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 observe the effects of Yiqi Huoxue Tuodu Prescription on Keap1Nrf2/HO-1 signaling pathway in rats with chronic nonbacterial prostatitis(CNP);To explore its mechanism for the treatment of CNP.Methods CNP rat model was prepared using castration combined with estrogen induction method.Totally 48 SD rats were divided into blank group,model group,celecoxib group and Yiqi Huoxue Tuodu Prescription group according to the random number table method,with 12 rats in each group.In the celecoxib group,celecoxib suspension was instilled 0.035 g/kg,and in the Yiqi Huoxue Tuodu Prescription group,Yiqi Huoxue Tuodu Prescription water decoction was instilled 8.64 g/kg,and the blank group and the model group were instilled with equal volume of normal saline for 28 days.Mechanical pain threshold in rats was measured using Von Frey fiber optic pain gauge,HE staining was used to observe pathological changes in prostate tissue and pathological scoring,the content of reactive oxygen species(ROS)in prostate tissue were detected by chemical fluorescence method and the glutathione peroxidase(GSH-Px)activity and malondialdehyde(MDA)content in prostate tissue were detected by colorimetric method,Western blot was used to detect the expressions of Kelch like ECH related protein 1(Keap1),nuclear factor E2 related factor 2(Nrf2),and heme oxygenase-1(HO-1)protein in prostate tissue.Results Compared with the blank group,rats in the model group had significantly lower mechanical pain threshold and significantly decreased prostate index(P<0.01);the size of the glandular cavity in prostate tissue varied,with the disappearance of secretions in the cavity,interstitial looseness and edema,a large amount of fibrous tissue hyperplasia and inflammatory cell infiltration,and a significant increase in pathological scores(P<0.01);the contents of ROS and MDA in prostate tissue significantly increased,the activity of GSH-Px significantly decreased(P<0.01),the expression of Keap1 and Nrf2 proteins significantly decreased,and the expression of HO-1 protein significantly increased(P<0.01,P<0.05).Compared with the model group,the mechanical pain threshold of the rats in the Yiqi Huoxue Tuodu Prescription group was significantly higher(P<0.01);there was mild damage to prostate tissue,with a small amount of fibrous hyperplasia and inflammatory cell infiltration,and a significant decrease in pathological scores(P<0.01,P<0.05);the contents of ROS and MDA in prostate tissue significantly decreased,and the GSH-Px activity significantly increased(P<0.01),the Keap1 and Nrf2 protein expressions significantly increased and HO-1 protein expression significantly decreased in prostate tissue(P<0.01,P<0.05).Conclusion Yiqi Huoxue Tuodu Prescription can effectively improve the histopathological morphology and increase the pain threshold of the prostate gland in CNP rats,and its mechanism of action may be related to the regulation of Keap1/Nrf2/HO-1 signaling pathway and reduction of oxidative stress damage in prostate tissue of rats.

Objective:To summarize the genotype and clinical characteristics of chylomicron retention disease (CMRD) caused by secretion associated Ras related GTPase 1B (SAR1B) gene variations.Methods:Clinical data and genetic testing results of 2 children with CMRD treated at Children′s Hospital of Fudan University and Jiangxi Provincial Children′s Hospital from May 2022 to July 2023 were summarized. To provide an overview of the clinical and genetic characteristics of CMRD caused by SAR1B gene variations, all of the literature was searched and reviewed from China National Knowledge Infrastructure, Wanfang Data Knowledge Service Platform, China VIP database, China Biology Medicine disc and PubMed database (up to January 2024) with "chylomicron retention disease" "Anderson disease" or "Anderson syndrome" as the search terms. All relevant literatures were reviewed to summarize the clinical and genetic features of CMRD caused by SAR1B gene variations.Results:One 11-year-old boy and one 4-month-old girl with CMRD. Both patients had lipid malabsorption, failure to thrive, decreased cholesterol, elevated transaminase and creatine kinase, and Vitamin E deficiency, with homozygous variations (c.224A>G) and compound heterozygous variations (c.224A>G and c.554G>T) in SAR1B gene, respectively. Case 1 was followed up for over a month, and he still occasionally experienced lower limb muscle pain. Case 2 was followed up for more than a year, and her had caught up to normal levels. Both patients had no other significant discomfort. Literature search retrieved 0 Chinese literature and 22 English literatures. In addition to the 2 cases reported in this study, a total of 51 patients were identified as CMRD caused by SAR1B gene variations. Twenty-one types of SAR1B variants 10 missense, 4 nonsense, 3 frameshift, 1 in-frame deletion, 1 splice, 1 gross deletion, and 1 gross insertion-deletion were found among the 51 CMRD cases. Among all the patients, 49 cases had lipid malabsorption (43 cases had diarrhea or fatty diarrhea, 17 cases had vomiting, and 12 cases had abdominal distension), 45 cases had lipid soluble Vitamin deficiency (43 cases had Vitamin E deficiency, 10 cases had Vitamin A deficiency, 9 case had Vitamin D deficiency, and 5 cases had Vitamin K deficiency), 35 cases had failure to thrive, 32 cases had liver involvement (32 cases had elevated transaminases, 5 cases had fatty liver, and 3 cases had hepatomegaly), 29 cases had white small intestinal mucosa under endoscopy, and 17 cases had elevated creatine kinase, 14 cases had neuropathy, 5 cases had ocular lesions, 2 cases had acanthocytosis, 1 case had decreased cardiac ejection fraction, and 1 case was symptom-free.Conclusions:Early infancy failure to thrive and lipid malabsorption are common issues for CMRD patients. The laboratory tests are characterized by hypocholesterolemia with or without fat-soluble Vitamin deficiency, elevated liver enzymes and (or) creatine kinase. Currently, missense variations are frequent among the primarily homozygous SAR1B genotypes that have been described.

Objective To compare the clinical effects of minimally invasive percutaneous plate osteosynthesis (MIPO) and minimally invasive intramedullary nailing osteosynthesis (MINO) in the treatment of humeral shaft fractures. Methods The clinical data of 53 patients with humeral shaft fractures treated with MIPO and MINO were retrospectively analyzed. The patients were divided into MIPO group of 25 patients and MINO group of 28 patients according to differed surgical approaches. The operation time, blood loss, length of hospital stay, fracture healing time, University of California at Los Angeles (UCLA) shoulder function score at 1 year postoperatively, and Mayo elbow performance score at 1 year postoperatively were compared between the two groups. Results All 53 patients successfully completed the surgery, and no postoperative complications such as surgical site infection, radial nerve injury, fracture nonunion, implant breakage, or loosening occurred. There were no statistically significant differences between the two groups in terms of operation time, blood loss, length of hospital stay, fracture healing time, and Mayo elbow performance score at 1 year postoperatively (P>0.05). The UCLA shoulder function score at 1 year postoperatively was better in the MIPO group than in the MINO group (P < 0.05). One patient in the MIPO group experienced wound fat liquefaction, and one patient in the MINO group experienced radial nerve palsy. Conclusion Both MIPO and MINO can achieve satisfactory results in the treatment of humeral shaft fractures, and both minimally invasive techniques are worthy of clinical promotion. However, MIPO has lesser impact on shoulder function.

Objective To summarize clinicopathologic features of papillary thyroid carcinoma (PTC) coexistent with chronic lymphocytic thyroiditis (CLT) and investigate risk factors for lymph node metastasis.Methods The medical records of 4 264 consecutive papillary thyroid carcinoma patients who received surgical treatment from Oct 2013 to Oct 2015 in Peking Union Medical College Hospital were reviewed.The diagnoses was confirmed by histopathological tests.Univariate analysis was performed to identify specific clinicopathologic features of PTC with CLT.Univariate and multivariate analysis were performed to determine whether each clinicopathologic feature was an independent risk factor for lymph node metastasis.Results In all 4 265 cases,there were 3 059 papillary thyroid microcarcinoma (PTMC) (71.7％),1 010 PTC patients (23.7％) with CLT.909 female patients (90％),624 cases with multifocal lesions (61.8％),422 cases with extra-thyroid extension (41.8％),429 cases with lymph node metastasis (42.5％),and 133 cases with metastatic lymph nodes(LNs) ≥6 (13.2％).The median age was 43 years old and median tumor size was 0.8 cm.Patients with CLT were more females (90.0％ vs.70.2％;P ＜ 0.001),younger median age (43 vs.44 years;P =0.001),and lower incidence of lymph node metastasis (42.5％ vs.50.9％;P ＜0.001).CLT was not associated with tumor size,multifocal lesions,extra-thyroid extension and metastatic LNs≥6 (0.8 cm vs.0.7 cm,61.8％ vs.62.9％,41.8％ vs.42.1％ and 13.2％ vs.14.8％,respectively,all P ＞ 0.05).In multivariate analysis,CLT was an independent protective factor for lymph node metastasis (OR =0.713,95％ CI 0.609-0.835,P ＜0.001).In PTC patients with lymph node metastasis,CLT was not associated with lymph node metastasis number (3 vs.3,P =0.300).Conclusions Chronic lymphocytic thyroiditis was an independent protective factor for papillary thyroid carcinoma patients with lymph node metastasis.But in patients with lymph node metastasis,the metastatic number didn't decrease.

Objective To evaluate the clinical and pathological feature,as well as risk factors of lymph node metastasis (LNM) and high-volume LNM (hvLNM) in papillary thyroid microcarcinoma (PTMC) with di ameter ≤0.5 cm.Methods PTMC patients who received surgical treatments in Peking Union Medical College Hospital from Nov.2013 to Nov.2014 were reviewed.Patients were allocated into the ≤0.5 cm group and (0.5-1)cm group according to tumor diameter.Clinical and pathological features were assessed and compared.Risk factors of LNM and hvLNM were also assessed through univariate and multivariate analysis.Results 1414 patients were enrolled,of which 315 patients (22.3％) were in the ≤0.5 cm group.76 LNM (24.1％) and 9 hvLNM (2.9％) were detected in the ≤0.5 cm group.There was significantly less capsule invasion (14.3％ vs 25.0％,P＜0.05),LNM (24.1％ vs 39.8％,P＜0.05) and hvLNM (2.9％ vs 7.9％,P＜0.05) in ≤0.5 cm group than in (0.5-1)cm group.In univariate analysis,patients aging ＜40 years old were more likely to have LNM than those older than 40(38.0％ vs 20.1％,P＜0.05),while male patients tended to have more LNM than female (32.4％ vs 21.9％,P=0.073).No risk factors were identified for hvLNM.In multivariate analysis,multifocality and younger than 40 years old were the independent risk factors of LNM (OR=2.082 and 2.899,P＜0.05),while male tended to be the independent risk factors of LNM (OR=l.807,P=0.058).No independent risk factors was identified for hvLNM.Conclusions A certain proportion of PTMC patients are with tumor diameter ≤0.5 cm,who have lower risk of LNM and hvLNM.Dynamic observation may be an option,especially in older ≥40 years old),unifocal and female patients.

Objective: To investigate the related factors for lymph node metastasis (LNM), especially for high volume LNM (>5 metastatic lymph nodes) in papillary thyroid carcinoma (PTC). Methods: The medical records of 2 073 consecutive PTC patients who underwent lobectomy, near-total thyroidectomy or total thyroidectomy with ipsilateral or bilateral central lymph node dissection in Department of General Surgery, Peking Union Medical College Hospital from November 2013 to October 2014 were reviewed. Clinical and pathological features were collected. Univariate and multivariate analysis were performed to identify the related factors for LNM/high volume LNM. Results: In all 2 073 patients, LNM and high volume LNM were confirmed in 936 (45.15%) cases and 254 (12.25%) cases respectively. In univariate analysis, large tumor size, young patients (<40 years), male were associated with both LNM and high volume LNM. In multivariate analysis, tumor size >2.0 cm, young patients (<40 years), male were independent related factors of LNM (OR=5.262, 95% CI: 3.468 to 7.986; OR=2.447, 95% CI: 2.000 to 2.995; OR=1.988, 95% CI: 1.593 to 2.480, respectively, all P=0.000) and high volume LNM (OR=6.687, 95% CI: 4.477 to 9.986; OR=2.975, 95% CI: 2.224 to 3.980; OR=2.354, 95% CI: 1.737 to 3.191, respectively, all P=0.000). In 1 414 PTMC patients, a similar result was also demonstrated.Compared with young patients (<40 years), old patients (≥60 years) had lower incidence of LNM (25.47% vs. 52.24%, χ²=62.903, P=0.000) and high volume LNM (1.89% vs. 13.18%, χ²=37.341, P=0.000). Additionally, old patients also had lower risk of both LNM (OR=0.316, 95% CI: 0.194 to 0.517, P=0.000) and high volume LNM (OR=0.142, 95% CI: 0.034 to 0.599, P=0.000). Conclusions The tumor size was the main related factor for both LNM and high volume LNM in PTC. The treatment should be more active in patients with tumor size >2 cm with consideration of higher incidence and risk for LNM and high volume LNM. Young patient was another important related factor for LNM and high volume LNM. In PTMC, old patients had lower incidence and risk for both LNM and high volume LNM. Dynamic observation or less surgical extent could be an option for these patients.

Objective To evaluate the clinical features of central nervous system involvement in brucellosis,and to provide references for clinical treatment and diagnosis.Methods A retrospective review was carried out in 14 hospitalized patients who were diagnosed as neurobrucellosis from October 2008 to September 2011 at the First Hospital of Jilin University.Patients' clinical manifestation,pathogen characteristics,cerebrospinal fluid analysis and imaging data were recorded.Results Among the 14 cases of patients with neurobrucellosis,10 cases had the clinical manifestations of headache and vomiting,11 cases meningeal irritation,2 cases dysphoria and seizures,3 cases apathia,3 cases coma,3 cases positive pathological sign,and 2 cases lower extremities weakness.From the perspective of clinical diagnosis of 14 patients with neurobrucellosis,4 cases were meningitis,of which,meningitis with both lower extremities paralysis were 2 cases; encephalitis in 2 cases; meningoencephalitis in 6 cases; abducent paralysis,decreased vision,myelitis and ataxic gait in 1 case,respectively.All patients were in acute phase and had irregular fever.After combination therapy with antibiotics for 2 to 9 days,body temperature of all patients returned to normal,and they were discharged from the hospital after 1 to 2 weeks.All cases were followed up for 12 months,finding no sequelae.Conclusions Due to the diversity of central nervous system involvement in brucellosis,in case of a patient with long-term fever and neurological symptoms,medical and epidemiological history should be inquired and diagnosis would be made easy based on combination of cerebrospinal fluid with laboratory tests.Early treatment of acute neurological brucellosis has showed a good prognosis.

OBJECTIVE:To establish a new semi-automatic drug dispensing mode,with proper cost,which falls in between full-automatic drug dispensing mode and manual drug dispensing mode,good work efficiency,standard and simple operation meth-od and meets national laws and regulations. METHODS:A semi-automatic drug dispensing system was designed,in which the in-formation in the drug dispensing sheet could be automatically printed on the drug bag,and automatic bagging,packaging and deliv-ery of drugs were realized. Such drug dispensing system included hardware(mechanical structures such as drug turntable and drug funnel,transmission device,etc.)and software control systems(the program of interface with hospital information system,micro control unit software,computer software,etc.). Through commissioning,formal operation and statistics,based on 18 oral drug dis-pensing sheets with the same contents,calculated the time of drug dispensing and the number of drug dispensing errors by 3 phar-macists respectively in manual drug bag dispensing mode and semi-automatic drug dispensing mode,to evaluate the effect of the semi-automatic drug dispensing system. RESULTS:From commissioning in May 2012 to formal operation in September 2012,the system operated normally and utility model patents were obtained. In the two modes,the total time of drug dispensing was 481 and 397 min (t=6.82,P<0.001),the numbers of drug dispensing errors were 25 and 7 (χ2=9.353 8,P=0.002 2),respectively. There was statistical significance. CONCLUSIONS:The semi-automatic drug dispensing system has higher efficiency and less num-ber of drug dispensing errors compared with manual drug bag dispensing mode and lower cost compared to full-automatic drug dis-pensing system. It deserves promotion.

Objective To investigate the effects of mannan-binding lectin(MBL) on TNF-α production induced by peptidoglycan (PGN) and its mechanism in human THP-1/CD14 monocytes.Methods The THP-1/CD14 cells were stimulated for 24 h with PGN at the indicated ratios after pretreated with human natural MBL at concentrations ranging from 1 to 20 mg/L for 2 h.The content of TNF-α and IL-6 in culture supernatants were detected by ELISA,and the levels of TNF-α and IL-6 mRNA expressions in these cells were determined by RT-PCR.FACS was used to investigate the interaction of MBL with THP-1/CD14 cells and the impact of MBL on PGN binding to THP-1/CD14 cells.Western blot was used to detect PGN-induced NF-κB translocation in THP-1/CD14 cells.Results ELISA showed that secretion of TNF-α and IL-6 from THP-1/CD14 cells could be induced by PGN ;The productions of TNF-α and IL-6 by THP-1/CD14 cells induced with PGN were profoundly inhibited by MBL at higher concentrations (10-20 mg/L) but not MBL at lower concentrations (1 mg/L).RT-PCR analysis also indicated that the mRNA expressions of TNF-α and IL-6 in THP-1/CD14 cells were decreased by MBL at higher concentration,compared to the corresponding THP-1/CD14 cells stimulated with PGN only.FACS showed that the binding of MBL to THP-1/CD14 cells was evident in a Ca2+-dependent manner.PGN could competitively inhibit the binding of MBL to THP-1/CD14 cells.MBL could competitively inhibit the binding of PGN to THP-1/CD14 cells by binding to THP-1/CD14 cells directly.Similarly,MBL at higher concentration (20 mg/L) decreased the NF-κB translocation in THP-1/CD14 cells.Conclusion MBL may inhibit TNF-α and IL-6 production induced by PGN in THP-1/CD14 cells through NF-κB signaling pathways,suggesting that MBL can play some roles in the regulation of PGN-induced inflammatory response.