Background Few data on the combined effects of bifurcation and calcification on coronary artery disease(CAD)patients undergoing percutaneous coronary intervention(PCI)are available.This study evaluated the impact of m...Background Few data on the combined effects of bifurcation and calcification on coronary artery disease(CAD)patients undergoing percutaneous coronary intervention(PCI)are available.This study evaluated the impact of main vessel(MV)calcification on the procedural and long-term outcomes in patients with CAD who underwent provisional single stent PCI.Methods This is a multicenter,prospective,observational study.Patients with bifurcation lesions were enrolled at 10 PCI centers in China from January 2015 to December 2017.Intravascular ultrasound or optical coherence tomography was performed in all patients to evaluate the MV calcification.Patients were treated with provisional single stent strategy using drug eluting stents and followed-up at 1 month,6 months and 12 months after discharge by telephone contact or outpatient visit.Repeated coronary imaging was performed within one year.We compared the procedural success rates in MV and in side branch(SB),and target lesion failure(TLF),defined as a composite of cardiac death,non-fatal myocardial infarction,definite or possible stent thrombosis and target lesion revascularization between patients with and without MV calcification.Results A total of 185 subjects were enrolled according to the inclusion and exclusion criteria of this study.MV calcification was detected in 119(64.3%,calcification group)and not found in 66(35.7%,non-calcification group)patients.The angiographic success rate of MV was 95.8%in the calcification group and 97.0%in the non-calcification group(P=0.91);the angiographic success rate of SB was 32.8%in the calcification group and 53.0%in the non-calcification group(P<0.05).During the one-year follow-up period,TLF occurred in 14(11.8%)patients in the calcification group and in 13(19.7%)in the non-calcification group{P=0.31).Multivariate regression analysis showed the same result(HR=1.23,95%CI:0.76-1.52,P=0.47).Calcification on group had higher recurrent angina than non-calcification group(13.51%vs.17.65%,P<0.05).Conclusions In patients with coronary bifurcation lesion treated with provisional one stent approach,calcification of MV is associated with lower SB procedural success rate,it could increase recurrence of angina;however,it was not associated with an increased risk of TLF.展开更多
Background: Leigh syndrome(LS) is a rare disease caused by mitochondrial defects and has high phenotypic and genotypic heterogeneity.We analyzed the clinical symptoms, neuroimaging, muscular histopathology, and genoty...Background: Leigh syndrome(LS) is a rare disease caused by mitochondrial defects and has high phenotypic and genotypic heterogeneity.We analyzed the clinical symptoms, neuroimaging, muscular histopathology, and genotypes of 13 Chinese LS patients with mitochondrial DNA(mtDNA) mutations.Methods: Mutations in mtDNA were identified by targeted sequencing. The brain imaging features on magnetic resonance imaging(MRI)were analyzed. The levels of lactate in fasting blood and cerebrospinal fluid(CSF) were routinely tested. The levels of urinary organic acids, plasma amino acids, and acylcarnitines were examined with gas chromatography–mass spectrometry and tandem mass spectrometry.The histopathological traits of skeletal muscles were analyzed under microscope.Results: Among 13 patients, mutations of MT?NDs(n = 8) and MT?ATP6(n = 4) genes were most common. Strabismus(8/13), muscle weakness(8/13), and ataxia(5/13) were also common, especially for the patients with late?onset age after 2 years old. However, respiratory distress was common in patients with early?onset age before 2 years old. The most frequently affected brain area in these patients was the brain stem(12/13), particularly the dorsal part of midbrain, followed by basal ganglia(6/13), thalamus(6/13), cerebellum(5/13),and supratentorial white matter(2/13). Besides, the elevated lactate levels in CSF(6/6) were more common than those in serum(7/13).However, the analysis of abnormal plasma amino acid and urinary organic acid showed limited results(0/3 and 1/4, respectively). Muscular histopathology showed mitochondrial myopathy in the three late?onset patients but not in the early?onset ones.Conclusions: Noninvasive genetic screening is recommended for mtDNA mutations in MT?NDs and MT?ATP6 genes in patients with ophthalmoplegia, muscle weakness, ataxia, and respiratory disorder. Furthermore, the lactate detection in CSF and the brain MRI scanning are suggested as the diagnosis methods for LS patients with mtDNA mutations.展开更多
Passive immunotherapy is one of the most promising interventions for Alzheimer’s disease(AD).However,almost all immune-modulating strategies fail in clinical trials with unclear causes although they attenuate neuropa...Passive immunotherapy is one of the most promising interventions for Alzheimer’s disease(AD).However,almost all immune-modulating strategies fail in clinical trials with unclear causes although they attenuate neuropathology and cognitive deficits in AD animal models.Here,we showed that Aβ-targeting antibodies including their lgG1 and lgG4 subtypes induced microglial engulfment of neuronal synapses by activating CR3 or FcγRIIb via the complex of Aβ,antibody,and complement.Notably,anti-Aβantibodies without Fc fragment,or with blockage of CR3 or FcγRIIb,did not exert these adverse effects.Consistently,Aβ-targeting antibodies,but not their Fab fragments,significantly induced acute microglial synapse removal and rapidly exacerbated cognitive deficits and neuroinflammation in APP/PS1 mice post-treatment,whereas the memory impairments in mice were gradually rescued thereafter.Since the recovery rate of synapses in humans is much lower than that in mice,our findings may clarify the variances in the preclinical and clinical studies assessing AD immunotherapies.Therefore,Aβ-targeting antibodies lack of Fc fragment,or with reduced Fc effector function,may not induce microglial synaptic pruning,providing a safer and more efficient therapeutic alternative for passive immunotherapy for AD.展开更多
Background Deoxyribonuclease 2(DNaseⅡ)plays a key role in clearing cytoplasmic double-stranded DNA(dsDNA).Deficiency of DNaseⅡleads to DNA accumulation in the cytoplasm.Persistent dsDNA in neurons is an early pathol...Background Deoxyribonuclease 2(DNaseⅡ)plays a key role in clearing cytoplasmic double-stranded DNA(dsDNA).Deficiency of DNaseⅡleads to DNA accumulation in the cytoplasm.Persistent dsDNA in neurons is an early pathological hallmark of senescence and neurodegenerative diseases including Alzheimer’s disease(AD).However,it is not clear how DNaseⅡand neuronal cytoplasmic dsDNA influence neuropathogenesis.Tau hyperphosphorylation is a key factor for the pathogenesis of AD.The effect of DNaseⅡand neuronal cytoplasmic dsDNA on neuronal tau hyperphosphorylation remains unclarified.Methods The levels of neuronal DNaseⅡand dsDNA in WT and Tau-P301S mice of different ages were measured by immunohistochemistry and immunolabeling,and the levels of DNaseⅡin the plasma of AD patients were measured by ELISA.To investigate the impact of DNaseⅡon tauopathy,the levels of phosphorylated tau,phosphokinase,phosphatase,synaptic proteins,gliosis and proinflammatory cytokines in the brains of neuronal DNaseⅡ-deficient WT mice,neuronal DNaseⅡ-deficient Tau-P301S mice and neuronal DNaseⅡ-overexpressing Tau-P301S mice were evaluated by immunolabeling,immunoblotting or ELISA.Cognitive performance was determined using the Morris water maze test,Y-maze test,novel object recognition test and open field test.Results The levels of DNaseⅡwere significantly decreased in the brains and the plasma of AD patients.DNaseⅡalso decreased age-dependently in the neurons of WT and Tau-P301S mice,along with increased dsDNA accumulation in the cytoplasm.The DNA accumulation induced by neuronal DNaseⅡdeficiency drove tau phosphorylation by upregulating cyclin-dependent-like kinase-5(CDK5)and calcium/calmodulin activated protein kinaseⅡ(CaMKⅡ)and downregulating phosphatase protein phosphatase 2A(PP2A).Moreover,DNaseⅡknockdown induced and significantly exacerbated neuron loss,neuroinflammation and cognitive deficits in WT and Tau-P301S mice,respectively,while overexpression of neuronal DNaseⅡexhibited therapeutic benefits.Conclusions DNaseⅡdeficiency and cytoplasmic dsDNA accumulation can initiate tau phosphorylation,suggesting DNaseⅡas a potential therapeutic target for tau-associated disorders.展开更多
Myotonic dystrophy type 1 （DM1） is the most common disease causing muscle weakness and atrophy in adults. The prevalence of DM1 in China is not clear. DM1 is an autosomal dominant genetic disorder associated with th...Myotonic dystrophy type 1 （DM1） is the most common disease causing muscle weakness and atrophy in adults. The prevalence of DM1 in China is not clear. DM1 is an autosomal dominant genetic disorder associated with the cytosine-thynline-guanine （CTG） repeat expansion in 3＇untranslated region in dystrophia myotonica-protein kinase （DMPK） gene on chromosome 19q 13.3. In DM 1, CTG pathological repeat numbers are more than 50. The size of CTG repeat expansion is associated with the time of clinical phenotypes onset and severity The coexistence of DMI and syrlngomyelia is rare. Here, we report DM1 coexisting with syringonlyelia in a Chinese male patient.展开更多
基金supported by the National Natural Science Foundation of China(No.81670218-Mechanism study of CKIP-1 Regulating programmed necrosis induced by Myocardial Reperfusion Injury)
文摘Background Few data on the combined effects of bifurcation and calcification on coronary artery disease(CAD)patients undergoing percutaneous coronary intervention(PCI)are available.This study evaluated the impact of main vessel(MV)calcification on the procedural and long-term outcomes in patients with CAD who underwent provisional single stent PCI.Methods This is a multicenter,prospective,observational study.Patients with bifurcation lesions were enrolled at 10 PCI centers in China from January 2015 to December 2017.Intravascular ultrasound or optical coherence tomography was performed in all patients to evaluate the MV calcification.Patients were treated with provisional single stent strategy using drug eluting stents and followed-up at 1 month,6 months and 12 months after discharge by telephone contact or outpatient visit.Repeated coronary imaging was performed within one year.We compared the procedural success rates in MV and in side branch(SB),and target lesion failure(TLF),defined as a composite of cardiac death,non-fatal myocardial infarction,definite or possible stent thrombosis and target lesion revascularization between patients with and without MV calcification.Results A total of 185 subjects were enrolled according to the inclusion and exclusion criteria of this study.MV calcification was detected in 119(64.3%,calcification group)and not found in 66(35.7%,non-calcification group)patients.The angiographic success rate of MV was 95.8%in the calcification group and 97.0%in the non-calcification group(P=0.91);the angiographic success rate of SB was 32.8%in the calcification group and 53.0%in the non-calcification group(P<0.05).During the one-year follow-up period,TLF occurred in 14(11.8%)patients in the calcification group and in 13(19.7%)in the non-calcification group{P=0.31).Multivariate regression analysis showed the same result(HR=1.23,95%CI:0.76-1.52,P=0.47).Calcification on group had higher recurrent angina than non-calcification group(13.51%vs.17.65%,P<0.05).Conclusions In patients with coronary bifurcation lesion treated with provisional one stent approach,calcification of MV is associated with lower SB procedural success rate,it could increase recurrence of angina;however,it was not associated with an increased risk of TLF.
基金the grants from the National Natural Science Foundation of China (No.81671235and 81701237) the Taishan Scholars Program of Shandong Province.
文摘Background: Leigh syndrome(LS) is a rare disease caused by mitochondrial defects and has high phenotypic and genotypic heterogeneity.We analyzed the clinical symptoms, neuroimaging, muscular histopathology, and genotypes of 13 Chinese LS patients with mitochondrial DNA(mtDNA) mutations.Methods: Mutations in mtDNA were identified by targeted sequencing. The brain imaging features on magnetic resonance imaging(MRI)were analyzed. The levels of lactate in fasting blood and cerebrospinal fluid(CSF) were routinely tested. The levels of urinary organic acids, plasma amino acids, and acylcarnitines were examined with gas chromatography–mass spectrometry and tandem mass spectrometry.The histopathological traits of skeletal muscles were analyzed under microscope.Results: Among 13 patients, mutations of MT?NDs(n = 8) and MT?ATP6(n = 4) genes were most common. Strabismus(8/13), muscle weakness(8/13), and ataxia(5/13) were also common, especially for the patients with late?onset age after 2 years old. However, respiratory distress was common in patients with early?onset age before 2 years old. The most frequently affected brain area in these patients was the brain stem(12/13), particularly the dorsal part of midbrain, followed by basal ganglia(6/13), thalamus(6/13), cerebellum(5/13),and supratentorial white matter(2/13). Besides, the elevated lactate levels in CSF(6/6) were more common than those in serum(7/13).However, the analysis of abnormal plasma amino acid and urinary organic acid showed limited results(0/3 and 1/4, respectively). Muscular histopathology showed mitochondrial myopathy in the three late?onset patients but not in the early?onset ones.Conclusions: Noninvasive genetic screening is recommended for mtDNA mutations in MT?NDs and MT?ATP6 genes in patients with ophthalmoplegia, muscle weakness, ataxia, and respiratory disorder. Furthermore, the lactate detection in CSF and the brain MRI scanning are suggested as the diagnosis methods for LS patients with mtDNA mutations.
基金This work was supported by funding from the Strategic Priority Research Program of the Chinese Academy of Sciences(XDB39050600)the National Natural Science Foundation of China(82150107,81971610)the foundation of Innovation Academy for Green Manufacture Institute,Chinese Academy of Sciences,under Grand No.IAGM2020C29.
文摘Passive immunotherapy is one of the most promising interventions for Alzheimer’s disease(AD).However,almost all immune-modulating strategies fail in clinical trials with unclear causes although they attenuate neuropathology and cognitive deficits in AD animal models.Here,we showed that Aβ-targeting antibodies including their lgG1 and lgG4 subtypes induced microglial engulfment of neuronal synapses by activating CR3 or FcγRIIb via the complex of Aβ,antibody,and complement.Notably,anti-Aβantibodies without Fc fragment,or with blockage of CR3 or FcγRIIb,did not exert these adverse effects.Consistently,Aβ-targeting antibodies,but not their Fab fragments,significantly induced acute microglial synapse removal and rapidly exacerbated cognitive deficits and neuroinflammation in APP/PS1 mice post-treatment,whereas the memory impairments in mice were gradually rescued thereafter.Since the recovery rate of synapses in humans is much lower than that in mice,our findings may clarify the variances in the preclinical and clinical studies assessing AD immunotherapies.Therefore,Aβ-targeting antibodies lack of Fc fragment,or with reduced Fc effector function,may not induce microglial synaptic pruning,providing a safer and more efficient therapeutic alternative for passive immunotherapy for AD.
基金supported by funding from the Strategic Priority Research Program of the Chinese Academy of Sciences(XDB39050600)the National Natural Science Foundation of China(82150107 and 81971073)the National Key Research and Development Program of China(2020YFA0712402).
文摘Background Deoxyribonuclease 2(DNaseⅡ)plays a key role in clearing cytoplasmic double-stranded DNA(dsDNA).Deficiency of DNaseⅡleads to DNA accumulation in the cytoplasm.Persistent dsDNA in neurons is an early pathological hallmark of senescence and neurodegenerative diseases including Alzheimer’s disease(AD).However,it is not clear how DNaseⅡand neuronal cytoplasmic dsDNA influence neuropathogenesis.Tau hyperphosphorylation is a key factor for the pathogenesis of AD.The effect of DNaseⅡand neuronal cytoplasmic dsDNA on neuronal tau hyperphosphorylation remains unclarified.Methods The levels of neuronal DNaseⅡand dsDNA in WT and Tau-P301S mice of different ages were measured by immunohistochemistry and immunolabeling,and the levels of DNaseⅡin the plasma of AD patients were measured by ELISA.To investigate the impact of DNaseⅡon tauopathy,the levels of phosphorylated tau,phosphokinase,phosphatase,synaptic proteins,gliosis and proinflammatory cytokines in the brains of neuronal DNaseⅡ-deficient WT mice,neuronal DNaseⅡ-deficient Tau-P301S mice and neuronal DNaseⅡ-overexpressing Tau-P301S mice were evaluated by immunolabeling,immunoblotting or ELISA.Cognitive performance was determined using the Morris water maze test,Y-maze test,novel object recognition test and open field test.Results The levels of DNaseⅡwere significantly decreased in the brains and the plasma of AD patients.DNaseⅡalso decreased age-dependently in the neurons of WT and Tau-P301S mice,along with increased dsDNA accumulation in the cytoplasm.The DNA accumulation induced by neuronal DNaseⅡdeficiency drove tau phosphorylation by upregulating cyclin-dependent-like kinase-5(CDK5)and calcium/calmodulin activated protein kinaseⅡ(CaMKⅡ)and downregulating phosphatase protein phosphatase 2A(PP2A).Moreover,DNaseⅡknockdown induced and significantly exacerbated neuron loss,neuroinflammation and cognitive deficits in WT and Tau-P301S mice,respectively,while overexpression of neuronal DNaseⅡexhibited therapeutic benefits.Conclusions DNaseⅡdeficiency and cytoplasmic dsDNA accumulation can initiate tau phosphorylation,suggesting DNaseⅡas a potential therapeutic target for tau-associated disorders.
文摘Myotonic dystrophy type 1 （DM1） is the most common disease causing muscle weakness and atrophy in adults. The prevalence of DM1 in China is not clear. DM1 is an autosomal dominant genetic disorder associated with the cytosine-thynline-guanine （CTG） repeat expansion in 3＇untranslated region in dystrophia myotonica-protein kinase （DMPK） gene on chromosome 19q 13.3. In DM 1, CTG pathological repeat numbers are more than 50. The size of CTG repeat expansion is associated with the time of clinical phenotypes onset and severity The coexistence of DMI and syrlngomyelia is rare. Here, we report DM1 coexisting with syringonlyelia in a Chinese male patient.
