AIM: To investigate multiple polyps in a Chinese PeutzJeghers syndrome(PJS) infant. METHODS: A nine-month-old PJS infant was admitted to our hospital for recurrent prolapsed rectal polyps for one month. The clinical c...AIM: To investigate multiple polyps in a Chinese PeutzJeghers syndrome(PJS) infant. METHODS: A nine-month-old PJS infant was admitted to our hospital for recurrent prolapsed rectal polyps for one month. The clinical characteristics, a colonoscopic image, the pathological characteristics of the polyps and X-ray images of the intestinal perforation were obtained. Serine threonine-protein kinase 11(STK11) gene analysis was also performed using a DNA sample from this infant.RESULTS: Here we describe the youngest known Chinese infant with PJS. Five polyps, including a giant polyp of approximately 4 cm × 2 cm in size, were removed from the infant's intestine. Laparotomy was performed to repair a perforation caused by pneumoperitoneum. The pathological results showed that this child had PJS. Molecular analysis of the STK11 gene further revealed a novel frameshift mutation(c.64_65het_del AT) in exon 1 in this PJS infant.CONCLUSION: The appropriate treatment method for multiple polyps in an infant must be carefully considered. Our results also show that the STK11 gene mutation is the primary cause of PJS.展开更多
Dysregulation of circadian rhythms associates with cardiovascular disorders.It is known that deletion of the core circadian gene Bma/1 in mice causes dilated car-diomyopathy.However,the biological rhythm regulation sy...Dysregulation of circadian rhythms associates with cardiovascular disorders.It is known that deletion of the core circadian gene Bma/1 in mice causes dilated car-diomyopathy.However,the biological rhythm regulation system in mouse is very different from that of humans.Whether BMAL1 plays a role in regulating human heart function remains unclear.Here we generated a BMAL1 knockout human embryonic stem cell(hESC)model and further derived human BMAL1 deficient cardiomy-ocytes.We show that BMAL1 deficient hESC-derived cardiomyocytes exhibited typical phenotypes of dilated cardiomyopathy including attenuated contractility,cal-cium dysregulation,and disorganized myofilaments.In addition,mitochondrial fission and mitophagy were suppressed in BMAL1 deficient hESC-cardiomyocytes,which resulted in significantly attenuated mitochondrial oxidative phosphorylation and compromised cardiomy-ocyte function.We also found that BMAL1 binds to the E-box element in the promoter region of BNIP3 gene and specifically controls BNIP3 protein expression.BMAL1 knockout directly reduced BNIP3 protein level,causing compromised mitophagy and mitochondria dysfunction and thereby leading to compromised cardiomyocyte function.Our data indicated that the core circadian gene S/VMLf is critical for normal mitochondria activities and cardiac function.Circadian rhythm disruption may directly link to compromised heart function and dilated cardiomyopathy in humans.展开更多
Objective:To investigate the potential mechanisms of electroacupuncture(EA)to prevent ischemic stroke.Methods:The method of middle cerebral artery occlusion(MCAO)was employed to establish a rat model of ischemic strok...Objective:To investigate the potential mechanisms of electroacupuncture(EA)to prevent ischemic stroke.Methods:The method of middle cerebral artery occlusion(MCAO)was employed to establish a rat model of ischemic stroke.Seventy-eight Sprague-Dawley rats were divided into the sham group,MCAO+EA control(EC)group,and MCAO+EA(EA)group according to a random number table(n=26 per group).EA was applied to the acupoints of Baihui(DU 20)and Shenting(DU 24)5 min and 6 h,respectively after the onset of MCAO for 30 min.Rats in the sham and EC groups received only light isoflurane anesthesia for 30 min after MCAO.The neuroprotective effects of EA were evaluated by rota-rod test,neurological deficit scores and infarct volumes.Additionally,Nissl staining and immunostaining were performed to examine brain damage,rod formation,cellular apoptosis,and neuronal loss induced by ischemia.The activities of caspase-3,and expression levels of cofilin and p-cofilin in mitochondria and cytoplasm after ischemic injury were determined by Western blot.Results:Compared with the EC group,EA significantly improved neuromotor function and cognitive ability after ischemic stroke(P<0.05 or P<0.01).Therapeutic use of EA also resulted in a significant decrease of cofilin rod formation and microtubule-associated protein-2(MAP2)degradation in the cortical penumbra area compared with the EC rats(P<0.01).Furthermore,Western blot analysis showed that EA stimulation significantly inhibited mitochondrial translocation of cofilin and caspase-3 cleavage(P<0.05 or P<0.01).Additionally,brain damage(infarct volume and neuropathy),cellular apoptosis and neuronal loss induced by ischemia were remarkably suppressed by EA in the cortical penumbra of rats(P<0.05 or P<0.01).Conclusion:EA treatment after ischemic stroke may attenuate ischemic brain injury and cellular apoptosis through the regulation of mitochondrial translocation of cofilin,a novel mechanism of EA therapy.展开更多
Background Congenital anomalies of the kidneys and urinary tract(CAKUT)are the most common cause of prenatally diagnosed developmental malformation.This study aimed to assess the relationship between maternal diseases...Background Congenital anomalies of the kidneys and urinary tract(CAKUT)are the most common cause of prenatally diagnosed developmental malformation.This study aimed to assess the relationship between maternal diseases and CAKUT in offspring.Methods This retrospective study enrolled all pregnant women registered from January 2020 to December 2022 at one medical center.Medical information on maternal noncommunicable diseases,including obesity,hypertension,diabetes mellitus,kidney disease,hyperthyroidism,hypothyroidism,psychiatric disease,epilepsy,cancer,and autoimmune disease was collected.Based on the records of ultrasound scanning during the third trimester,the diagnosis was classified as isolated urinary tract dilation(UTD)or kidney anomalies.Multivariate logistic regression was performed to establish models to predict antenatal CAKUT.Results Among the 19,656 pregnant women,perinatal ultrasound detected suspicious CAKUT in 114(5.8/1000)fetuses,comprising 89 cases with isolated UTD and 25 cases with kidney anomalies.The risk of antenatal CAKUT was increased in the fetuses of mothers who experienced gestational diabetes,thyroid dysfunction,neuropsychiatric disease,anemia,ovarian and uterine disorders.A prediction model for isolated UTD was developed utilizing four confounding factors,namely gestational diabetes,gestational hypertension,maternal thyroid dysfunction,and hepatic disease.Similarly,a separate prediction model for kidney anomalies was established based on four distinct confounding factors,namely maternal thyroid dysfunction,gestational diabetes,disorders of ovarian/uterine,and kidney disease.Conclusions Isolated UTD and kidney anomalies were associated with different maternal diseases.The results may inform the clinical management of pregnancy and highlight potential differences in the genesis of various subtypes of CAKUT.展开更多
Kidney disease is manifested in a wide variety of phenotypes,many of which have an important hereditary component.To delineate the genotypic and phenotypic spectrum of pediatric nephropathy,a multicenter registration ...Kidney disease is manifested in a wide variety of phenotypes,many of which have an important hereditary component.To delineate the genotypic and phenotypic spectrum of pediatric nephropathy,a multicenter registration system is being imple-mented based on the Chinese Children Genetic Kidney Disease Database(CCGKDD).In this study,all the patients with kidney and urological diseases were recruited from 2014 to 2020.Genetic analysis was conducted using exome sequencing for families with multiple affected individuals with nephropathy or clinical suspicion of a genetic kidney disease owing to early-onset or extrarenal features.The genetic diagnosis was confirmed in 883 of 2256(39.1%)patients from 23 provinces in China.Phenotypic profiles showed that the primary diagnosis included steroid-resistant nephrotic syndrome(SRNS,23.5%),glomerulonephritis(GN,32.2%),congenital anomalies of the kidney and urinary tract(CAKUT,21.2%),cystic renal disease(3.9%),renal calcinosis/stone(3.6%),tubulopathy(9.7%),and chronic kidney disease of unknown etiology(CKDu,5.8%).The pathogenic variants of 105 monogenetic disorders were identified.Ten distinct genomic disorders were identified as pathogenic copy number variants(CNVs)in 11 patients.The diagnostic yield differed by subgroups,and was highest in those with cystic renal disease(66.3%),followed by tubulopathy(58.4%),GN(57.7%),CKDu(43.5%),SRNS(29.2%),renal calcinosis/stone(29.3%)and CAKUT(8.6%).Reverse phenotyping permitted correct identification in 40 cases with clinical reassessment and unexpected genetic conditions.We present the results of the largest cohort of children with kidney disease in China where diagnostic exome sequencing was performed.Our data demonstrate the utility of family-based exome sequencing,and indicate that the combined analysis of genotype and phenotype based on the national patient registry is pivotal to the genetic diagnosis of kidney disease.展开更多
Dear Editor,Dilated cardiomyopathy(DCM)is a common form of inherited cardiomyopathy.In the past decades,single mutations in various genes encoding sarcomeric,cytoskeletal,and channel proteins etc.have been found to be...Dear Editor,Dilated cardiomyopathy(DCM)is a common form of inherited cardiomyopathy.In the past decades,single mutations in various genes encoding sarcomeric,cytoskeletal,and channel proteins etc.have been found to be associated with DCM(Hershberger et al.,2013;McNally and Mestroni,2017).However,the mechanisms how single mutations in sarcomeric or structural genes lead to the disease remain elusive.An interesting phenomenon often seen in familial cardiomyopathy is that different single mutations on the same gene can cause either DCM or hypertrophic cardiomyopathy(HCM)(Kathiresan and Srivastava,2012),which exhibit almost opposite disease phenotypes.DCM is characterized by thinned myocardium and septum,ventricular chamber dilation,and systolic dysfunction(Jefferies and Towbin,2010;McNally and Mestroni,2017),while HCM exhibits thickened myocardium and septum,reduced ventricular chamber,and diastolic dysfunction(Richard et al.,2003).At the cellular level,HCM cardiomyocytes exhibit concentric hypertrophy characterized by assembly of myofilaments in parallel and widening of the myocytes.In contrast,DCM cardiomyocytes show eccentric hypertrophy,with assembly of the myofilaments in series and myocyte elongation(Kehat and Molkentin,2010).展开更多
文摘AIM: To investigate multiple polyps in a Chinese PeutzJeghers syndrome(PJS) infant. METHODS: A nine-month-old PJS infant was admitted to our hospital for recurrent prolapsed rectal polyps for one month. The clinical characteristics, a colonoscopic image, the pathological characteristics of the polyps and X-ray images of the intestinal perforation were obtained. Serine threonine-protein kinase 11(STK11) gene analysis was also performed using a DNA sample from this infant.RESULTS: Here we describe the youngest known Chinese infant with PJS. Five polyps, including a giant polyp of approximately 4 cm × 2 cm in size, were removed from the infant's intestine. Laparotomy was performed to repair a perforation caused by pneumoperitoneum. The pathological results showed that this child had PJS. Molecular analysis of the STK11 gene further revealed a novel frameshift mutation(c.64_65het_del AT) in exon 1 in this PJS infant.CONCLUSION: The appropriate treatment method for multiple polyps in an infant must be carefully considered. Our results also show that the STK11 gene mutation is the primary cause of PJS.
基金This work was supported by the National Natural Science Foundation of China(NSFC No.81322003,No.31571527,N.S.No.31501098,Q.L.,No.81500241,C.X.,No.81870600,C.L.,No-81570771 and 31871189,RZ.Q.)+1 种基金the Science and Technology Commission of Shanghai Municipality(No.17XD1400300,No.17JC1400200)the National Key R&D Program of China 2018YFC2000202,and the Haiju program of National Children’s Medical Center EK1125180102.We apologize to people whose work was relevant to but not cited in this study due to limited space。
文摘Dysregulation of circadian rhythms associates with cardiovascular disorders.It is known that deletion of the core circadian gene Bma/1 in mice causes dilated car-diomyopathy.However,the biological rhythm regulation system in mouse is very different from that of humans.Whether BMAL1 plays a role in regulating human heart function remains unclear.Here we generated a BMAL1 knockout human embryonic stem cell(hESC)model and further derived human BMAL1 deficient cardiomy-ocytes.We show that BMAL1 deficient hESC-derived cardiomyocytes exhibited typical phenotypes of dilated cardiomyopathy including attenuated contractility,cal-cium dysregulation,and disorganized myofilaments.In addition,mitochondrial fission and mitophagy were suppressed in BMAL1 deficient hESC-cardiomyocytes,which resulted in significantly attenuated mitochondrial oxidative phosphorylation and compromised cardiomy-ocyte function.We also found that BMAL1 binds to the E-box element in the promoter region of BNIP3 gene and specifically controls BNIP3 protein expression.BMAL1 knockout directly reduced BNIP3 protein level,causing compromised mitophagy and mitochondria dysfunction and thereby leading to compromised cardiomyocyte function.Our data indicated that the core circadian gene S/VMLf is critical for normal mitochondria activities and cardiac function.Circadian rhythm disruption may directly link to compromised heart function and dilated cardiomyopathy in humans.
基金Supported by the National Natural Science Foundation of China(No.81804175 and 81803883)Natural Science Foundation of Fujian Province(No.2019J01497)+2 种基金Foundation of Fujian Key Laboratory of Rehabilitation Technology(No.KF2019006)Special Research Project of National Clinical Research Base of Traditional Chinese Medicine(No.JDZX2019040)Educational Research Project for Young and Middle-Aged Teachers of Education Bureau of Fujian Province(No.JT180216)。
文摘Objective:To investigate the potential mechanisms of electroacupuncture(EA)to prevent ischemic stroke.Methods:The method of middle cerebral artery occlusion(MCAO)was employed to establish a rat model of ischemic stroke.Seventy-eight Sprague-Dawley rats were divided into the sham group,MCAO+EA control(EC)group,and MCAO+EA(EA)group according to a random number table(n=26 per group).EA was applied to the acupoints of Baihui(DU 20)and Shenting(DU 24)5 min and 6 h,respectively after the onset of MCAO for 30 min.Rats in the sham and EC groups received only light isoflurane anesthesia for 30 min after MCAO.The neuroprotective effects of EA were evaluated by rota-rod test,neurological deficit scores and infarct volumes.Additionally,Nissl staining and immunostaining were performed to examine brain damage,rod formation,cellular apoptosis,and neuronal loss induced by ischemia.The activities of caspase-3,and expression levels of cofilin and p-cofilin in mitochondria and cytoplasm after ischemic injury were determined by Western blot.Results:Compared with the EC group,EA significantly improved neuromotor function and cognitive ability after ischemic stroke(P<0.05 or P<0.01).Therapeutic use of EA also resulted in a significant decrease of cofilin rod formation and microtubule-associated protein-2(MAP2)degradation in the cortical penumbra area compared with the EC rats(P<0.01).Furthermore,Western blot analysis showed that EA stimulation significantly inhibited mitochondrial translocation of cofilin and caspase-3 cleavage(P<0.05 or P<0.01).Additionally,brain damage(infarct volume and neuropathy),cellular apoptosis and neuronal loss induced by ischemia were remarkably suppressed by EA in the cortical penumbra of rats(P<0.05 or P<0.01).Conclusion:EA treatment after ischemic stroke may attenuate ischemic brain injury and cellular apoptosis through the regulation of mitochondrial translocation of cofilin,a novel mechanism of EA therapy.
基金supported by the National Key Research and Development Program of China(2021YFC2701101,to RJ)the Program of Shanghai Academic/Technology Research(23141900700,to RJ).
文摘Background Congenital anomalies of the kidneys and urinary tract(CAKUT)are the most common cause of prenatally diagnosed developmental malformation.This study aimed to assess the relationship between maternal diseases and CAKUT in offspring.Methods This retrospective study enrolled all pregnant women registered from January 2020 to December 2022 at one medical center.Medical information on maternal noncommunicable diseases,including obesity,hypertension,diabetes mellitus,kidney disease,hyperthyroidism,hypothyroidism,psychiatric disease,epilepsy,cancer,and autoimmune disease was collected.Based on the records of ultrasound scanning during the third trimester,the diagnosis was classified as isolated urinary tract dilation(UTD)or kidney anomalies.Multivariate logistic regression was performed to establish models to predict antenatal CAKUT.Results Among the 19,656 pregnant women,perinatal ultrasound detected suspicious CAKUT in 114(5.8/1000)fetuses,comprising 89 cases with isolated UTD and 25 cases with kidney anomalies.The risk of antenatal CAKUT was increased in the fetuses of mothers who experienced gestational diabetes,thyroid dysfunction,neuropsychiatric disease,anemia,ovarian and uterine disorders.A prediction model for isolated UTD was developed utilizing four confounding factors,namely gestational diabetes,gestational hypertension,maternal thyroid dysfunction,and hepatic disease.Similarly,a separate prediction model for kidney anomalies was established based on four distinct confounding factors,namely maternal thyroid dysfunction,gestational diabetes,disorders of ovarian/uterine,and kidney disease.Conclusions Isolated UTD and kidney anomalies were associated with different maternal diseases.The results may inform the clinical management of pregnancy and highlight potential differences in the genesis of various subtypes of CAKUT.
基金J.R.is supported by National Natural Science Foundation of China(NSFC-8182207)Shanghai Academic/Technology Research Leader(19XD1420600)Chinese Academy of Medical Sciences(2019-RC-HL_020).
文摘Kidney disease is manifested in a wide variety of phenotypes,many of which have an important hereditary component.To delineate the genotypic and phenotypic spectrum of pediatric nephropathy,a multicenter registration system is being imple-mented based on the Chinese Children Genetic Kidney Disease Database(CCGKDD).In this study,all the patients with kidney and urological diseases were recruited from 2014 to 2020.Genetic analysis was conducted using exome sequencing for families with multiple affected individuals with nephropathy or clinical suspicion of a genetic kidney disease owing to early-onset or extrarenal features.The genetic diagnosis was confirmed in 883 of 2256(39.1%)patients from 23 provinces in China.Phenotypic profiles showed that the primary diagnosis included steroid-resistant nephrotic syndrome(SRNS,23.5%),glomerulonephritis(GN,32.2%),congenital anomalies of the kidney and urinary tract(CAKUT,21.2%),cystic renal disease(3.9%),renal calcinosis/stone(3.6%),tubulopathy(9.7%),and chronic kidney disease of unknown etiology(CKDu,5.8%).The pathogenic variants of 105 monogenetic disorders were identified.Ten distinct genomic disorders were identified as pathogenic copy number variants(CNVs)in 11 patients.The diagnostic yield differed by subgroups,and was highest in those with cystic renal disease(66.3%),followed by tubulopathy(58.4%),GN(57.7%),CKDu(43.5%),SRNS(29.2%),renal calcinosis/stone(29.3%)and CAKUT(8.6%).Reverse phenotyping permitted correct identification in 40 cases with clinical reassessment and unexpected genetic conditions.We present the results of the largest cohort of children with kidney disease in China where diagnostic exome sequencing was performed.Our data demonstrate the utility of family-based exome sequencing,and indicate that the combined analysis of genotype and phenotype based on the national patient registry is pivotal to the genetic diagnosis of kidney disease.
文摘Dear Editor,Dilated cardiomyopathy(DCM)is a common form of inherited cardiomyopathy.In the past decades,single mutations in various genes encoding sarcomeric,cytoskeletal,and channel proteins etc.have been found to be associated with DCM(Hershberger et al.,2013;McNally and Mestroni,2017).However,the mechanisms how single mutations in sarcomeric or structural genes lead to the disease remain elusive.An interesting phenomenon often seen in familial cardiomyopathy is that different single mutations on the same gene can cause either DCM or hypertrophic cardiomyopathy(HCM)(Kathiresan and Srivastava,2012),which exhibit almost opposite disease phenotypes.DCM is characterized by thinned myocardium and septum,ventricular chamber dilation,and systolic dysfunction(Jefferies and Towbin,2010;McNally and Mestroni,2017),while HCM exhibits thickened myocardium and septum,reduced ventricular chamber,and diastolic dysfunction(Richard et al.,2003).At the cellular level,HCM cardiomyocytes exhibit concentric hypertrophy characterized by assembly of myofilaments in parallel and widening of the myocytes.In contrast,DCM cardiomyocytes show eccentric hypertrophy,with assembly of the myofilaments in series and myocyte elongation(Kehat and Molkentin,2010).
