OBJECTIVE: To investigate the clinical and genetic characteristics of a family with Vissers-Bodmer Syndrome (VIBOS) and to review the relevant literature on VIBOS caused by CNOT1 gene variants. METHODS: A child diagnosed with VIBOS due to "growth retardation for over 6 years" at the Linyi People's Hospital on March 1, 2024 and her family members were selected as the study subjects. Clinical data of the family were collected. Peripheral venous blood samples were collected from the family members. Whole-exome sequencing (WES) was performed on the proband's peripheral blood, and Sanger sequencing was used for verification of the candidate variant in the family. Pathogenicity of the candidate variant was classified according to the "Standards and Guidelines for the Interpretation of Sequence Variants" established by the American College of Medical Genetics and Genomics American College of Medical Genetics (ACMG). Bioinformatics analysis, including pathogenicity prediction using Mutation Taster, three-dimensional protein structure modeling using SWISS-MODEL, and functional impact assessment using PyMOL, was performed. Relevant literature on VIBOS patients due to variants of the CNOT1 gene was retrieved from databases such as CNKI, Wanfang Data, and PubMed. The clinical phenotypes and genotypes of the patients were summarized. This study was approved by the Medical Ethics Committee of the Hospital (Ethics No.: YX200303). RESULTS: The proband, a 6-year-and-7-month-old female, presented with short stature, distinctive facial features (esotropia, hypertelorism, prominent nasolabial folds), webbed neck, clinodactyly, and intellectual disability. WES revealed that she has carried a heterozygous c.736delG (p.V246*) variant of the CNOT1 gene, which was unreported previously. The proband's father exhibited borderline intellectual function but no short stature or distinctive facial features. Sanger sequencing confirmed that he has carried the same heterozygous variant. According to the ACMG guidelines, this genetic variant was predicted as "likely pathogenic" (PVS1+PM2_Supporting). The c.736delG (p.V246*) variant was predicted to have a deleterious effect by Mutation Taster. Subsequent homology modeling using SWISS-MODEL, coupled with structural visualization and comparison using PyMOL, confirmed that it may cause premature termination of translation and produce a truncated protein. Literature search has retrieved five articles on VIBOS due to CNOT1 gene variants, which included 45 cases. Together with the proband and her father, the common clinical features among these 47 patients included distinctive facial features (83.0%, 39/47), speech delay (70.2%, 33/47), motor delay (70.2%, 33/47), intellectual disability (59.6%, 28/47), and short stature (48.9%, 23/47). In terms of the types of the variants, missense variants were the most common (47.4%, 18/38), followed by frameshift variants (21.0%, 8/38). The variant sites have mainly located in exons 7, 25, and 31. No significant genotype-phenotype correlation was noted. CONCLUSION The c.736delG (p.V246*) frameshift variant of the CNOT1 gene is likely the genetic etiology of VIBOS in this proband. The clinical manifestations of the proband were more severe than in her fathers, which suggested phenotypic variability associated with this variant. This study has provided new evidence for the understanding of the genetic basis of VIBOS.
Child ; Female ; Humans ; Male ; Exome Sequencing ; Intellectual Disability/genetics* ; Mutation ; Pedigree ; Transcription Factors/genetics* ; East Asian People/genetics*

Objective To screen the mutations of ABCC8 gene in probands of maturity-onset diabetes of the young pedigrees,and investigate it sgenetic and clinical characteristics.Methods Whole exome sequencing were performed to screen ABCC8 mutations in 56 MODY probands who were admitted to Department of Endocrinology and Metabolism,Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine from July 2021 to December 2023.The mutations were verified by Sanger sequencing,and all participants were genotyped.Clinical phenotypes of the mutation carriers were compared with non-DM controls within the families.The identified mutations were evaluated by bioinformatic softwires.Then the pharmacogenomic characteristics of the mutation carriers were analyzed.Results Two heterozygous mutations D655V and R825Q were identified in two MODY probands and their families respectively,and the D655V was a novel mutation.Bioinformatics studies showed that both mutations were deleterious and pathogenic.In comparison with non-DM controls in the two families,mutation carriers with diabetes exhibited significantly lower fasting insulin/fasting plasma glucose,two-hour postprandial insulin/two-hour postprandial insulin plasma glucose,homeostatic model assessment-β(P<0.05).Treatment with oral hypoglycemic agents such as metformin or insulin in these mutation carriers resulted in a moderate reduction in plasma glucose levels.However,switching to targeted Sulfonylurea's(SUs)proved to be more effective.Conclusions In this study,the prevalence of MODY12 is 3.6%in these MODY pedigrees.The remarkable hypoglycemic efficacy of SUs suggests that both D655V and R825Q were activating mutations of ABCC8,and maybe the cause of MODY12 characterized by impaired insulin secretion.

Objective:To characterize the clinical and genetic features of 2 patients with interleukin-1 receptor associated kinase (IRAK) 4 deficiency and to assess the pathogenicity of their genetic variants.Methods:This case series included two patients diagnosed with IRAK4 gene deficiency at Shenzhen Children′s Hospital and the University of Hong Kong-Shenzhen Hospital between 2019 and 2024. Six healthy children without recent infections or immunodeficiency served as controls. Peripheral blood mononuclear cells were stimulated in vitro with Toll-like receptor 4 (TLR4) agonists, and cytokine levels were quantified using a protein chip assay.Results:The 2 patients, a 5-year-old boy and a 10-year-old girl, presented with recurrent invasive or non-invasive bacterial infections and impaired acute-phase inflammatory responses. Genetic testing identified a homozygous frameshift variant (c.540delT, p.F180Lfs*26) in Patient 1 and compound heterozygous frameshift variants (c.166delT, p.F56fs and c.629delG, p.R210fs) in Patient 2, all predicted to result in truncated IRAK4 proteins. Both patients received regular infection prophylaxis with favorable clinical outcomes. Controls consists of 3 males and 3 females, aged 5-17 years. Following TLR4 stimulation, cytokine levels in Patient 1, Patient 2, and controls (tumor necrosis factor-α 68.6, 103.0, 618.7 (392.7, 824.1); interleukin (IL)-1β 39.8, 10.8, 1 975.5 (1 556.0, 2 096.5); interferon-γ 8.6, 6.2, 13.5 (12.7, 14.9); granulocyte colony-stimulating factor 17.6, 15.9, 2 890.0 (1 622.0, 4 692.8); IL-6 140.1, 352.7, 7 222.5 (5 768.5, 8 043.5); and IL-17 47.5, 44.5, 59.7 (43.4, 69.5), respectively.Conclusions:IRAK4 deficiency should be suspected in patients with early-onset recurrent bacterial infections and attenuated inflammatory response. Homozygous and compound heterozygous frameshift variants in IRAK4 gene lead to truncated IRAK4 proteins and impared innate immune signaling.

BACKGROUND:Liuwei Dihuang Wan takes"three tonifying and three reducing effects"as its compatibility feature to nourish yin and tonify the kidneys,while Zuogui Wan takes"seeking yin in yang"as its compatibility feature to nourish yin and tonify the kidneys by promoting yang.Both of them belong to the same method of nourishing yin and tonifying the kidneys,and have better curative effects at the symptomatic and cellular molecular levels. OBJECTIVE:To observe the effects of Liuwei Dihuang Wan and Zuogui Wan in bone metabolism,and to explore their mechanism of action in the osteoprotegerin(OPG)/receptor activator of nuclear factor-κB ligand(RANKL)osteoblastic pathway. METHODS:Thirty-two Sprague-Dawley rats were randomized into model,Liuwei Dihuang Wan,Zuogui Wan,and sham operation group,with eight rats in each group.Osteoporosis models were prepared using removal of both ovaries in the first three groups.Starting at 30 days postoperatively,rats in the Liuwei Dihuang Wan group were gavaged with Liuwei Dihuang Wan 1.125 g/kg/d;rats in the Zuoqui Wan group were gavaged with Zuogui Wan 2.25 g/kg/d;and rats in the sham operation group and the model group were gavaged with saline 10 mL/kg/d.After 12 weeks of gavage,the rat tibia was taken to measure bone mineral density.The serum levels of estrogen,bone alkaline phosphatase,and cAMP/cGMP were measured using ELISA,and the expression of OPG/RANKL in the femur was detected using western blot. RESULTS AND CONCLUSION:Compared with the sham operation group,the model group showed a decrease in bone mineral density and levels of estrogen and bone alkaline phosphatase(P＜0.05)and an increase in cAMP/cGMP level(P＜0.05).Compared with the model group,the Liuwei Dihuang Wan group and the Zuogui Wan group significantly increased bone mineral density(P＜0.05)and bone alkaline phosphatase levels(P＜0.05);the Zuogui Wan group significantly decreased cAMP/cGMP levels(P＜0.05)and upregulated OPG expression(P＜0.05);the Liuwei Dihuang Wan group upregulated OPG expression and downregulated RANKL expression(P＜0.05);and both groups were unable to significantly increase estrogen levels(P＞0.05).To conclude,Zuogui Wan,which seeks yin from yang,can effectively increase the expression of OPG but cannot downregulate the expression of RANKL.However,Liuwei Dihuang Wan,which has three tonifying and three reducing effects,can bidirectionally regulate the expression of OPG and RANKL.This result suggests that Liuwei Dihuang Wan can significantly inhibit osteoclastic function compared with Zuogui Wan,and further research is needed to verify this conclusion.

Objective To screen the mutations of ABCC8 gene in probands of maturity-onset diabetes of the young pedigrees,and investigate it sgenetic and clinical characteristics.Methods Whole exome sequencing were performed to screen ABCC8 mutations in 56 MODY probands who were admitted to Department of Endocrinology and Metabolism,Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine from July 2021 to December 2023.The mutations were verified by Sanger sequencing,and all participants were genotyped.Clinical phenotypes of the mutation carriers were compared with non-DM controls within the families.The identified mutations were evaluated by bioinformatic softwires.Then the pharmacogenomic characteristics of the mutation carriers were analyzed.Results Two heterozygous mutations D655V and R825Q were identified in two MODY probands and their families respectively,and the D655V was a novel mutation.Bioinformatics studies showed that both mutations were deleterious and pathogenic.In comparison with non-DM controls in the two families,mutation carriers with diabetes exhibited significantly lower fasting insulin/fasting plasma glucose,two-hour postprandial insulin/two-hour postprandial insulin plasma glucose,homeostatic model assessment-β(P<0.05).Treatment with oral hypoglycemic agents such as metformin or insulin in these mutation carriers resulted in a moderate reduction in plasma glucose levels.However,switching to targeted Sulfonylurea's(SUs)proved to be more effective.Conclusions In this study,the prevalence of MODY12 is 3.6%in these MODY pedigrees.The remarkable hypoglycemic efficacy of SUs suggests that both D655V and R825Q were activating mutations of ABCC8,and maybe the cause of MODY12 characterized by impaired insulin secretion.

Objective:To characterize the clinical and genetic features of 2 patients with interleukin-1 receptor associated kinase (IRAK) 4 deficiency and to assess the pathogenicity of their genetic variants.Methods:This case series included two patients diagnosed with IRAK4 gene deficiency at Shenzhen Children′s Hospital and the University of Hong Kong-Shenzhen Hospital between 2019 and 2024. Six healthy children without recent infections or immunodeficiency served as controls. Peripheral blood mononuclear cells were stimulated in vitro with Toll-like receptor 4 (TLR4) agonists, and cytokine levels were quantified using a protein chip assay.Results:The 2 patients, a 5-year-old boy and a 10-year-old girl, presented with recurrent invasive or non-invasive bacterial infections and impaired acute-phase inflammatory responses. Genetic testing identified a homozygous frameshift variant (c.540delT, p.F180Lfs*26) in Patient 1 and compound heterozygous frameshift variants (c.166delT, p.F56fs and c.629delG, p.R210fs) in Patient 2, all predicted to result in truncated IRAK4 proteins. Both patients received regular infection prophylaxis with favorable clinical outcomes. Controls consists of 3 males and 3 females, aged 5-17 years. Following TLR4 stimulation, cytokine levels in Patient 1, Patient 2, and controls (tumor necrosis factor-α 68.6, 103.0, 618.7 (392.7, 824.1); interleukin (IL)-1β 39.8, 10.8, 1 975.5 (1 556.0, 2 096.5); interferon-γ 8.6, 6.2, 13.5 (12.7, 14.9); granulocyte colony-stimulating factor 17.6, 15.9, 2 890.0 (1 622.0, 4 692.8); IL-6 140.1, 352.7, 7 222.5 (5 768.5, 8 043.5); and IL-17 47.5, 44.5, 59.7 (43.4, 69.5), respectively.Conclusions:IRAK4 deficiency should be suspected in patients with early-onset recurrent bacterial infections and attenuated inflammatory response. Homozygous and compound heterozygous frameshift variants in IRAK4 gene lead to truncated IRAK4 proteins and impared innate immune signaling.

Objective To investigate the overweight and obesity of primary and middle school students in Sijing area of Shanghai from 2020 to 2022,so as to provide scientific basis for the intervention of childhood obesity.Methods In October 2020 and October 2022,all primary and middle school students in Sijing area underwent physical examination by cluster sampling method.A cross-sectional study was conducted to investigate the obesity and overweight in primary and middle school students of different ages and genders in Sijing area.Results In 2020 and 2022,7 766 and 10 594 students completed physical examination,respectively,and 4 626 of them underwent two consecutive physical examinations.The incidences of overweight and obesity were 15.14%and 21.89%in 2020,respectively.The incidences of overweight and obesity were 15.41%and 21.11%in 2022,respectively.There were no significant differences in the incidences of overweight or obesity between 2020 and 2022(P>0.05).In 2020,the incidences of overweight and obesity of male students were 14.91%and 24.70%;the incidences of overweight and obesity of female students were 15.40%and 18.80%,respectively.In 2022,the incidences of overweight and obesity of male students were 15.04%and 24.14%;the incidences of overweight and obesity of female students were 15.82%and 17.82%,respectively.There was no significant difference in the overweight rate between males and females(P>0.05).The incidence of obesity of male students was significantly higher than that of female students in both 2020 and 2022(P<0.05).In the students aged 12 years old,the incidence of obesity was 27.42%in 2022,which was significantly higher than that in 2020(P<0.05).There was no significant difference in the incidence of obesity between other age groups(P>0.05).Among the 4 626 children who participated in two consecutive physical examinations,the overweight/obesity rates were 14.46%/21.25%in 2020 and 16.04%/21.78%in 2022;there was significant difference in the overweight rates(P<0.05),while no significant difference was found in obesity rates(P>0.05).Among the 4 626 children,there were 2 402 boys and 2 224 girls.In 2020,the overweight/obesity rates were 13.70%/24.48%in these boys and 15.29%/17.76%in these girls.In 2022,the overweight/obesity rates were 16.07%/25.44%in these boys and 16.01%/17.72%in these girls.There was no significant difference in the incidence of overweight between these girls and boys in 2020 and 2022(P>0.05),but the obesity rate of boys was significantly higher than that of girls(P<0.05).Conclusion There are high incidences of overweight and obesity among primary and middle school students in Sijing area of Shanghai,and dietary and exercise guidances should be strengthened.Meanwhile,the incidences of overweight and obesity are higher among boys,and obesity prevention and control measures should be strengthened for boys.

Objective To discuss the application value of video health education mode in patient's self-maintenance of totally implantable venous access port(TIVAP).Methods A total of 208 patients,who received implantation of TIVAP at the Second Affiliated Hospital of Naval Military Medical University of China From September 2021 to December 2022,were enrolled in this study.The patients were divided into control group(n=108)and observation group(n=100).Traditional health education was conducted for the patients of the control group,while on the basis of traditional health education an additional video health education based on visual communication theory was carried out for the patients of the observation group.Evaluation of self-care ability(ESCA)was used to evaluate the self-care ability before the intervention and 6 months after the implantation of TIVAP in the two groups.The complications,the incidence of adverse events,and the indwelling duration of the infusion port were compared between the two groups.Results Before intervention,the differences in each dimension score and total score of ESCA table between the two groups were not statistically significant(all P＞0.05).After intervention,the each dimension score and total score of ESCA table in the observation group were significantly higher than those in the control group(all P＜0.05).After intervention,both the total incidence of complications and the total incidence of adverse events in the observation group were remarkably lower than those in the control group(both P＜0.05),besides,the indwelling duration of the infusion port in the observation group was obviously longer than that in the control group.Conclusion The use of video health education mode can significantly improve the self-care ability of patients carrying a TIVAP,reduce the incidence of complications and adverse events,and extend the effective duration of TIVAP.Therefore,it is an effective health education mode.

Objective To explore the effectiveness of building block assembly games in the upper limb functional exercise of school-aged children with peripherally inserted central catheter catheterization.Methods Using convenience sampling,90 catheterized children who met the inclusion criteria in the pediatric ward of a tertiary hospital in Henan Province from November 2022 to April 2023 were selected as research subjects.They were randomly divided into an experimental group and a control group,with 45 cases in each group.The experimental group participated in building block assembly games in addition to conventional ball-gripping exercises,while the control group engaged solely in conventional ball-gripping exercises.The compliance rates of upper limb exercises,time average peak flow rate of axillary vein of the catheterization side,and the incidence of catheter-related complications were compared between the 2 groups.Results During the study,2 cases in the experimental group and 3 in the control group dropped out,resulting in 43 cases in the experimental group and 42 in the control group.The compliance rate of upper limb exercises in the experimental group during hospitalization was 93.03％,significantly higher than 64.29％in the control group(P＜0.001).On the third day after catheterization,the time average peak flow rate of axillary vein of the catheterization side was(5.58±1.24)cm/s and(5.37±1.24)cm/s on the seventh day in the experimental group,compared to(3.87±1.06)cm/s and(3.56±0.81)cm/s,respectively,in the control group.These differences were statistically significant(P＜0.001).The incidence of catheter-related thrombosis in the experimental group was 4.65％,significantly lower than 21.43％in the control group(P=0.021).The rates of bleeding at the puncture site and catheter displacement in the experimental group were both 4.65％,compared to 7.14％and 4.76％,respectively,in the control group.These differences were not statistically significant(both P＞0.05).Conclusion Incorporating building block assembly games into routine ball-gripping exercises can improve the compliance of upper limb exercises in children with PICC placement,improve the blood flow velocity in the axillary vein of the catheterization upper limb,and reduce the incidence of catheter-related thrombosis,without increasing the risk of bleeding at the puncture site or catheter displacement.

Objective:To investigate the clinical efficacy and safety of pulmonary rehabilitation in elderly patients with chronic obstructive pulmonary disease(COPD)who are undergoing long-term home oxygen therapy.Methods:The study included a total of 60 elderly patients with COPD who were successfully discharged after receiving treatment at the First Hospital of Shanxi Medical University from November 2021 to October 2022.The enrolled patients were randomly divided into two groups: the pulmonary rehabilitation group and the control group, with 30 patients in each group.The allocation was determined using a random number table and prospective research methods.Patients in the pulmonary rehabilitation group underwent a 12-week pulmonary rehabilitation training program, while patients in the control group received pulmonary rehabilitation education and nutrition education.The general data of the two groups of patients were compared, including lung function parameters[forced expiratory volume in one second(FEV 1), forced vital capacity(FVC), forced expiratory volume in one second to forced vital capacity ratio(FEV 1/FVC), and percentage of predicted forced expiratory volume in one second(FEV 1%pred)], blood gas analysis[partial pressure of arterial oxygen(PaO 2), partial pressure of arterial carbon dioxide(PaCO 2), arterial oxygen saturation(SaO 2)], 6-minute walking distance(6MWD), grip strength, 5-round sit to stand test(5R-STST), modified British medical research council(mMRC)score, COPD assessment test(CAT)score, closed cycles test(CCT), Berg balance scale(BBS), and safety measures.These parameters were assessed before and after the intervention. Results:A total of 29 patients in the pulmonary rehabilitation group and 28 patients in the control group completed the study.The general data between the two groups showed no significant difference(all P>0.05).After the intervention, patients in the pulmonary rehabilitation group showed improvements in FEV 1/FVC, PaO 2, PaCO 2, SaO 2, 6MWD, grip strength, 5R-STST, CAT, CCT, and BBS( t=-2.242, -4.630, W=-3.439, t=-6.512, -10.563, -6.197, W=-3.968, t=10.847, -7.334, W=-4.189, all P<0.05).Additionally, 6MWD, CAT, and CCT showed significant improvement after the intervention compared to the control group( t=-2.104, 2.183, 2.106, all P<0.05).No training-related adverse effects were observed during the study. Conclusions:The 12-week pulmonary rehabilitation program is shown to be effective for elderly patients with COPD who are undergoing long-term home oxygen therapy.This program helps to improve respiratory function, systemic symptoms, exercise endurance, muscle strength, and balance function.It is designed to be simple and easy to implement, allowing patients to achieve their training goals and improve their clinical symptoms.Additionally, the program has been found to be safe and well-tolerated by patients, making it a valuable intervention that should be promoted and widely applied.