Discovery and druggability evaluation of pyrrolamide-type GyrB/ParE inhibitor against drug-resistant bacterial infection

The bacterial ATP-competitive GyrB/ParE subunits of type II topoisomerase are important anti-bacterial targets to treat super drug-resistant bacterial infections. Herein we discovered novel pyrrolamide-type GyrB/ParE inhibitors based on the structural modifications of the candidate AZD5099 that was withdrawn from the clinical trials due to safety liabilities such as mitochondrial toxicity. The hydroxyisopropyl pyridazine compound 28 had a significant inhibitory effect on Gyrase (GyrB, IC50 = 49 nmol/L) and a modest inhibitory effect on Topo IV (ParE, IC50 = 1.513 μmol/L) of Staphylococcus aureus. It also had significant antibacterial activities on susceptible and resistant Gram-positive bacteria with a minimum inhibitory concentration (MIC) of less than 0.03 μg/mL, which showed a time-dependent bactericidal effect and low frequencies of spontaneous resistance against S. aureus. Compound 28 had better protective effects than the positive control drugs such as DS-2969 ( 5) and AZD5099 ( 6) in mouse models of sepsis induced by methicillin-resistant Staphylococcus aureus (MRSA) infection. It also showed better bactericidal activities than clinically used vancomycin in the mouse thigh MRSA infection models. Moreover, compound 28 has much lower mitochondrial toxicity than AZD5099 ( 6) as well as excellent therapeutic indexes and pharmacokinetic properties. At present, compound 28 has been evaluated as a pre-clinical drug candidate for the treatment of drug-resistant Gram-positive bacterial infection. On the other hand, compound 28 also has good inhibitory activities against stubborn Gram-negative bacteria such as Escherichia coli (MIC = 1 μg/mL), which is comparable with the most potent pyrrolamide-type GyrB/ParE inhibitors reported recently. In addition, the structure-activity relationships of the compounds were also studied.

Associations of genetic polymorphisms in Corin with blood pressure responses to salt and potassium intake / 西安交通大学学报(医学版)

【Objective】 Corin, a transmembrane serine protease that can cleave atrial natriuretic peptide precursor (pro-ANP) into atrial natriuretic peptide with smaller bioactive molecules, participates in the pathophysiological process of hypertension and cardiac hypertrophy. The purpose of this study was to explore the relationship of Corin gene variation with blood pressure responses to sodium and potassium dietary interventions. 【Methods】 In 2004, we recruited 514 participants from 124 families in 7 villages of Baoji, Shaanxi Province, China. All the subjects received a 3-day normal diet, a 7-day low-salt diet, a 7-day high-salt diet, and finally a 7-day high-salt and potassium supplementation. Fifteen single nucleotide polymorphisms (SNPs) of Corin gene were selected for final analysis. 【Results】 SNPs rs12509275 were significantly associated with diastolic blood pressure (DBP) response to low-salt diet, while rs3749584 was associated with pulse pressure (PP) response to low-salt diet.SNP rs3749584 and rs10517195 were significantly associated with PP response to high-salt diet. In addition,rs17654278 were significantly associated with systolic blood pressure (SBP) response to high-salt and potassium supplementation, rs2271037 was significantly correlated with DBP responses to high-salt and potassium supplementation, and rs4695253, rs12509275, rs2351783, rs36090894 were significantly associated with PP response to high-salt and potassium supplementation. 【Conclusion】 Corin gene polymorphisms were associated with blood pressure response to sodium and potassium, suggesting that Corin gene may be involved in pathophysiological process of salt sensitivity and potassium sensitivity.

Research progress on predictors of suicidal behavior in adolescents with depressive disorder / 中国学校卫生

Abstract@#In recent years, the incidence of adolescent suicide has been increasing, and it has become a serious public health problem that threatens the physical and mental health and even the life of adolescents. Adolescents with depressive disorder are a high risk group for suicidal behavior. The paper reviews the personal psychological factors, as well as the family, school and social factors that play a role in the suicidal behavior of adolescents with depressive disorder, providing a scientific basis for the effective prevention of suicidal behavior in adolescents.

A cohort study of vincristine-induced peripheral neuropathy in children / 中国当代儿科杂志

OBJECTIVES@#To study the characteristics of vincristine-induced peripheral neuropathy (VIPN) in children with acute lymphoblastic leukemia (ALL) and the factors influencing the development of VIPN.@*METHODS@#The children with ALL, aged 1-18 years, who were treated with CCCG-ALL2015 or CCCG-ALL2020 regimen in the Affiliated Hospital of Guizhou Medical University from January 2018 to February 2022 were enrolled as subjects. According to the influence of age on risk, the children were divided into 1-10 years group with 91 children and >10 years group with 29 children. VIPN was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (5th edition), and the incidence rate, severity, and type of VIPN were compared between different groups.@*RESULTS@#A total of 120 children were enrolled in this study, among whom 56 (46.7%) developed VIPN. The >10 years group had a significantly higher incidence rate of VIPN than the 1-10 years group (69% vs 40%, P<0.05). Among the 56 children with VIPN, 12 (21%) had grade 3 VIPN or above, and 44 (79%) had grade 2 VIPN. There were 77 cases of autonomic nerve symptoms (59.7%), 42 cases of peripheral nerve injury (32.5%), and 10 cases of cranial nerve injury (7.8%). There were no significant differences in the severity and type of VIPN between the groups with different ages, sexes, degrees of risk, or treatment regimens (P>0.05). The results of binary logistic regression analysis showed that age is the influencing factor for the occurrence of VIPN (P>0.05).@*CONCLUSIONS@#There is a relatively high incidence rate of VIPN in children with ALL, with the highest incidence rate of autonomic nervous symptoms. The incidence of VIP in children over 10 years old is relatively high.

Leonurine inhibits ferroptosis in renal tubular epithelial cells by activating p62/Nrf2/HO-1 signaling pathway / 中国中药杂志

To investigate the protective effect and the potential mechanism of leonurine(Leo) against erastin-induced ferroptosis in human renal tubular epithelial cells(HK-2 cells), an in vitro erastin-induced ferroptosis model was constructed to detect the cell viability as well as the expressions of ferroptosis-related indexes and signaling pathway-related proteins. HK-2 cells were cultured in vitro, and the effects of Leo on the viability of HK-2 cells at 10, 20, 40, 60, 80 and 100 μmol·L~(-1) were examined by CCK-8 assay to determine the safe dose range of Leo administration. A ferroptosis cell model was induced by erastin, a common ferroptosis inducer, and the appropriate concentrations were screened. CCK-8 assay was used to detect the effects of Leo(20, 40, 80 μmol·L~(-1)) and positive drug ferrostatin-1(Fer-1, 1, 2 μmol·L~(-1)) on the viability of ferroptosis model cells, and the changes of cell morphology were observed by phase contrast microscopy. Then, the optimal concentration of Leo was obtained by Western blot for nuclear factor erythroid 2-related factor 2(Nrf2) activation, and transmission electron microscope was further used to detect the characteristic microscopic morphological changes during ferroptosis. Flow cytometry was performed to detect reactive oxygen species(ROS), and the level of glutathione(GSH) was measured using a GSH assay kit. The expressions of glutathione peroxidase 4(GPX4), p62, and heme oxygenase 1(HO-1) in each group were quantified by Western blot. RESULTS:: showed that Leo had no side effects on the viability of normal HK-2 cells in the concentration range of 10-100 μmol·L~(-1). The viability of HK-2 cells decreased as the concentration of erastin increased, and 5 μmol·L~(-1) erastin significantly induced ferroptosis in the cells. Compared with the model group, Leo dose-dependently increased cell via-bility and improved cell morphology, and 80 μmol·L~(-1) Leo promoted the translocation of Nrf2 from the cytoplasm to the nucleus. Further studies revealed that Leo remarkably alleviated the characteristic microstructural damage of ferroptosis cells caused by erastin, inhibited the release of intracellular ROS, elevated GSH and GPX4, promoted the nuclear translocation of Nrf2, and significantly upregulated the expression of p62 and HO-1 proteins. In conclusion, Leo exerted a protective effect on erastin-induced ferroptosis in HK-2 cells, which might be associated with its anti-oxidative stress by activating p62/Nrf2/HO-1 signaling pathway.

Interventional embolization treatment of pelvic lymphatic leakage after radical prostatectomy two cases report / 中华泌尿外科杂志

Lymphatic leakage and lymphatic cysts are common complications after radical resection of middle- and high-risk prostate cancer. There are many treatment methods but the effect is not accurate. This article reports two patients who were diagnosed by lipiodol lymphangiography under ultrasound guidance and used a mixture of n-butyl cyanoacrylate and lipiodol to embolize lymphatic leakage. Among them, one patient achieved success after one session of interventional embolization. Another patient achieved success after 3 interventions and embolization. Two patients had no complications related to lymphatic interventional therapy, and no lymphatic leakage recurred during the 3-month follow-up. Ultrasound-guided lymphangiography and lymphatic embolization through the inguinal lymph nodes are a feasible option for the treatment of refractory lymphoma leakage

Clinical characterization and genetic testing for a patient with creatine deficiency syndrome 1 / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis for a child affected with cerebral creatine deficiency syndrome 1 (CCDS1).@*METHODS@#High-throughput sequencing was carried out to screen pathogenic variant associated with the clinical phenotype of the proband. The candidate variant was verified by Sanger sequencing.@*RESULTS@#High-throughput sequencing revealed that the proband has carried heterozygous c.327delG variant of the SLC6A8 gene, which was verified by Sanger sequencing.Neither parent was found to carry the same variant.@*CONCLUSION@#The de novo heterozygous c.327delG variant of the SLC6A8 gene probably underlay the CCDS1 in this child.

Identification of pathogenic variant and preimplantation genetic testing for a Chinese family affected with osteogenesis imperfecta / 中华医学遗传学杂志

OBJECTIVE@#To identify the pathogenic variant for a husband with osteogenesis imperfecta and provide preimplantation genetic testing (PGT) for the couple.@*METHODS@#High-throughput sequencing and Sanger sequencing were carried out to identify the pathologic variant in the husband patients. PGT of embryos was performed through direct detection of the mutation site. Meanwhile, chromosome aneuploidy of the blastocysts was screened. Following transplantation, cytogenetic and genetic testing of fetal amniotic fluid sample was carried out during mid-pregnancy. Chromosome copy number variant (CNV) was detected at multiple sites of the placenta after delivery.@*RESULTS@#The husband was found to harbor heterozygous c.544-2A>G variant of the COL1A1 gene. The same variant was not detected in either of his parents. PGT revealed that out of three embryos of the couple, one was wild-type for the c.544-2A site but mosaicism for duplication of 16p13.3.11.2. The other two embryos were both heterozygous for the c.544-2A>G variant. Following adequate genetic counseling, the wild-type embryo was transplanted. Amniotic fluid testing confirmed that the fetus had normal chromosomes and did not carry the c.544-2A>G variant. The copy number of chromosomes at different parts of placenta was normal after birth.@*CONCLUSION@#For couples affected with monogenic disorders, e.g., osteogenesis imperfecta, direct detection of the mutation site may be used for PGT after identifying the pathogenic variant. After adequate genetic counseling, prenatal diagnosis must be carried out to ensure the result.

Help-seeking efficacy and the intention of social assistance among medical care personnel during the major public health events / 中华劳动卫生职业病杂志

Objective: To explore the help seeking efficacy and social assistance willingness of medical staff during major public health events, so as to provide basis for improving the psychological resources and service quality of medical staff and further optimizing the prevention and treatment policies. Methods: In February 2020, a convenient sampling method was used to conduct an online questionnaire survey on medical staff in Henan Province, and a total of 2136 questionnaires were collected. Among them, there were 1940 valid questionnaires, and the effective recovery rate was 90.82%. The questionnaire of help seeking efficacy and willingness to social assistance under epidemic situation was used to investigate the help seeking efficacy and willingness of medical staff. The frequency and rate (%) were used to analyze the overall situation of medical staff's help seeking efficacy and social assistance willingness. The differences among different demographic variables were tested by χ(2) test. Results: Among the 1940 medical and nursing staff, 18.81% (365/1940) did not know how to obtain appropriate psychological assistance. Compared with the low age group, the medical staff in the high age group had the ability of information query, the ability to occupy knowledge resources, the ability to distinguish rumors and facts and the sense of efficacy of obtaining appropriate medical help, and the difference was statistically significant (P<0.05) . The willingness of medical and nursing staff to actively cooperate with the government, maintain social stability and volunteer work were 99.43% (1929/1940) , 98.81% (1917/1940) and 97.11% (1884/1940) . Conclusion: The medical staff had a higher sense of help seeking efficacy and willingness to social assistance. It is necessary to further strengthen the resource support of psychological, social and humanistic care for medical staff.

Aesthetic reconstruction of distal segment of finger with modified second toe nail flap without sacrifice a toe / 中华显微外科杂志

Objective:To explore the method and effect of aesthetic reconstruction of distal segment of finger with modified second toe nail flap while retains the full length of the second toe.Methods:From April 2018 to June 2020, 16 patients with degloving injury of distal segment of fingers were treated. The patients were 11 males and 5 females aged 18 to 45 years in an average of 29 years. All injuries were degloving injury of the distal segment of finger, including 5 index fingers, 7 middle fingers, 3 ring fingers and 1 little finger. The time from injury to operation was 0.5-3.0 hours, with an average of 1.5 hours. The second toe nail flap was used for the reconstruction. After the dorsal flap of the second toe was rotated to the plantar side of the foot, the donor site defect was repaired by a skin graft. The regular follow up reviews were carried out.Results:All 16 flaps survived except 1 flap had necrosis and underwent toe amputation of the distal segment of the second toe. All patients entered follow-up for 4-12 months, with an average of 5.7 months. The blood supply of all flaps was good. After the flaps having atrophied, they were equivalent to the diameter of the body of normal fingers with the TPD at 6.5(4-10) mm; All patients returned to work. According to the Evaluation Standard of Upper Limb Function of Chinese Hand Surgery Society, 13 cases were graded as excellent, 2 were good and 1 was fair.Conclusion:The techniques of modified second toe toenail flap in aesthetic reconstruction of the distal segment of a finger can effectively restore the length and aesthetic appearance of the affected finger, without sacrificing the donor toe. Clinical application of it should be promoted.

Preliminary study on the application of third-generation sequencing technology for the detection of chromosomal aneuploidies / 中华医学遗传学杂志

OBJECTIVE@#To apply nanopore third-generation sequencing for the detection of chromosomal aneuploidy samples, and explore its performance and application prospects.@*METHODS@#DNA extracted from two human cell lines with X chromosome monosomy and 22.5 Mb deletion in 7q11.23-q21.3 region was sequenced with a MinION sequencer, and the results were analyzed.@*RESULTS@#Respectively, 555 872 and 2 679 882 reads were obtained from the two samples within 24 hours, with genome coverage being 53.75% and 88.63%. With a sequencing depth of 0.81× and 2.40× , respectively, the abnormal chromosomal regions could be detected by comparative analysis using Minimap2.@*CONCLUSION@#With low-depth whole genome sequencing, the use of nanopore third-generation sequencing is expected to complete the detection and analysis of chromosomal aneuploidy samples within 24 hours, but its further application and promotion needs to overcome the cost constraints.

Knockdown of Homeobox D12 Inhibits 7 Factor-Induced Somatic Cell Reprogramming / 中国生物化学与分子生物学报

Differentiated cells can be reprogrammed into induced pluripotent stem cells (iPSCs) by overexpressing defined transcription factors. The process of reprogramming requires the interaction of various transcription factors to regulate the transformation of cell fate. Hoxd12 (Homeobox D12) is one of the transcription factors regulating the embryonic development of vertebrates, and it plays an outstanding role in the development of the limb, body axis formation, and cell signal transduction. However, any roles of Hoxd12 may play in the somatic cell reprogramming and the pluripotency of embryonic stem cells (ESCs) have not been reported. In this study, we firstly used 7 factors (Sall4-Esrrb-Jdp2-Glis1-Mkk6-Nanog-Kdm2b) and Yamanaka factors (Oct4-Klf4-Sox2) as the research model, combined with RNA interference (shRNA) and gene overexpression, to explore the mechanism of Hoxd12 in somatic cell reprogramming. Moreover, we used CRISPR/Cas9 gene editing to construct Hoxd12 knockout embryonic stem cell lines, and combined embryoid body formation (EB) and RNA sequencing (RNA-seq) to explore the function of Hoxd12 in the pluripotency of ESCs. The conclusions are as follows: (1) Knocking down of Hoxd12 inhibits 7 factor-induced reprogramming (

Umbilical Cord Mesenchymal Stem Cells for Inhibiting the Fibrosis and Autoimmune Development in HOCl-Induced Systemic Scleroderma Mouse Model

Background and Objectives@#Systemic scleroderma (SSc) is a rare and serious connective tissue disease, an autoimmune disease, and a rare refractory disease. In this study, preventive effect of single systemic human umbilical cord mesenchymal stem cells (UC-MSCs) transfusion on SSc was preliminarily explored. @*Methods@#and Results: SSc mouse model was established by daily intradermal injection of Hypochlorite (HOCl). SSc mice were treated by single transfusion of UC-MSCs at 0.625×10 5 , 2.5×105 and 1×106 respectively. At the 42nd day of intradermal injection of HOCl, the symptoms showed up by skin and alveolar wall thickening, lymphocytic infiltration, increased collagen in skin/lung, and the increased proportion of CD3 ＋ CD4＋ CD25＋ FoxP3＋ cells (a Treg subset) in spleen. After UC-MSCs transfusion, the degree of skin thickening, alveolar wall thickening and lymphocyte infiltration were decreased, the collagen sedimentation in skin/lung was decreased, and the proportion of CD3＋ CD4＋ CD25＋FoxP3＋ cells was decreased. @*Conclusions@#UC-MSC can achieve a preventive effect in SSc mice by fibrosis attenuation and immunoregulation.

Umbilical Cord Mesenchymal Stem Cells for Inhibiting the Fibrosis and Autoimmune Development in HOCl-Induced Systemic Scleroderma Mouse Model

Background and Objectives@#Systemic scleroderma (SSc) is a rare and serious connective tissue disease, an autoimmune disease, and a rare refractory disease. In this study, preventive effect of single systemic human umbilical cord mesenchymal stem cells (UC-MSCs) transfusion on SSc was preliminarily explored. @*Methods@#and Results: SSc mouse model was established by daily intradermal injection of Hypochlorite (HOCl). SSc mice were treated by single transfusion of UC-MSCs at 0.625×10 5 , 2.5×105 and 1×106 respectively. At the 42nd day of intradermal injection of HOCl, the symptoms showed up by skin and alveolar wall thickening, lymphocytic infiltration, increased collagen in skin/lung, and the increased proportion of CD3 ＋ CD4＋ CD25＋ FoxP3＋ cells (a Treg subset) in spleen. After UC-MSCs transfusion, the degree of skin thickening, alveolar wall thickening and lymphocyte infiltration were decreased, the collagen sedimentation in skin/lung was decreased, and the proportion of CD3＋ CD4＋ CD25＋FoxP3＋ cells was decreased. @*Conclusions@#UC-MSC can achieve a preventive effect in SSc mice by fibrosis attenuation and immunoregulation.

Preliminary experience of Bacillus Calmette-Guerin in the treatment of bladder cancer secondary to kidney transplantation / 中华泌尿外科杂志

Objective:To summarize the experience of Bacillus Calmette-Guerin(BCG) in the treatment of bladder cancer secondary to renal transplantation.Methods:The clinical data of 5 patients who underwent BCG bladder irrigation after secondary bladder cancer after kidney transplantation in Tianjin First Central Hospital from January 2015 to December 2019 were analyzed. There were 1 male and 4 female cases. During the period of immunosuppression after transplantation, 1 case developed secondary high-level non-muscular invasive bladder cancer (NMIBC), 3 cases developed secondary low-grade NMIBC, and 1 case developed secondary glandular cystitis (4 cases). The mean age of the 5 patients with secondary bladder cancer was 59.7±4.0 years. Case one with high level NMIBC was treated with transurethral resection of bladder tumor (TURBT) and postoperative irrigation of epirubicin. Case 3 and 5 with low-level NMIBC accepted regular postoperative irrigation of gemcitabine. No irrigative therapy was performed in case 2. Bladder cancer recurred in case 1, 2, 3 and 5 after 20.1±9.7 months. TURBT was observed in all the 4 patients, among which 3 were of high grade NMIBC and 1 was of low grade NMIBC. Four patients were irrigated with BCG 2 weeks after operation. Postoperative pathology indicated low-level NMIBC in case 4, and BCG was irrigated 2 weeks after the operation. During perfusion therapy, immunosuppressive agents were continued.Results:During BCG perfusion, 4 of the 5 cases showed BCG related local inflammation, among which 2 cases presented symptoms of bladder irritation, 1 case presented hematuria, and 1 case presented hematuria with low fever. Patients with frequent urination, pain in urine, hematuria and other symptoms improved after drinking plenty of water, taking bed rest and taking levofloxacin (0.5g/ day ×7 days). Patients with low fever were treated with antipyretic treatment. No antituberculous agents were used prophylactically during BCG perfusion. There were no symptoms of tuberculosis infection or sepsis. The function of transplantated kidney was normal and no tendency of rejection. The 5 patients were followed up for 7-24 months, 1 patient was lost to follow-up after 7 months of BCG bladder perfusion, and no tumor recurrence or metastasis was found in 5 patients during the follow-up.Conclusions:The use of immunosuppressive agents does not reduce the biological activity of BCG, and BCG does not increase the risk of systemic toxicity or affect the function of transplanted kidneys in immunocompromised patients. BCG is a treatment option for bladder cancer secondary to renal transplantation.

Clinical and genetic analysis of a child with mental retardation and microcephaly with pontine and cerebellar hypoplasia / 中华医学遗传学杂志

OBJECTIVE@#To analyze the clinical phenotype and pathogenic variant in a child diagnosed with mental retardation and microcephaly with pontine and cerebellar hypoplasia (MICPCH).@*METHODS@#Clinical phenotype of the child was reviewed. Whole exome sequencing was carried out for the child. Candidate variant was verified by Sanger sequencing of the family member.@*RESULTS@#The proband manifested dyskinesia, development delay, cerebellar hypoplasia and bilateral hearing impairment. WES results revealed that the proband has carried a pathogenic c.1641_1644delACAA (p.Thr548Trpfs*69) variant of the CASK gene, which was verified by Sanger sequencing to be a de novo variant.@*CONCLUSION@#The c.1641_1644delACAA (p.Thr548Trpfs*69) variant of the CASK gene probably underlay the MICPCH in the proband. Above finding has provided a basis for genetic counseling. WES should be considered for the diagnosis of neurological dysplasia.

Clinical feature and genetic analysis of a fetus with autosomal recessive polycystic kidney disease / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic etiology of a fetus with autosomal recessive polycystic kidney disease (ARPKD).@*METHODS@#Prenatal ultrasonography has revealed oligohydramnios and abnormal structure of fetal kidneys. After careful counseling, the couple opted induced abortion. With informed consent, genomic DNA was extracted from the muscle sample of the abortus and peripheral blood samples of the couple. High throughput whole exome sequencing was carried out to detect potential variants in relation with the disease. Suspected variants were verified by Sanger sequencing.@*RESULTS@#Prenatal ultrasound revealed increased size of fetal kidneys, with multiple hyperechos from the right kidney, and multiple hyperechos with anechoic masses within the left kidney. DNA sequencing revealed that the fetus has carried heterozygous variants of the PKHD1 gene, including c.7994T>C inherited from its father, and two heterozygous variants of the PKHD1 gene c.5681G>A from its mother.@*CONCLUSION@#The compound heterozygous c.7994T>C and c.5681G>A variants of the PKHD1 gene probably underlay the pathogenesis of ARPKD in this fetus. Above results can provide guidance for subsequent pregnancies of the couple.

Clinical manifestation and genetic analysis of a child with early infantile epileptic encephalopathy 42 / 中华医学遗传学杂志

OBJECTIVE@#To analyze the clinical phenotype and genetic characterization of a child with early infantile epileptic encephalopathy.@*METHODS@#The proband was subjected to history taking and was diagnosed based on his clinical manifestation, magnetic resonance imaging (MRI) and whole exome sequencing (WES). Sanger sequencing was carried out to determine the origin of pathogenic variant.@*RESULTS@#The proband unconsciously tilts his head to one side with squint, which revealed an abnormal discharge. MRI indicated suspicious abnormal signal shadow in the left posterior frontal cortex in addition with inflammation signs in the right maxillary sinus and ethmoid sinus. WES revealed that the proband has carried a heterozygous c.5789G>A variant in the CACNAIA gene. The result of Sanger sequencing was in keeping with that of WES. Neither of his parents has carried the same variant.@*CONCLUSION@#The heterozygous c.5789G>A variant of the CACNAIA gene probably underlay the early infantile epileptic encephalopathy 42 in the proband, which has a de novo origin.

Phenotypic and mutation analysis of a fetus with Cornelia de Lange syndrome Ⅰ / 中华医学遗传学杂志

OBJECTIVE@#To carry out genetic testing for an abortus suspected with Cornelia de Lange syndrome (CdLS).@*METHODS@#History of gestation and the family was taken. Combined with prenatal ultrasonography and the phenotype of the abortus, a diagnosis was made for the proband. Fetal tissue and peripheral blood samples of its parents were collected for the extraction of genomic DNA. Whole exome sequencing was carried out to detect mutations related to the phenotype. Suspected mutations were verified in the parents through Sanger sequencing.@*RESULTS@#Prenatal ultrasound found that the forearms and hands of the fetus were anomalous, in addition with poorly formed vermis cerebellum, slight micrognathia, and increased echo of bilateral renal parenchyma. Examination of the abortus has noted upper limb and facial malformations. Whole exome sequencing revealed that the fetus carried a heterozygous c.2118delG (p.Lys706fs) frameshift mutation of the NIPBL gene. The same mutation was not found in either parent.@*CONCLUSION@#The heterozygous c.2118delG (p.Lys706fs) frameshift mutation of the NIPBL gene probably underlies the CdLS in the fetus. Above finding has provided a basis for the genetic counseling for the family.

Relationship between newly onset atrial fibrillation and long-term cardiovascular adverse events in STEMI patients / 医学研究生学报

ObjectiveNeNewly onset atrial fibrillation (AF) is a common complication of acute myocardial infarction (AMI), which is considered to be related to cardiovascular adverse events. This paper aims to discuss the relationship between atrial fibrillation and long-term cardiovascular adverse events after acute myocardial infarction.MethodsA retrospective analysis of 483 STEMI patients with multivessel disease, who underwent emergency percutaneous coronary intervention (PCI) in Beijing Chaoyang Hospital from January 2014 to May 2017, was conducted. Patients were divided into two groups: AF group: n=52(10.8%) and non-AF group: n=431(89.2%) according to including criteria. The primary endpoint event was long-term major adverse cardiovascular events, including cardiovascular death, acute heart failure or ischemia stroke. The secondary endpoint event was defined as 30-day cardiovascular death. Multivariate logistic regression analysis and Cox proportional hazards mode were performed to analyze the relationship between newly onset atrial fibrillation and cardiovascular adverse events, such as cardiovascular death. ResultsCompared with non-AF group, AF group had older age, higher levels of C-reactive protein, erythrocyte sedimentation rate, creatinine, troponin, SYNTAX score and GRACE score and lower levels of total cholesterol, low density lipoproteins and ejection fraction (P<0.01). In the multivariate logistic regression analysis model, newly onset atrial fibrillation, age, high-sensitivity C-reactive protein, erythrocyte sedimentation rate, admission creatinine level, fasting blood glucose, and coronary SYNTAX score were all independent risk factors associated with higher risks of 30-day cardiovascular death (OR=1.983, 95% CI=1.036-3.795, P=0.04). Using Cox proportional hazards mode, newly onset atrial fibrillation following primary PCI was associated with long-term clinical adverse cardiovascular event (HR=1.983, 95% CI=1.036-3.795, P=0.04) after adjusting all covariates. The area under the ROC curve for combined prediction mode with GRACE score and newly onset AF was comparable to the one for the model with GRACE score alone (0.788 vs 0.767，P=0.08).ConclusionNewly onset atrial fibrillation in STEMI patients with multivessel disease who underwent emergency PCI is associated with 30-day cardiovascular death and long-term clinical adverse cardiovascular events. However, newly onset atrial fibrillation does not increase the predictive value of GRACE score.