Cardiac or respiratory arrest lasting only a few minutes can inflict grave harm on numerous bodily organs, not least of all, the brain. Neurocognitive deficits, which are often severe and profoundly life altering, rem...Cardiac or respiratory arrest lasting only a few minutes can inflict grave harm on numerous bodily organs, not least of all, the brain. Neurocognitive deficits, which are often severe and profoundly life altering, remain a major source of morbidity among survivors.展开更多
Ethical concerns about stem cell-based research have delayed important advances in many areas of medicine,including cardiology.The introduction of induced pluripotent stem cells(iPSCs)has supplanted the need to use hu...Ethical concerns about stem cell-based research have delayed important advances in many areas of medicine,including cardiology.The introduction of induced pluripotent stem cells(iPSCs)has supplanted the need to use human stem cells for most purposes,thus eliminating all ethical controversies.Since then,many new avenues have been opened in cardiology research,not only in approaches to tissue replacement but also in the design and testing of antiarrhythmic drugs.This methodology has advanced to the point where induced human cardiomyocyte cell lines can now also be obtained from commercial sources or tissue banks.Initial studies with readily available iPSCs have generally confirmed that their behavioral characteristics accurately predict the behavior of beating cardiomyocytes in vivo.As a result,iPSCs can provide new ways to study arrhythmias and heart disease in general,accelerating the development of new,more effective antiarrhythmic drugs,clinical diagnoses,and personalized medical care.The focus on producing cardiomyocytes that can be used to replace damaged heart tissue has somewhat diverted interest in a host of other applications.This manuscript is intended to provide non-specialists with a brief introduction and overview of the research carried out in the field of heart rhythm disorders.展开更多
P21Waf1/Cip1 is a potent cyclin-dependent kinase inhibitor. As a downstream mediator of p53, p21Waf1/Cip1 involves in cell cycle arrest, differentiation and apoptosis. Previous studies in human cells provided evidence...P21Waf1/Cip1 is a potent cyclin-dependent kinase inhibitor. As a downstream mediator of p53, p21Waf1/Cip1 involves in cell cycle arrest, differentiation and apoptosis. Previous studies in human cells provided evidence for a link between p21Waf1/Cip1 and cellular senescence. While in murine cells, the role of p21Waf1/Cip1 is indefinite. We explored this issue using NIH3T3 cells with inducible p21Waf1/Cip1 expression. Induction of p21Waf1/Cip1 triggered G1 growth arrest, and NIH3T3-p21 cells exhibited morphologic features, such as enlarged and flattened cellular shape, specific to the senescence phenotype. We also showed that p21Waf1/Cip1-transduced NIH3T3 cells expressed β-galactosidase activity at pH 6.0, which is known to be a marker of senescence. Our results suggest that p21Waf1/Cip1 can also induce senescence-like changes in murine cells.展开更多
P21Waf1/Cip1 is a potent cyclin-dependent kinase inhibitor. As a downstream mediator of p53, p21Waf1/Cip1 involves in cell cycle arrest, differentiation and apoptosis. Previous studies in human cells provided evidence...P21Waf1/Cip1 is a potent cyclin-dependent kinase inhibitor. As a downstream mediator of p53, p21Waf1/Cip1 involves in cell cycle arrest, differentiation and apoptosis. Previous studies in human cells provided evidence for a link between p21Waf1/Cip1 and cellular senescence. While in murine cells, the role of p21Waf1/Cip1 is indefinite. We explored this issue using NIH3T3 cells with inducible p21Waf1/Cip1 expression. Induction of p21Waf1/Cip1 triggered G1 growth arrest, and NIH3T3-p21 cells exhibited morphologic features, such as enlarged and flattened cellular shape, specific to the senescence phenotype. We also showed that p21Waf1/Cip1-transduced NIH3T3 cells expressed β-galactosidase activity at pH 6.0, which is known to be a marker of senescence. Our results suggest that p21Waf1/Cip1 can also induce senescence-like changes in murine cells.展开更多
In order to obtain reasonable schemes of arrester in converter stations, the arrester scheme of "Xiluodu-Guangdong HVDC ± 500 kV double circuit transmission" project against lighting induced overvoltage...In order to obtain reasonable schemes of arrester in converter stations, the arrester scheme of "Xiluodu-Guangdong HVDC ± 500 kV double circuit transmission" project against lighting induced overvoltage, which was designed according to the main principle of lightning protection in converter station, is discussed. A calculation of the lighting induced overvoltage in Zhaotong converter station un- der various operation modes is performed with ATP-EMTP software, then the surge arrester configuration of the converter station is decided, and the arrester protection schemes of smoothing reactor and neutral line are studied. It is concluded that additional protection is necessary because of the relatively large gap between protected disconnecting switch and arrester of metallic return transfer bus. Plus, the smoothing reactor (SR) arrester near the valve hall could be removed to improve the scheme’s economic performance.展开更多
Cardiomyopathy is a pathological condition characterized by cardiac pump failure due to myocardial dysfunction and the major cause of advanced heart failure requiring heart transplantation.Although optimized medical t...Cardiomyopathy is a pathological condition characterized by cardiac pump failure due to myocardial dysfunction and the major cause of advanced heart failure requiring heart transplantation.Although optimized medical therapies have been developed for heart failure during the last few decades,some patients with cardiomyopathy exhibit advanced heart failure and are refractory to medical therapies.Desmosome,which is a dynamic cell-to-cell junctional component,maintains the structural integrity of heart tissues.Genetic mutations in desmo-somal genes cause arrhythmogenic cardiomyopathy(AC),a rare inheritable disease,and predispose patients to sudden cardiac death and heart failure.Recent advances in sequencing technologies have elucidated the genetic basis of cardiomyopathies and revealed that desmosome-related cardiomyopathy is concealed in broad cardiomyopathies.Among desmosomal genes,mutations in PKP2(which encodes PKP2)are most frequently identified in patients with AC.PKP2 deficiency causes various pathological cardiac phenotypes.Human cardiomyocytes differentiated from patient-derived induced pluripotent stem cells(iPSCs)in combination with genome editing,which allows the precise arrangement of the targeted genome,are powerful experimental tools for studying disease.This review summarizes the current issues associated with practical medicine for advanced heart failure and the recent advances in disease modeling using iPSC-derived cardiomyocytes targeting desmosome-related cardiomyopathy caused by PKP2 deficiency.展开更多
The post-resuscitation period is recognized as the main predictor of cardiopul-monary resuscitation(CPR)outcomes.The first description of post-resuscitation syndrome and stony heart was published over 50 years ago.Maj...The post-resuscitation period is recognized as the main predictor of cardiopul-monary resuscitation(CPR)outcomes.The first description of post-resuscitation syndrome and stony heart was published over 50 years ago.Major manifestations may include but are not limited to,persistent precipitating pathology,systemic ischemia/reperfusion response,post-cardiac arrest brain injury,and finally,post-cardiac arrest myocardial dysfunction(PAMD)after successful resuscitation.Why do some patients initially survive successful resuscitation,and others do not?Also,why does the myocardium response vary after resuscitation?These ques-tions have kept scientists busy for several decades since the first successful resuscitation was described.By modifying the conventional modalities of resu-scitation together with new promising agents,rescuers will be able to salvage the jeopardized post-resuscitation myocardium and prevent its progression to a dismal,stony heart.Community awareness and staff education are crucial for shortening the resuscitation time and improving short-and long-term outcomes.Awareness of these components before and early after the restoration of circulation will enhance the resuscitation outcomes.This review extensively addresses the underlying pathophysiology,management,and outcomes of post-resuscitation syndrome.The pattern,management,and outcome of PAMD and post-cardiac arrest shock are different based on many factors,including in-hospital cardiac arrest vs out-of-hospital cardiac arrest(OHCA),witnessed vs unwitnessed cardiac arrest,the underlying cause of arrest,the duration,and protocol used for CPR.Although restoring spontaneous circulation is a vital sign,it should not be the end of the game or lone primary outcome;it calls for better understanding and aggressive multi-disciplinary interventions and care.The development of stony heart post-CPR and OHCA remain the main challenges in emergency and critical care medicine.展开更多
Background:Anoxic brain injuries represent the main determinant of poor outcome after cardiac arrest(CA).Large animal models have been described to investigate new treatments during CA and post-resuscitation phase,but...Background:Anoxic brain injuries represent the main determinant of poor outcome after cardiac arrest(CA).Large animal models have been described to investigate new treatments during CA and post-resuscitation phase,but a detailed model that includes extensive neuromonitoring is lacking.Method:Before an electrically-induced 10-minute CA and resuscitation,46 adult pigs underwent neurosurgery for placement of a multifunctional probe(intracranial pressure or ICP,tissue oxygen tension or PbtO_(2) and cerebral temperature)and a bolt-based technique for the placement and securing of a regional blood flow probe and two sEEG electrodes;two modified cerebral microdialysis(CMD)probes were also inserted in the frontal lobes and accidental misplacement was prevented using a perforated head support.Result:42 animals underwent the CA procedure and 41 achieved the return of spontaneous circulation(ROSC).In 4 cases(8.6%)an adverse event took place during preparation,but only in two cases(4.3%)this was related to the neurosurgery.In 6 animals(13.3%)the minor complications that occurred resolved after probe repositioning.Conclusion:Herein we provide a detailed comprehensive neuromonitoring approach in a large animal model of CA that might help future research.展开更多
BACKGROUND Pulmonary arterial hypertension(PAH)is a disease of the arterioles resulting in an increased resistance in pulmonary circulation with associated high pressures in the pulmonary arteries,causing irreversible...BACKGROUND Pulmonary arterial hypertension(PAH)is a disease of the arterioles resulting in an increased resistance in pulmonary circulation with associated high pressures in the pulmonary arteries,causing irreversible remodeling of the pulmonary arterial walls.Coronavirus disease 2019(COVID-19)has been associated with development of new onset PAH in the literature leading to symptoms of dyspnea,cough and fatigue that persist in spite of resolution of acute COVID-19 infection.However,the majority of these cases of COVID related PAH were diagnosed using echocardiographic data or via right heart catheterization in mechanically ventilated patients.CASE SUMMARY Our case is the first reported case of COVID related PAH diagnosed by right heart catheterization in a non-mechanically ventilated patient.Right heart catheterization has been the gold standard for diagnosis of pulmonary hypertension.Our patient had right heart catheterization four months after her initial COVID-19 infection due to persistent dyspnea.CONCLUSION This revealed new onset PAH that developed following her infection with COVID-19,an emerging sequela of the infection.展开更多
In this study,one immortalized human normal prostatic epithelial cell line(BPH) and four human prostate cancer cell lines(LNCa P,22Rv1,PC-3,and DU-145) were treated with Ganoderma Lucidum triterpenoids(GLT) at d...In this study,one immortalized human normal prostatic epithelial cell line(BPH) and four human prostate cancer cell lines(LNCa P,22Rv1,PC-3,and DU-145) were treated with Ganoderma Lucidum triterpenoids(GLT) at different doses and for different time periods. Cell viability,apoptosis,and cell cycle were analyzed using flow cytometry and chemical assays. Gene expression and binding to DNA were assessed using real-time PCR and Western blotting. It was found that GLT dose-dependently inhibited prostate cancer cell growth through induction of apoptosis and cell cycle arrest at G1 phase. GLT-induced apoptosis was due to activation of Caspases-9 and-3 and turning on the downstream apoptotic events. GLT-induced cell cycle arrest(mainly G1 arrest) was due to up-regulation of p21 expression at the early time and down-regulation of cyclin-dependent kinase 4(CDK4) and E2F1 expression at the late time. These findings demonstrate that GLT suppresses prostate cancer cell growth by inducing growth arrest and apoptosis,which might suggest that GLT or Ganoderma Lucidum could be used as a potential therapeutic drug for prostate cancer.展开更多
Fifty-three patients with congenital heart disease were follwed up 14 to 57months after cardiac surgery with profound hypothermia and circulatory arrest.Meanintelligence quotient(IQ)was 88.6±16.1The incidence of ...Fifty-three patients with congenital heart disease were follwed up 14 to 57months after cardiac surgery with profound hypothermia and circulatory arrest.Meanintelligence quotient(IQ)was 88.6±16.1The incidence of psychological underdevelopedwas 13.2(7/53),higher than normal children population,The high incidence may be attri-buted to poor preoperative intellecutual development.The circulatory arrest time weremore than 60 minutes in 9 cases,41-60 minutes in 32 cases and less than 40 minutes inanother 12 cases.The IQ of these three groups were 84.8±11.9,86.2±15.7and 95.3±19.2respctively and incidence of psychological underdeveloped were 11.1%,15.6% and 8.5%respectively,No significant difference existed between groups.The time of circulatory ar-rest also had no obvious correlation with IQ.展开更多
BACKGROUND Prolonged cardiac arrest(CA)produces extensive neuronal death and microglial proliferation and activation resulting in neuro-cognitive disabilities.Among other potential mechanisms,microglia have been impli...BACKGROUND Prolonged cardiac arrest(CA)produces extensive neuronal death and microglial proliferation and activation resulting in neuro-cognitive disabilities.Among other potential mechanisms,microglia have been implicated as triggers of neuronal death after hypoxic-ischemic insults.Minocycline is neuroprotective in some brain ischemia models,either by blunting the microglial response or by a direct effect on neurons.AIM To improve survival,attenuate neurologic deficits,neuroinflammation,and histological damage after ventricular fibrillation(VF)CA in rats.METHODS Adult male isoflurane-anesthetized rats were subjected to 6 min VF CA followed by 2 min resuscitation including chest compression,epinephrine,bicarbonate,and defibrillation.After return of spontaneous circulation(ROSC),rats were randomized to two groups:(1)Minocycline 90 mg/kg intraperitoneally(i.p.)at 15 min ROSC,followed by 22.5 mg/kg i.p.every 12 h for 72 h;and(2)Controls,receiving the same volume of vehicle(phosphate-buffered saline).The rats were kept normothermic during the postoperative course.Neurologic injury was assessed daily using Overall Performance Category(OPC;1=normal,5=dead)and Neurologic Deficit Score(NDS;0%=normal,100%=dead).Rats were sacrificed at 72 h.Neuronal degeneration(Fluoro-Jade C staining)and microglia proliferation(anti-Iba-1 staining)were quantified in four selectively vulnerable brain regions(hippocampus,striatum,cerebellum,cortex)by three independent reviewers masked to the group assignment.RESULTS In the minocycline group,8 out of 14 rats survived to 72 h compared to 8 out of 19 rats in the control group(P=0.46).The degree of neurologic deficit at 72 h[median,(interquartile range)]was not different between survivors in minocycline vs controls:OPC 1.5(1-2.75)vs 2(1.25-3),P=0.442;NDS 12(2-20)vs 17(7-51),P=0.328)or between all studied rats.The number of degenerating neurons(minocycline vs controls,mean±SEM:Hippocampus 58±8 vs 76±8;striatum 121±43 vs 153±32;cerebellum 20±7 vs 22±8;cortex 0±0 vs 0±0)or proliferating microglia(hippocampus 157±15 vs 193 cortex 0±0 vs 0±0;16;striatum 150±22 vs 161±23;cerebellum 20±7 vs 22±8;cortex 26±6 vs 31±7)was not different between groups in any region(all P>0.05).Numerically,there were approximately 20%less degenerating neurons and proliferating microglia in the hippocampus and striatum in the minocycline group,with a consistent pattern of histological damage across the individual regions of interest.CONCLUSION Minocycline did not improve survival and failed to confer substantial benefits on neurologic function,neuronal loss or microglial proliferation across multiple brain regions in our model of rat VF CA.展开更多
BACKGROUND Chronic biliary obstruction results in ischemia and hypoxia of hepatocytes,and leads to apoptosis.Apoptosis is very important in regulating the homeostasis of the hepatobiliary system.Endoplasmic reticulum(...BACKGROUND Chronic biliary obstruction results in ischemia and hypoxia of hepatocytes,and leads to apoptosis.Apoptosis is very important in regulating the homeostasis of the hepatobiliary system.Endoplasmic reticulum(ER)stress is one of the signaling pathways that induce apoptosis.Moreover,the protein kinase RNA-like endoplasmic reticulum kinase(PERK)-induced apoptotic pathway is the main way;but its role in liver injury remains unclear.Yinchenhao decoction(YCHD)is a traditional Chinese medicine formula that alleviates liver injury and apoptosis,yet its mechanism is unknown.We undertook this study to investigate the effects of YCHD on the expression of ER stress proteins and hepatocyte apoptosis in rats with obstructive jaundice(OJ).AIM To investigate whether YCHD can attenuate OJ-induced liver injury and hepatocyte apoptosis by inhibiting the PERK-CCAAT/enhancer-binding protein homologous protein(CHOP)-growth arrest and DNA damage-inducible protein 34(GADD34)pathway and B cell lymphoma/leukemia-2 related X protein(Bax)/B cell lymphoma/leukemia-2(Bcl-2)ratio.METHODS For in vivo experiments,30 rats were divided into three groups:control group,OJ model group,and YCHD-treated group.Blood was collected to detect the indicators of liver function,and liver tissues were used for histological analysis.For in vitro experiments,30 rats were divided into three groups:G1,G2,and G3.The rats in group G1 had their bile duct exposed without ligation,the rats in group G2 underwent total bile duct ligation,and the rats in group G3 were given a gavage of YCHD.According to the serum pharmacology,serum was extracted and centrifuged from the rat blood to cultivate the BRL-3A cells.Terminal deoxynucleotidyl transferase mediated dUTP nick end-labelling(TUNEL)assay was used to detect BRL-3A hepatocyte apoptosis.Alanine aminotransferase(ALT)and aspartate transaminase(AST)levels in the medium were detected.Western blot and quantitative real-time polymerase chain reaction(qRT-PCR)analyses were used to detect protein and gene expression levels of PERK,CHOP,GADD34,Bax,and Bcl-2 in the liver tissues and BRL-3A cells.RESULTS Biochemical assays and haematoxylin and eosin staining suggested severe liver function injury and liver tissue structure damage in the OJ model group.The TUNEL assay showed that massive BRL-3A rat hepatocyte apoptosis was induced by OJ.Elevated ALT and AST levels in the medium also demonstrated that hepatocytes could be destroyed by OJ.Western blot or qRT-PCR analyses showed that the protein and mRNA expression levels of PERK,CHOP,and GADD34 were significantly increased both in the rat liver tissue and BRL-3A rat hepatocytes by OJ.The Bax and Bcl-2 levels were increased,and the Bax/Bcl-2 ratio was also increased.When YCHD was used,the PERK,CHOP,GADD34,and Bax levels quickly decreased,while the Bcl-2 levels increased,and the Bax/Bcl-2 ratio decreased.CONCLUSION OJ-induced liver injury and hepatocyte apoptosis are associated with the activation of the PERK-CHOP-GADD34 pathway and increased Bax/Bcl-2 ratio.YCHD can attenuate these changes.展开更多
Objective:To investigate the influence of edaravone on the expression of growth arrest and DNA damage-inducible protein 34(GADD34).Methods:A total of 108 healthy male Sprague-Dawlcy rats were randomly divided into sha...Objective:To investigate the influence of edaravone on the expression of growth arrest and DNA damage-inducible protein 34(GADD34).Methods:A total of 108 healthy male Sprague-Dawlcy rats were randomly divided into sham operation group,model group and edaravone.group(36 cases for each group).Transient focal cerebral ischemia was induced by middle cerebral artery occlusion for 2 h followed by reperfusion in Sprague-Dawlev rats.Then.GAOD34 expression was measured with immunohistochemistry at different time-points after reperfusion in the peri-infarct regions of all rats.Results:The GADD34 expression was detected in the peri-infaret regions of rats 1 h after reperfusion,which reached its peak 24 h after reperfusion.And edaravone could significantly down-regulate the GAOD34 expression.Conclusions:Edaravon could down-regulate GADD34 expression,which suggests that edaravone may exert an important function in inhibiting endoplasmic reticulum stress reaction by scavenging free radicals in the upper stream.展开更多
Background: Chronic excessive alcohol consumption has been strongly associated with alcohol-induced cardiomyopathy (AC) in patients with no evidence of coronary artery disease (CAD). AC may cause cardiovascular c...Background: Chronic excessive alcohol consumption has been strongly associated with alcohol-induced cardiomyopathy (AC) in patients with no evidence of coronary artery disease (CAD). AC may cause cardiovascular complications and significant impact on the quality of life. We discuss an interesting case of dilated cardiomyopathy, associated complication, diagnostic work-up and management. Case Report: A young male presented to our service with worsening dyspnea, orthopnea, and scrotal and lower extremity edema. On average, he consumed a pack of 12 beers every day and had a 30-pack-years smoking history. He was found to be in acute heart failure with evidence of pulmonary edema and cardiomegaly on chest imaging. He had biventricular dilatation and severely reduced left ventricular ejection fraction (LVEF) 15% in addition to a thrombus in the LV apex. The cardiac catheterization was unremarkable for CAD. He was diuresed appropriately resulting in significant weight loss and resolution of symptoms. LV thrombus was treated with unfractionated heparin infusion that was transitioned to warfarin. He was maintained on guidelines-directed medical therapy for heart failure. Extensive counseling was provided regarding alcohol and tobacco cessation. On follow-up echocardiogram, his LVEF improved and there was no evidence of LV thrombus. We think, the readership will benefit from our experience of treating a case of AC, and the importance of clinical history. Conclusion: Chronic excessive alcohol use is detrimental to cardiac function leading to alcohol-induced cardiomyopathy. A careful approach to clinical history of alcohol consumption and prompt diagnostic workup negative for ischemic causes may confirm the diagnosis. Cardiac function improves with guidelines-directed medical therapy for heart failure and abstinence from alcohol.展开更多
The deleterious effects of long term right ventricular pacing are increasingly being recognized today.Current clinical practice favors the implantation of dual-chamber permanent pacemaker which maintains atrioventricu...The deleterious effects of long term right ventricular pacing are increasingly being recognized today.Current clinical practice favors the implantation of dual-chamber permanent pacemaker which maintains atrioventricular synchrony and is associated with better quality of life.However,despite the popular belief and common sense surrounding the superiority of dual-chamber pacing over single chamber pacing,the same has never been conclusively verified in clinical trials.Some observational evidence however,does exists which supports the improved cardiac hemodynamics,lower the rate of atrial fibrillation,heart failure and stroke in dual-chamber pacing compared to single-chamber pacing.In the index study by Haque et al,right ventricular pacing,particularly in ventricular paced,ven-tricular sensed,inhibited response and rate responsive pacemaker adversely im-pacted the left ventricular functions over 9-months compared to dual pacing,dual sensing,dual responsive and rate responsive pacemaker.Although there are key limitations of this study,these findings does support a growing body of evidence reinstating the superiority of dual chamber pacing compared to single chamber pacing.展开更多
文摘Cardiac or respiratory arrest lasting only a few minutes can inflict grave harm on numerous bodily organs, not least of all, the brain. Neurocognitive deficits, which are often severe and profoundly life altering, remain a major source of morbidity among survivors.
文摘Ethical concerns about stem cell-based research have delayed important advances in many areas of medicine,including cardiology.The introduction of induced pluripotent stem cells(iPSCs)has supplanted the need to use human stem cells for most purposes,thus eliminating all ethical controversies.Since then,many new avenues have been opened in cardiology research,not only in approaches to tissue replacement but also in the design and testing of antiarrhythmic drugs.This methodology has advanced to the point where induced human cardiomyocyte cell lines can now also be obtained from commercial sources or tissue banks.Initial studies with readily available iPSCs have generally confirmed that their behavioral characteristics accurately predict the behavior of beating cardiomyocytes in vivo.As a result,iPSCs can provide new ways to study arrhythmias and heart disease in general,accelerating the development of new,more effective antiarrhythmic drugs,clinical diagnoses,and personalized medical care.The focus on producing cardiomyocytes that can be used to replace damaged heart tissue has somewhat diverted interest in a host of other applications.This manuscript is intended to provide non-specialists with a brief introduction and overview of the research carried out in the field of heart rhythm disorders.
基金We thank Dr. Gordon Peters of Imperial CancerResearch Fund for providing p21(Waf1/Cip1) cDNA,Dr. Hong-Bing Shu of National Jewish Medica1and Reearch Center for pRetro-on-Bax and 293-10A1 packaging line. We also thank Drs. WeiTAO and Zhi Gang LU
文摘P21Waf1/Cip1 is a potent cyclin-dependent kinase inhibitor. As a downstream mediator of p53, p21Waf1/Cip1 involves in cell cycle arrest, differentiation and apoptosis. Previous studies in human cells provided evidence for a link between p21Waf1/Cip1 and cellular senescence. While in murine cells, the role of p21Waf1/Cip1 is indefinite. We explored this issue using NIH3T3 cells with inducible p21Waf1/Cip1 expression. Induction of p21Waf1/Cip1 triggered G1 growth arrest, and NIH3T3-p21 cells exhibited morphologic features, such as enlarged and flattened cellular shape, specific to the senescence phenotype. We also showed that p21Waf1/Cip1-transduced NIH3T3 cells expressed β-galactosidase activity at pH 6.0, which is known to be a marker of senescence. Our results suggest that p21Waf1/Cip1 can also induce senescence-like changes in murine cells.
文摘P21Waf1/Cip1 is a potent cyclin-dependent kinase inhibitor. As a downstream mediator of p53, p21Waf1/Cip1 involves in cell cycle arrest, differentiation and apoptosis. Previous studies in human cells provided evidence for a link between p21Waf1/Cip1 and cellular senescence. While in murine cells, the role of p21Waf1/Cip1 is indefinite. We explored this issue using NIH3T3 cells with inducible p21Waf1/Cip1 expression. Induction of p21Waf1/Cip1 triggered G1 growth arrest, and NIH3T3-p21 cells exhibited morphologic features, such as enlarged and flattened cellular shape, specific to the senescence phenotype. We also showed that p21Waf1/Cip1-transduced NIH3T3 cells expressed β-galactosidase activity at pH 6.0, which is known to be a marker of senescence. Our results suggest that p21Waf1/Cip1 can also induce senescence-like changes in murine cells.
基金Project supported by Key Project of National Natural Science Foundation of China (50737003).
文摘In order to obtain reasonable schemes of arrester in converter stations, the arrester scheme of "Xiluodu-Guangdong HVDC ± 500 kV double circuit transmission" project against lighting induced overvoltage, which was designed according to the main principle of lightning protection in converter station, is discussed. A calculation of the lighting induced overvoltage in Zhaotong converter station un- der various operation modes is performed with ATP-EMTP software, then the surge arrester configuration of the converter station is decided, and the arrester protection schemes of smoothing reactor and neutral line are studied. It is concluded that additional protection is necessary because of the relatively large gap between protected disconnecting switch and arrester of metallic return transfer bus. Plus, the smoothing reactor (SR) arrester near the valve hall could be removed to improve the scheme’s economic performance.
基金Supported by JSPS KAKENHI,No.20K21602,No.21H02915,and No.22K19526the Japan Agency for Medical Research and Development,No.21bm0804008h0005+2 种基金the Cell Science Research Foundationthe Grant for Basic Research of the Japanese Circulation Society(2018)SENSHIN Medical Research Foundation.
文摘Cardiomyopathy is a pathological condition characterized by cardiac pump failure due to myocardial dysfunction and the major cause of advanced heart failure requiring heart transplantation.Although optimized medical therapies have been developed for heart failure during the last few decades,some patients with cardiomyopathy exhibit advanced heart failure and are refractory to medical therapies.Desmosome,which is a dynamic cell-to-cell junctional component,maintains the structural integrity of heart tissues.Genetic mutations in desmo-somal genes cause arrhythmogenic cardiomyopathy(AC),a rare inheritable disease,and predispose patients to sudden cardiac death and heart failure.Recent advances in sequencing technologies have elucidated the genetic basis of cardiomyopathies and revealed that desmosome-related cardiomyopathy is concealed in broad cardiomyopathies.Among desmosomal genes,mutations in PKP2(which encodes PKP2)are most frequently identified in patients with AC.PKP2 deficiency causes various pathological cardiac phenotypes.Human cardiomyocytes differentiated from patient-derived induced pluripotent stem cells(iPSCs)in combination with genome editing,which allows the precise arrangement of the targeted genome,are powerful experimental tools for studying disease.This review summarizes the current issues associated with practical medicine for advanced heart failure and the recent advances in disease modeling using iPSC-derived cardiomyocytes targeting desmosome-related cardiomyopathy caused by PKP2 deficiency.
文摘The post-resuscitation period is recognized as the main predictor of cardiopul-monary resuscitation(CPR)outcomes.The first description of post-resuscitation syndrome and stony heart was published over 50 years ago.Major manifestations may include but are not limited to,persistent precipitating pathology,systemic ischemia/reperfusion response,post-cardiac arrest brain injury,and finally,post-cardiac arrest myocardial dysfunction(PAMD)after successful resuscitation.Why do some patients initially survive successful resuscitation,and others do not?Also,why does the myocardium response vary after resuscitation?These ques-tions have kept scientists busy for several decades since the first successful resuscitation was described.By modifying the conventional modalities of resu-scitation together with new promising agents,rescuers will be able to salvage the jeopardized post-resuscitation myocardium and prevent its progression to a dismal,stony heart.Community awareness and staff education are crucial for shortening the resuscitation time and improving short-and long-term outcomes.Awareness of these components before and early after the restoration of circulation will enhance the resuscitation outcomes.This review extensively addresses the underlying pathophysiology,management,and outcomes of post-resuscitation syndrome.The pattern,management,and outcome of PAMD and post-cardiac arrest shock are different based on many factors,including in-hospital cardiac arrest vs out-of-hospital cardiac arrest(OHCA),witnessed vs unwitnessed cardiac arrest,the underlying cause of arrest,the duration,and protocol used for CPR.Although restoring spontaneous circulation is a vital sign,it should not be the end of the game or lone primary outcome;it calls for better understanding and aggressive multi-disciplinary interventions and care.The development of stony heart post-CPR and OHCA remain the main challenges in emergency and critical care medicine.
基金Dr Annoni F.has been supported by the"Fonds Erasme pour la Recherche Médicale"for the entire length of the project.
文摘Background:Anoxic brain injuries represent the main determinant of poor outcome after cardiac arrest(CA).Large animal models have been described to investigate new treatments during CA and post-resuscitation phase,but a detailed model that includes extensive neuromonitoring is lacking.Method:Before an electrically-induced 10-minute CA and resuscitation,46 adult pigs underwent neurosurgery for placement of a multifunctional probe(intracranial pressure or ICP,tissue oxygen tension or PbtO_(2) and cerebral temperature)and a bolt-based technique for the placement and securing of a regional blood flow probe and two sEEG electrodes;two modified cerebral microdialysis(CMD)probes were also inserted in the frontal lobes and accidental misplacement was prevented using a perforated head support.Result:42 animals underwent the CA procedure and 41 achieved the return of spontaneous circulation(ROSC).In 4 cases(8.6%)an adverse event took place during preparation,but only in two cases(4.3%)this was related to the neurosurgery.In 6 animals(13.3%)the minor complications that occurred resolved after probe repositioning.Conclusion:Herein we provide a detailed comprehensive neuromonitoring approach in a large animal model of CA that might help future research.
文摘BACKGROUND Pulmonary arterial hypertension(PAH)is a disease of the arterioles resulting in an increased resistance in pulmonary circulation with associated high pressures in the pulmonary arteries,causing irreversible remodeling of the pulmonary arterial walls.Coronavirus disease 2019(COVID-19)has been associated with development of new onset PAH in the literature leading to symptoms of dyspnea,cough and fatigue that persist in spite of resolution of acute COVID-19 infection.However,the majority of these cases of COVID related PAH were diagnosed using echocardiographic data or via right heart catheterization in mechanically ventilated patients.CASE SUMMARY Our case is the first reported case of COVID related PAH diagnosed by right heart catheterization in a non-mechanically ventilated patient.Right heart catheterization has been the gold standard for diagnosis of pulmonary hypertension.Our patient had right heart catheterization four months after her initial COVID-19 infection due to persistent dyspnea.CONCLUSION This revealed new onset PAH that developed following her infection with COVID-19,an emerging sequela of the infection.
基金supported by Science and Technology Plan ning Project of Guangdong Province,China(No2011B080701075)
文摘In this study,one immortalized human normal prostatic epithelial cell line(BPH) and four human prostate cancer cell lines(LNCa P,22Rv1,PC-3,and DU-145) were treated with Ganoderma Lucidum triterpenoids(GLT) at different doses and for different time periods. Cell viability,apoptosis,and cell cycle were analyzed using flow cytometry and chemical assays. Gene expression and binding to DNA were assessed using real-time PCR and Western blotting. It was found that GLT dose-dependently inhibited prostate cancer cell growth through induction of apoptosis and cell cycle arrest at G1 phase. GLT-induced apoptosis was due to activation of Caspases-9 and-3 and turning on the downstream apoptotic events. GLT-induced cell cycle arrest(mainly G1 arrest) was due to up-regulation of p21 expression at the early time and down-regulation of cyclin-dependent kinase 4(CDK4) and E2F1 expression at the late time. These findings demonstrate that GLT suppresses prostate cancer cell growth by inducing growth arrest and apoptosis,which might suggest that GLT or Ganoderma Lucidum could be used as a potential therapeutic drug for prostate cancer.
文摘Fifty-three patients with congenital heart disease were follwed up 14 to 57months after cardiac surgery with profound hypothermia and circulatory arrest.Meanintelligence quotient(IQ)was 88.6±16.1The incidence of psychological underdevelopedwas 13.2(7/53),higher than normal children population,The high incidence may be attri-buted to poor preoperative intellecutual development.The circulatory arrest time weremore than 60 minutes in 9 cases,41-60 minutes in 32 cases and less than 40 minutes inanother 12 cases.The IQ of these three groups were 84.8±11.9,86.2±15.7and 95.3±19.2respctively and incidence of psychological underdeveloped were 11.1%,15.6% and 8.5%respectively,No significant difference existed between groups.The time of circulatory ar-rest also had no obvious correlation with IQ.
基金Supported by the Laerdal Foundation for Acute Medicine to Janata Athe Erwin Schroedinger Stipend by the Austrian Science Fund(#J 2931-818)to Janata A+3 种基金Medical Student Anesthesia Research Foundation Award from the International Anesthesia Research Society to Wilson CDSeed Grant from The Department of Anesthesiology,University of Pittsburgh to Drabek TStarter Grant from the Society of Cardiovascular Anesthesiologists to Drabek Tthe Laerdal Foundation for Acute Medicine to Drabek T
文摘BACKGROUND Prolonged cardiac arrest(CA)produces extensive neuronal death and microglial proliferation and activation resulting in neuro-cognitive disabilities.Among other potential mechanisms,microglia have been implicated as triggers of neuronal death after hypoxic-ischemic insults.Minocycline is neuroprotective in some brain ischemia models,either by blunting the microglial response or by a direct effect on neurons.AIM To improve survival,attenuate neurologic deficits,neuroinflammation,and histological damage after ventricular fibrillation(VF)CA in rats.METHODS Adult male isoflurane-anesthetized rats were subjected to 6 min VF CA followed by 2 min resuscitation including chest compression,epinephrine,bicarbonate,and defibrillation.After return of spontaneous circulation(ROSC),rats were randomized to two groups:(1)Minocycline 90 mg/kg intraperitoneally(i.p.)at 15 min ROSC,followed by 22.5 mg/kg i.p.every 12 h for 72 h;and(2)Controls,receiving the same volume of vehicle(phosphate-buffered saline).The rats were kept normothermic during the postoperative course.Neurologic injury was assessed daily using Overall Performance Category(OPC;1=normal,5=dead)and Neurologic Deficit Score(NDS;0%=normal,100%=dead).Rats were sacrificed at 72 h.Neuronal degeneration(Fluoro-Jade C staining)and microglia proliferation(anti-Iba-1 staining)were quantified in four selectively vulnerable brain regions(hippocampus,striatum,cerebellum,cortex)by three independent reviewers masked to the group assignment.RESULTS In the minocycline group,8 out of 14 rats survived to 72 h compared to 8 out of 19 rats in the control group(P=0.46).The degree of neurologic deficit at 72 h[median,(interquartile range)]was not different between survivors in minocycline vs controls:OPC 1.5(1-2.75)vs 2(1.25-3),P=0.442;NDS 12(2-20)vs 17(7-51),P=0.328)or between all studied rats.The number of degenerating neurons(minocycline vs controls,mean±SEM:Hippocampus 58±8 vs 76±8;striatum 121±43 vs 153±32;cerebellum 20±7 vs 22±8;cortex 0±0 vs 0±0)or proliferating microglia(hippocampus 157±15 vs 193 cortex 0±0 vs 0±0;16;striatum 150±22 vs 161±23;cerebellum 20±7 vs 22±8;cortex 26±6 vs 31±7)was not different between groups in any region(all P>0.05).Numerically,there were approximately 20%less degenerating neurons and proliferating microglia in the hippocampus and striatum in the minocycline group,with a consistent pattern of histological damage across the individual regions of interest.CONCLUSION Minocycline did not improve survival and failed to confer substantial benefits on neurologic function,neuronal loss or microglial proliferation across multiple brain regions in our model of rat VF CA.
基金Supported by the National Natural Science Foundation of China,No.81273952
文摘BACKGROUND Chronic biliary obstruction results in ischemia and hypoxia of hepatocytes,and leads to apoptosis.Apoptosis is very important in regulating the homeostasis of the hepatobiliary system.Endoplasmic reticulum(ER)stress is one of the signaling pathways that induce apoptosis.Moreover,the protein kinase RNA-like endoplasmic reticulum kinase(PERK)-induced apoptotic pathway is the main way;but its role in liver injury remains unclear.Yinchenhao decoction(YCHD)is a traditional Chinese medicine formula that alleviates liver injury and apoptosis,yet its mechanism is unknown.We undertook this study to investigate the effects of YCHD on the expression of ER stress proteins and hepatocyte apoptosis in rats with obstructive jaundice(OJ).AIM To investigate whether YCHD can attenuate OJ-induced liver injury and hepatocyte apoptosis by inhibiting the PERK-CCAAT/enhancer-binding protein homologous protein(CHOP)-growth arrest and DNA damage-inducible protein 34(GADD34)pathway and B cell lymphoma/leukemia-2 related X protein(Bax)/B cell lymphoma/leukemia-2(Bcl-2)ratio.METHODS For in vivo experiments,30 rats were divided into three groups:control group,OJ model group,and YCHD-treated group.Blood was collected to detect the indicators of liver function,and liver tissues were used for histological analysis.For in vitro experiments,30 rats were divided into three groups:G1,G2,and G3.The rats in group G1 had their bile duct exposed without ligation,the rats in group G2 underwent total bile duct ligation,and the rats in group G3 were given a gavage of YCHD.According to the serum pharmacology,serum was extracted and centrifuged from the rat blood to cultivate the BRL-3A cells.Terminal deoxynucleotidyl transferase mediated dUTP nick end-labelling(TUNEL)assay was used to detect BRL-3A hepatocyte apoptosis.Alanine aminotransferase(ALT)and aspartate transaminase(AST)levels in the medium were detected.Western blot and quantitative real-time polymerase chain reaction(qRT-PCR)analyses were used to detect protein and gene expression levels of PERK,CHOP,GADD34,Bax,and Bcl-2 in the liver tissues and BRL-3A cells.RESULTS Biochemical assays and haematoxylin and eosin staining suggested severe liver function injury and liver tissue structure damage in the OJ model group.The TUNEL assay showed that massive BRL-3A rat hepatocyte apoptosis was induced by OJ.Elevated ALT and AST levels in the medium also demonstrated that hepatocytes could be destroyed by OJ.Western blot or qRT-PCR analyses showed that the protein and mRNA expression levels of PERK,CHOP,and GADD34 were significantly increased both in the rat liver tissue and BRL-3A rat hepatocytes by OJ.The Bax and Bcl-2 levels were increased,and the Bax/Bcl-2 ratio was also increased.When YCHD was used,the PERK,CHOP,GADD34,and Bax levels quickly decreased,while the Bcl-2 levels increased,and the Bax/Bcl-2 ratio decreased.CONCLUSION OJ-induced liver injury and hepatocyte apoptosis are associated with the activation of the PERK-CHOP-GADD34 pathway and increased Bax/Bcl-2 ratio.YCHD can attenuate these changes.
基金Supported by Clinical Special Funds of Chinese University Medical Journals.China(Grant No:11321937)
文摘Objective:To investigate the influence of edaravone on the expression of growth arrest and DNA damage-inducible protein 34(GADD34).Methods:A total of 108 healthy male Sprague-Dawlcy rats were randomly divided into sham operation group,model group and edaravone.group(36 cases for each group).Transient focal cerebral ischemia was induced by middle cerebral artery occlusion for 2 h followed by reperfusion in Sprague-Dawlev rats.Then.GAOD34 expression was measured with immunohistochemistry at different time-points after reperfusion in the peri-infarct regions of all rats.Results:The GADD34 expression was detected in the peri-infaret regions of rats 1 h after reperfusion,which reached its peak 24 h after reperfusion.And edaravone could significantly down-regulate the GAOD34 expression.Conclusions:Edaravon could down-regulate GADD34 expression,which suggests that edaravone may exert an important function in inhibiting endoplasmic reticulum stress reaction by scavenging free radicals in the upper stream.
文摘Background: Chronic excessive alcohol consumption has been strongly associated with alcohol-induced cardiomyopathy (AC) in patients with no evidence of coronary artery disease (CAD). AC may cause cardiovascular complications and significant impact on the quality of life. We discuss an interesting case of dilated cardiomyopathy, associated complication, diagnostic work-up and management. Case Report: A young male presented to our service with worsening dyspnea, orthopnea, and scrotal and lower extremity edema. On average, he consumed a pack of 12 beers every day and had a 30-pack-years smoking history. He was found to be in acute heart failure with evidence of pulmonary edema and cardiomegaly on chest imaging. He had biventricular dilatation and severely reduced left ventricular ejection fraction (LVEF) 15% in addition to a thrombus in the LV apex. The cardiac catheterization was unremarkable for CAD. He was diuresed appropriately resulting in significant weight loss and resolution of symptoms. LV thrombus was treated with unfractionated heparin infusion that was transitioned to warfarin. He was maintained on guidelines-directed medical therapy for heart failure. Extensive counseling was provided regarding alcohol and tobacco cessation. On follow-up echocardiogram, his LVEF improved and there was no evidence of LV thrombus. We think, the readership will benefit from our experience of treating a case of AC, and the importance of clinical history. Conclusion: Chronic excessive alcohol use is detrimental to cardiac function leading to alcohol-induced cardiomyopathy. A careful approach to clinical history of alcohol consumption and prompt diagnostic workup negative for ischemic causes may confirm the diagnosis. Cardiac function improves with guidelines-directed medical therapy for heart failure and abstinence from alcohol.
文摘The deleterious effects of long term right ventricular pacing are increasingly being recognized today.Current clinical practice favors the implantation of dual-chamber permanent pacemaker which maintains atrioventricular synchrony and is associated with better quality of life.However,despite the popular belief and common sense surrounding the superiority of dual-chamber pacing over single chamber pacing,the same has never been conclusively verified in clinical trials.Some observational evidence however,does exists which supports the improved cardiac hemodynamics,lower the rate of atrial fibrillation,heart failure and stroke in dual-chamber pacing compared to single-chamber pacing.In the index study by Haque et al,right ventricular pacing,particularly in ventricular paced,ven-tricular sensed,inhibited response and rate responsive pacemaker adversely im-pacted the left ventricular functions over 9-months compared to dual pacing,dual sensing,dual responsive and rate responsive pacemaker.Although there are key limitations of this study,these findings does support a growing body of evidence reinstating the superiority of dual chamber pacing compared to single chamber pacing.