available. The polyvinyl alcohol (PVA) formaldehyde absorbent sponge, a medical bio-absorbent sponge with good water absorption and biophilic properties, can be used to develop a new noninvasive endometrial fluid sampler. This study aims to investigate the toxicity of PVA acetal absorbent sponges on endometrial epithelial cells and its effect on RNA sequencing (RNA-Seq). METHODS: The experimental group using PVA formaldehyde absorbent sponge was prepared into 0.005%, 0.01% and 0.02% (w/v) suspension, and 0.01%, 0.05% and 0.1% (v/v) extract groups. The control group was only the complete culture medium. Nothing was added to the blank group. In vitro cytotoxicity assay was used to evaluate the survival rate of cells. Eight patients underwent in vitro fertilization treatment in the Reproductive Center of Xiangya Hospital, Central South University from November 2019 to January 2020. The uterine fluid of each patient was aspirated. The experimental group was inhaled with sterile PVA formaldehyde absorbent sponge and then immersed RNA-later solution. The control group was directly injected into the same amount of RNA-later solution. RNA-seq and data analysis was performed later. RESULTS: The vitro cytotoxicity assay showed that in suspension groups, there was no significance difference in cell survival between different co-culture time in 0.005% group (P=0.255). In the 0.01% and 0.02% group, there was no difference at each incubation time within 12 h (all P>0.05), but the cell survival rate was decreased at 24 h compared with 0 h (P<0.01, P<0.05). At the same co-culture time, the cell survival of the 3 concentration gradient groups were significantly lower than that of the control group (all P<0.05). The cell viability of the 0.005% concentration group was decreased less than 30% at 24 h, the 0.01% concentration group decreased more than 30% at 12 h, and the 0.02% concentration group was decreased more than 30% at 0 h. For extract groups, there was no significant difference in the survival rate within 6 h in 0.01% concentration group (all P>0.05), and the survival rate of 12 h and 24 h was lower than that of 0 h group (both P<0.01). In 0.05% group, there was no significant difference at each incubation time within 12 h (all P>0.05), but the survival rate at 24 h was lower than that at 0 h (P<0.05). There was no significant difference in survival rate at different culture time in 0.1% concentration group (P=0.082). At the same culture time, there was no significant difference in survival rate between 0.01% group and control group at 0, 3 and 24 h (all P>0.05). Except for 3 h, the survival rate of 0.05% and 0.1% groups was lower than that of control group (all P<0.05), and the decrease was all less than 30%. Uterine fluid RNA-seq showed that there was no significance difference in exonic rate, the detected genes and transcripts of RNA between the experiment groups and the control group (all P>0.05). CONCLUSIONS The in vitro cytotoxic of PVA formaldehyde absorbent sponge on human endometrial epithelial cell meet the national standard of the cytotoxic of medical materials. Sampling the uterine fluid with this material does not affect the RNA-Seq results. PVA formaldehyde absorbent sponge is safe and feasible when appling to the noninvasive uterine fluid sampling and RNA sequencing.
Humans ; Social Group ; Sequence Analysis, RNA ; RNA

【Objective】 To investigate the clinical features and gene analysis of one pedigree with multiple endocrine neoplasia type 2A （MEN2A） so as to clarify the diagnosis and classification of the disease， guide treatment and prevention， and improve prognosis. 【Methods】 The clinical data of a 36-member MEN2A family， including 6 probands， with medullary thyroid carcinoma， were investigated， and the peripheral blood genomic DNA of 28 family members （blood sample of one proband was not collected） was extracted. PCR amplification was performed on exons 8， 10， 11， 13， 14， 15 and 16 of the RET gene， and the products were directly sequenced. 【Results】 Review of the medical history showed that two probands with medullary thyroid carcinoma were accompanied with hyperparathyroidism， and one family member had pheochromocytoma. The RET gene mutation test confirmed that 13 family members， consisting of 5 probands and 8 family members， had the RET proto-oncogene exon 10 missense mutation. The heterozygous missense had mutation c.1852T>A， leading to the conversion of cysteine （TGC） at position 618 to serine （AGC） （Cys618Ser）. All subjects carrying RET gene Cys618Ser mutation had abnormal thyroid ultrasound change， accompanied with elevated calcitonin levels. Subjects carrying wild type of RET gene had normal calcitonin levels. The family was finally diagnosed with MEN2A by RET gene detection. 【Conclusion】 RET gene detection plays key role in the diagnosis and treatment of patients with MEN2A family and has guiding value in the follow-up and prognosis of asymptomatic carriers. There is a positive correlation between calcitonin level and the RET protooncogene mutation Cys618Ser. Patients suspected of MEN2A should be screened in time.

Objective : To investigate the protective effect of adiponectin APN on myocardial injury caused by sep⁃ sis and its possible mechanism. : Methods Results : Compared with sham group , the expression of Bax , cleaved Caspase3 protein increased and the expression of Bcl⁃2 protein decreased in LPS group. Compared with LPS group , the injury in APN + LPS group was significantly alleviated , showing that the expression of Bax , cleaved caspase3 protein decreased and the expression of Bcl⁃2 protein increased. Meanwhile , compared with sham group , the expression of Cx43 increased in LPS group and decreased in APN + LPS group. Conclusion Adiponectin can attenuate LPS⁃induced cardiac injury in septic mice. The mechanism may be through the inhibition of apoptotic signal pathway and the expression of Cx43.

[摘 要] 目的：探讨幽门螺杆菌（Helicobacter pylori, Hp）感染对胃癌细胞共济失调毛细血管扩张突变（ataxia-telangiectasia mutated，ATM）基因表达的影响及其临床意义。方法：从TCGA数据库中获取胃癌相关RNAseq数据，比较ATM基因的表达差异，分析ATM表达与患者临床病理参数的相关性及预后价值，用Kaplan-Meier法进行生存分析，LinkedOmics数据库分析ATM相关基因，用R语言进行GO、KEGG富集分析。选用2019年3月至2019年12月贵州医科大学附属医院12例手术切除的胃癌及癌旁组织标本，以及胃癌细胞系AGS和BGC823，用感染复数40∶1的Hp GZ7菌感染细胞，用免疫组织化学染色法检测胃癌组织中ATM蛋白的表达，qPCR法检测胃癌组织和细胞中ATM mRNA的表达。结果：TCGA数据显示胃癌和Hp感染胃癌组织中ATM miRNA表达水平均显著高于癌旁组织（均P<0.01）；胃癌组织中ATM miRNA表达与患者的T分期、AJCC分期等病理参数呈正相关（均P<0.05），ATM高表达时生存率显著降低（P<0.05）。实验检测显示，胃癌组织标本中ATM蛋白的表达水平明显高于癌旁组织（P<0.01）；Hp感染胃癌细胞中ATM miRNA表达水平显著高于未感染胃癌细胞（P<0.01）。胃癌中ATM基因与NPAT等12 461个基因呈正相关（P<0.05），与MIF等7 764个基因呈负相关（P<0.05）。GO、KEGG富集分析显示，ATM富集到DNA修复复合体、癌症中的转录失调等信号通路。结论：ATM基因在胃癌组织中高表达，患者生存率随表达水平的增高而降低，其与患者的T分期、AJCC分期等病理参数相关，且Hp感染引起ATM表达水平升高可能是Hp引起胃癌的原因之一。

Clinical data of 4 cases of infants with hemophilia complicated with hematorrhachis diagnosed in Guangzhou Women and Children′s Medical Center from January 2017 to December 2018 was retrospectively analyzed.The clinical manifestations of 4 children was atypical, only showing irritability and crying, poor spirit and weak head in the early stage, and torticollis and limb weakness in the late stage may easily contribute to a misdiagnosis.The spinal magnetic resonance imaging is an important diagnosis of hematorrhachis.The most common site of disease was cervicothoracic and thoracolumbar spinal epidural hemorrhage.Of the 4 patients in this article, 1 patient was treated with surgery combined with infusion factor Ⅷ replacement therapy.Three patients were treated with infusion factor Ⅷ replacement therapy alone to obtain clinical rehabilitation.The prognosis of early diagnosis was good, the time from onset to diagnosis in 3 cases was within 1 week, after treatment all had rehabilitation; 1 case within 2 weeks of diagnosis, partial rehabilitation.It is suggested that hemophilia complicated with hematorrhachis in infants is hidden, and it can only be irritable and crying in the early stage, and neurological symptoms appear in the late stage.Improving diagnostic awareness, early diagnosis and early infusion factor replacement therapy are critical for prognosis.

The high incidence and fatality rate of recurrent ovarian cancer (ROC) have always been the clinical problem. For part of patients with platinum-sensitive recurrent ovarian cancer, the secondary cytoreductive surgery (SCS) followed by platinum-based combination chemotherapy can prolong their survival time and improve quality of life. Therefore, it's a critical matter to accurately identify the patients who will benefit from surgery treatment. Several predictive models have been proposed for the selection of the patients for SCS. This article summarizes the research progress in the surgical treatment of platinum-sensitive recurrent ovarian cancer in recent years.

Objective:To compare anti-mullerian hormone (AMH) , sex hormone and inhibitor B (Inhibin B, INH-B) levels in children with different karyotypes, ages, and gender disorders of sex developmemt (DSD).Methods:A total of 101 patients with suspected gonadal dysplasia in children who underwent serological examination at the Children′s Hospital of Hunan Province from January 2019 to June 2019 were finally diagnosed by pathological biopsy. With reference to previous studies of the same type, the 101 patients included in this study were divided into 4 levels (<1 year old, 1-2 years old, 2-4 years old, >4 years old), and the social gender was divided into two levels: male and female. At the same time, 89 cases of normal gonadal development children without endocrine abnormality were selected as control. Serum levels of AMH, INH-B, luteinizing hormone (LH), follicle stimulating hormone (FSH), estradiol (E2), prolactin (PRL) and testosterone (T) were measured by chemiluminescence method.Results:Among the 101 cases, 62 were male and 39 were female; aged 23 days to 12 years, with a median age of 3.3 years; karyotype: 52 cases were 46, XX; 21 cases were 46, XY; 12 cases were 45, X; 7 cases were 46X, del (Xq); 5 cases were 46X, i (Xq); 2 cases were 45X, inv9; 2 cases were 45X / 46XX. There were 65 cases of partial gonadal dysplasia, 25 cases of disappearing testicular syndrome, and 11 cases of mixed gonadal dysplasia. One patient had a family history of infertility. Among the causes of children′s consultation, the most common were abnormal appearance of the external genitalia (54 cases, 53.47%), followed by small penile development and / or scrotal emptiness (25 cases, 24.75%). Other reasons included primary amenorrhea, double lateral groin mass, hypertension, clitoral hypertrophy, and labia minora adhesions. The levels of serum AMH, INH-B, and T in the gonadal dysplasia group were significantly higher than those in the normal gonadal development group, while the levels of LH, FSH, E2, and PRL were significantly lower than those in the normal gonadal development group ( P<0.05). The INH-B level of children with gonadal dysplasia in different age groups was statistically significant ( P<0.05), in which the INH-B level was the highest in <1-year-old children with gonadal dysplasia, and the lowest in 2-4-year-old children with gonadal dysplasia; the LH, FSH, E2, PRL, T levels of 46, XX and other karyotypes were statistically significant ( P<0.05); Compared with other age groups, the levels of LH, FSH, E2, and PRL were relatively higher in >4 year-old children with gonadal dysplasia, while the level of T was relatively lower; There were significant differences in E2, PRL and T levels in children with gonadal dysplasia in different age groups of 46, XY karyotype ( P<0.05). Compared with other age groups, E2, PRL and T levels of children with gonadal dysplasia >4 year-old old were relatively higher and T levels were relatively lower. The levels of AMH, LH, FSH, E2 and PRL in boys with glandular dysplasia were lower than those in girls ( P<0.05), while the levels of INH-B and T were higher in boys than those in girls ( P<0.05). Conclusions:The levels of anti-mullerian hormones, inhibin B, and sex hormones in children with gonadal dysplasia are different from the normal population, and may be related to the age, chromosome karyotype, and gender distribution of the child, but there are some confounding factors (such as etiology, treatment Scheme), so more samples are needed to verify it.