Blood vessels constitute a closed pipe system distributed throughout the body,transporting blood from the heart to other organs and delivering metabolic waste products back to the lungs and kidneys.Changes in blood ve...Blood vessels constitute a closed pipe system distributed throughout the body,transporting blood from the heart to other organs and delivering metabolic waste products back to the lungs and kidneys.Changes in blood vessels are related to many disorders like stroke,myocardial infarction,aneurysm,and diabetes,which are important causes of death worldwide.Translational research for new appro-aches to disease modeling and effective treatment is needed due to the huge socio-economic burden on healthcare systems.Although mice or rats have been widely used,applying data from animal studies to human-specific vascular physiology and pathology is difficult.The rise of induced pluripotent stem cells(iPSCs)provides a reliable in vitro resource for disease modeling,regenerative medicine,and drug discovery because they carry all human genetic information and have the ability to directionally differentiate into any type of human cells.This review summarizes the latest progress from the establishment of iPSCs,the strategies for differentiating iPSCs into vascular cells,and the in vivo trans-plantation of these vascular derivatives.It also introduces the application of these technologies in disease modeling,drug screening,and regenerative medicine.Additionally,the application of high-tech tools,such as omics analysis and high-throughput sequencing,in this field is reviewed.展开更多
It is difficult to control the degree of ischemic postconditioning in the brain and other isch- emia-sensitive organs. Remote ischemic postconditioning could protect some ischemia-sensitive organs through measures on ...It is difficult to control the degree of ischemic postconditioning in the brain and other isch- emia-sensitive organs. Remote ischemic postconditioning could protect some ischemia-sensitive organs through measures on terminal organs. In this study, a focal cerebral ischemia-reperftlsion injury model was established using three cycles of remote ischernic postconditioning, each cycle consisted of 10-minute occlusion of the femoral artery and 10-minute opening. The results showed that, remote ischemic postconditioning significantly decreased the percentage of the in- farct area and attenuated brain edema. In addition, inflammatory nuclear factor-KB expression was significantly lower, while anti-apoptotic Bcl-2 expression was significantly elevated in the ce- rebral cortex on the ischemic side. Our findings indicate that remote ischemic postconditioning attenuates focal cerebral ischemia/reperfusion injury, and that the neuroprotective mechanism is mediated by an anti-apoptotic effect and reduction of the inflammatory response.展开更多
Objective To explore predictors of the 6-month clinical outcome ofthalamic hemorrhage, and evaluate if minimally invasive thalamic hematoma drainage （THD） could improve its prognosis. Methods A total of 54 patients ...Objective To explore predictors of the 6-month clinical outcome ofthalamic hemorrhage, and evaluate if minimally invasive thalamic hematoma drainage （THD） could improve its prognosis. Methods A total of 54 patients with spontaneous thalamic hemorrhage were evaluated retrospectively. Clinical data, including demographics, stroke risk factors, neuroimaging variables, Glasgow Coma Score （GCS） on admission, surgical strategy, and outcome, were collected. Clinical outcome was assessed using a modified Rankin Scale, six months after onset. Univariate analysis and multivariate logistic regression analysis were performed to determine predictors of a poor outcome. Results Conservative treatnaent was performed for five patients （9.3%）, external ventricular drainage （EVD） for 20 patients （37.0%）, THD for four patients （7.4%）, and EVD combined with THD for 25 patients （46.3%）. At six months after onset, 21 （38.9%） patients achieved a favorable outcome, while 33 （61.1%） had a poor outcome. In the univariate analysis, predictors of poor 6-month outcome were lower GCS on admis- sion （P = 0.001）, larger hematoma volume （P 〈 0.001）, midline shift （P = 0.035）, acute hydrocephalus （P = 0.039）, and no THD （P = 0.037）. The independent predictors of poor outcome, according to the multivariate logistic regression analysis, were no THD and larger hematoma volume. Conclusions Minimally invasive THD, which removes most of the hematoma within a few days, with limited damage to perihematomal brain tissue, improved the 6-month outcome of thalamic hemorrhage. Thus, THD can be widely applied to treat patients with thalamic hemorrhage.展开更多
Previous studies have shown that exogenous gangliosides promote nervous system regeneration and synapse formation. In this study, 10 mm sciatic nerve segments from New Zealand rabbits were thawed from cryopreservation...Previous studies have shown that exogenous gangliosides promote nervous system regeneration and synapse formation. In this study, 10 mm sciatic nerve segments from New Zealand rabbits were thawed from cryopreservation and were used for the repair of left sciatic nerve defects through allograft bridging. Three days later, 1 mL ganglioside solution （1 g/L） was sub- cutaneously iniected into the right hind leg of rabbits. Compared with non-injected rats, muscle wet weight ratio was increased at 2-12 weeks after modeling. The quantity of myelinated fibers in regenerated sciatic nerve, myelin thickness and fiber diameter were elevated at 4-12 weeks after modeling. Sciatic nerve potential amplitude and conduction velocity were raised at 8 and 12 weeks, while conduction latencies were decreased at 12 weeks. Experimental findings indicate that ganglioside can promote the regeneration of sciatic nerve defects after repair with cryopre- served peripheral nerve allografts.展开更多
Objective:To To investigate the changes of MicroRNA-134,CREB and p-CREB expression in epileptic rat brains in order to elucidate the molecular mechanisms of epilepsy,providing new ideas for clinical treatment.Methods:...Objective:To To investigate the changes of MicroRNA-134,CREB and p-CREB expression in epileptic rat brains in order to elucidate the molecular mechanisms of epilepsy,providing new ideas for clinical treatment.Methods:Sixty-four Spraque-Dawley(SD)rats were divided into groups randomly,including control group,six hours after seizure group,24-hour group,threeday group,one-week group,two-week group,four-week group,and eight-week group.All groups were placed under a pilocarpine-induced epilepsy model except the control group,and all rats were decapitated in different points of time.Brain specimens were taken for quantitative PCR experiments,immunohistochemistry and Western blot experiments.The results of the epilepsy model groups and the control group were compared.Results:There were no significant differences between the six hours after seizure group,the 24-hour group and the control group about the MicroRNA-134 levels.MicroRNA-134 in the hippocampus tissue of the three-day group significantly reduced compared with the control group;same result was observed with the one-week,two-week,four-week and eight-week groups.The CREB and p-CREB levels in the three-day group's rat hippocampus significantly increased compared with the control group;and the high levels of CREB and p-CREB were constantly maintained in the one-week,two-week,four-week and eight-week groups.Conclusions:The MicroRNA-134 level of the epileptic rat hippocampus is significantly lower than normal after three days,and continues to maintain a low level:while CREB and p-CREB levels are rsignificantly increased after three days,and continue to remain at a high level.MicroRNA-134 plays a role in inhibiting synaptic plasticity by inhibiting CREB and p-CREB expressions.展开更多
Hydrogen sulfide,which can be generated in the central nervous system from the sulfhydryl-containing amino acid,L-cysteine,by cystathionine-β-synthase,may exert protective effects in experimental subarachnoid hemorrh...Hydrogen sulfide,which can be generated in the central nervous system from the sulfhydryl-containing amino acid,L-cysteine,by cystathionine-β-synthase,may exert protective effects in experimental subarachnoid hemorrhage;however,the mechanism underlying this effect is unknown.This study explored the mechanism using a subarachnoid hemorrhage rat model induced by an endovascular perforation technique.Rats were treated with an intraperitoneal injection of 100 mM L-cysteine(30μL)30 minutes after subarachnoid hemorrhage.At 48 hours after subarachnoid hemorrhage,hematoxylin-eosin staining was used to detect changes in prefrontal cortex cells.L-cysteine significantly reduced cell edema.Neurological function was assessed using a modified Garcia score.Brain water content was measured by the wet-dry method.L-cysteine significantly reduced neurological deficits and cerebral edema after subarachnoid hemorrhage.Immunofluorescence was used to detect the number of activated microglia.Reverse transcription-polymerase chain reaction(RT-PCR)was used to detect the levels of interleukin 1β and CD86 mRNA in the prefrontal cortex.L-cysteine inhibited microglial activation in the prefrontal cortex and reduced the mRNA levels of interleukin 1βand CD86.RT-PCR and western blot analysis of the complement system showed that L-cysteine reduced expression of the complement factors,C1q,C3αand its receptor C3aR1,and the deposition of C1q in the prefrontal cortex.Dihydroethidium staining was applied to detect changes in reactive oxygen species,and immunohistochemistry was used to detect the number of NRF2-and HO-1-positive cells.L-cysteine reduced the level of reactive oxygen species in the prefrontal cortex and the number of NRF2-and HO-1-positive cells.Western blot assays and immunohistochemistry were used to detect the protein levels of CHOP and GRP78 in the prefrontal cortex and the number of CHOP-and GRP78-positive cells.L-cysteine reduced CHOP and GRP78 levels and the number of CHOP-and GRP78-positive cells.The cystathionine-β-synthase inhibitor,aminooxyacetic acid,significantly reversed the above neuroprotective effects of L-cysteine.Taken together,L-cysteine can play a neuroprotective role by regulating neuroinflammation,complement deposition,oxidative stress and endoplasmic reticulum stress.The study was approved by the Animals Ethics Committee of Shandong University,China on February 22,2016(approval No.LL-201602022).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
To the Editor:Mitochondrial encephalomyopathy with lactate acidosis and stroke-like episodes(MELAS)is one of the most common multisystem mitochondrial disorders with broad clinical manifestations.[1]It is usually caus...To the Editor:Mitochondrial encephalomyopathy with lactate acidosis and stroke-like episodes(MELAS)is one of the most common multisystem mitochondrial disorders with broad clinical manifestations.[1]It is usually caused by point mutations in the mitochondrial MT-TL1 gene,which accounts for approximately 80%of mutations in individuals with MELAS syndrome.[2]Pathogenic mitochondrial DNA(mtDNA)mutations were first described in 1980[3]and m.l4487T>C is a known pathogenic mtDNA mutation,[4]which has been reported in patients with Leigh syndrome,optic neuropathy,ptosis,dystonia,and encephalomyopathy.We herein report a patient with late-onset MELAS syndrome with the m.l4487T>C mutation for the first time.展开更多
Background：The immunopathologic mechanism underlying dermatomyositis （DM） and polymyositis （PM） remains poorly understood.Many cytokines play a pathogenic role in DM and PM.lnterleukin 21 （IL-21） has a pleiotro...Background：The immunopathologic mechanism underlying dermatomyositis （DM） and polymyositis （PM） remains poorly understood.Many cytokines play a pathogenic role in DM and PM.lnterleukin 21 （IL-21） has a pleiotropic effect on inflammation regulation.This study aimed to detect the serum IL-21 level and investigate the expression of IL-21 and IL-21 receptor （IL-21 R） in muscle tissues of patients with DM and PM.Methods：Biopsied muscle samples were obtained from 11 patients with DM,12 with PM,and six controls;mRNA levels of IL-21 and IL-21 R were analyzed by real-time quantitative reverse transcription-polymerase chain reaction;and immunohistochemical staining was used to evaluate the protein expression of IL-21 and IL-21R.Serum samples were obtained from 36 patients with DM,19 with PM,and 20 healthy controls.The serum IL-21 level was detected by enzyme-linked immunosorbent assay.Results：The expression of IL-21 was upregulated in patients with DM and PM.The IL-21 mRNA level was significantly increased in muscle tissues of patients with DM and PM （DM vs.control,P =0.001;PM vs.control,P =0.001）,whereas IL-21R mRNA level in patients with DM/PM was not statistically different from that of healthy controls.Immunohistochemical staining showed both I L-21 and IL-21R were significantly expressed in the inflammatory cells in muscle tissues of patients with DM and PM.The serum IL-21 level was also significantly higher in patients with DM/PM than in controls （DM vs.control,49.12 [45.28,60.07] pg/ml vs.42.54 [38.69,48.85] pg/ml,P =0.00l;PM vs.control,50.77 [44.19,60.62] pg/ml vs.42.54 [38.69,48.85] pg/ml,P =0.005）.Conclusions：IL-21 expression is upregulated in patients with DM and PM in both muscle tissue and serum.In addition,IL-21R protein is highly expressed in affected muscle tissues of patients with DM and PM.IL-21 may play a pathogenic role through IL-21R in patients with DM and PM.展开更多
Background:Abnormally activated mechanistic target of rapamycin(mTOR)pathway has been reported in several model animals with inherited metabolic myopathies(IMMs).However,the profiles of mTOR pathway in skeletal muscle...Background:Abnormally activated mechanistic target of rapamycin(mTOR)pathway has been reported in several model animals with inherited metabolic myopathies(IMMs).However,the profiles of mTOR pathway in skeletal muscles from patients are still unknown.This study aimed to analyze the activity of mTOR pathway in IMMs muscles.Methods:We collected muscle samples from 25 patients with mitochondrial myopathy(MM),lipid storage disease(LSD)or Pompe disease(PD).To evaluate the activity of mTOR pathway in muscle specimens,phosphorylation of S6 ribosomal protein(p-S6)and p70S6 kinase(p-p70S6K)were analyzed by Western blotting and immunohistochemistry.Results:Western blotting results showed that p-p70S6K/p70S6K in muscles from LSD and MM was up-regulated when compared with normal controls(NC)(NC vs.LSD,U=2.000,P=0.024;NC vs.MM:U=6.000,P=0.043).Likewise,p-S6/S6 was also upregulated in muscles from all three subgroups of IMMs(NC vs.LSD,U=0.000,P=0.006);NC vs.PD,[7=0.000,P=0.006;NC vs.MM,U=1.000,P=0.007].Immunohistochemical study revealed that p-S6 was mainly expressed in fibers with metabolic defect.In MM muscles,most p-S6 positive fibers showed cytochrome C oxidase(COX)deficiency(U=5.000,P=0.001).In LSD and PD muscles,p-S6 was mainly overexpressed in fibers with intramuscular vacuoles containing lipid droplets(17=0.000,P=0.002)or basophilic materials(U=0.000,P=0.002).Conclusion:The mTOR pathway might be activated in myofibers with various metabolic defects,which might provide evidence for mTOR inhibition therapy in human IMMs.展开更多
文摘Blood vessels constitute a closed pipe system distributed throughout the body,transporting blood from the heart to other organs and delivering metabolic waste products back to the lungs and kidneys.Changes in blood vessels are related to many disorders like stroke,myocardial infarction,aneurysm,and diabetes,which are important causes of death worldwide.Translational research for new appro-aches to disease modeling and effective treatment is needed due to the huge socio-economic burden on healthcare systems.Although mice or rats have been widely used,applying data from animal studies to human-specific vascular physiology and pathology is difficult.The rise of induced pluripotent stem cells(iPSCs)provides a reliable in vitro resource for disease modeling,regenerative medicine,and drug discovery because they carry all human genetic information and have the ability to directionally differentiate into any type of human cells.This review summarizes the latest progress from the establishment of iPSCs,the strategies for differentiating iPSCs into vascular cells,and the in vivo trans-plantation of these vascular derivatives.It also introduces the application of these technologies in disease modeling,drug screening,and regenerative medicine.Additionally,the application of high-tech tools,such as omics analysis and high-throughput sequencing,in this field is reviewed.
基金supported by the Natural Science Foundation(Joint Fund)of Liaoning Provincial Science and Technology Department,No.2013022021
文摘It is difficult to control the degree of ischemic postconditioning in the brain and other isch- emia-sensitive organs. Remote ischemic postconditioning could protect some ischemia-sensitive organs through measures on terminal organs. In this study, a focal cerebral ischemia-reperftlsion injury model was established using three cycles of remote ischernic postconditioning, each cycle consisted of 10-minute occlusion of the femoral artery and 10-minute opening. The results showed that, remote ischemic postconditioning significantly decreased the percentage of the in- farct area and attenuated brain edema. In addition, inflammatory nuclear factor-KB expression was significantly lower, while anti-apoptotic Bcl-2 expression was significantly elevated in the ce- rebral cortex on the ischemic side. Our findings indicate that remote ischemic postconditioning attenuates focal cerebral ischemia/reperfusion injury, and that the neuroprotective mechanism is mediated by an anti-apoptotic effect and reduction of the inflammatory response.
基金This study was supported by National Natural Science Foundation of China （81501054）, and Kejihuimin Project of Shandong Province （2014kjhm0101）.
文摘Objective To explore predictors of the 6-month clinical outcome ofthalamic hemorrhage, and evaluate if minimally invasive thalamic hematoma drainage （THD） could improve its prognosis. Methods A total of 54 patients with spontaneous thalamic hemorrhage were evaluated retrospectively. Clinical data, including demographics, stroke risk factors, neuroimaging variables, Glasgow Coma Score （GCS） on admission, surgical strategy, and outcome, were collected. Clinical outcome was assessed using a modified Rankin Scale, six months after onset. Univariate analysis and multivariate logistic regression analysis were performed to determine predictors of a poor outcome. Results Conservative treatnaent was performed for five patients （9.3%）, external ventricular drainage （EVD） for 20 patients （37.0%）, THD for four patients （7.4%）, and EVD combined with THD for 25 patients （46.3%）. At six months after onset, 21 （38.9%） patients achieved a favorable outcome, while 33 （61.1%） had a poor outcome. In the univariate analysis, predictors of poor 6-month outcome were lower GCS on admis- sion （P = 0.001）, larger hematoma volume （P 〈 0.001）, midline shift （P = 0.035）, acute hydrocephalus （P = 0.039）, and no THD （P = 0.037）. The independent predictors of poor outcome, according to the multivariate logistic regression analysis, were no THD and larger hematoma volume. Conclusions Minimally invasive THD, which removes most of the hematoma within a few days, with limited damage to perihematomal brain tissue, improved the 6-month outcome of thalamic hemorrhage. Thus, THD can be widely applied to treat patients with thalamic hemorrhage.
文摘Previous studies have shown that exogenous gangliosides promote nervous system regeneration and synapse formation. In this study, 10 mm sciatic nerve segments from New Zealand rabbits were thawed from cryopreservation and were used for the repair of left sciatic nerve defects through allograft bridging. Three days later, 1 mL ganglioside solution （1 g/L） was sub- cutaneously iniected into the right hind leg of rabbits. Compared with non-injected rats, muscle wet weight ratio was increased at 2-12 weeks after modeling. The quantity of myelinated fibers in regenerated sciatic nerve, myelin thickness and fiber diameter were elevated at 4-12 weeks after modeling. Sciatic nerve potential amplitude and conduction velocity were raised at 8 and 12 weeks, while conduction latencies were decreased at 12 weeks. Experimental findings indicate that ganglioside can promote the regeneration of sciatic nerve defects after repair with cryopre- served peripheral nerve allografts.
基金supported by National Natural Science Foundation(No:81371439)
文摘Objective:To To investigate the changes of MicroRNA-134,CREB and p-CREB expression in epileptic rat brains in order to elucidate the molecular mechanisms of epilepsy,providing new ideas for clinical treatment.Methods:Sixty-four Spraque-Dawley(SD)rats were divided into groups randomly,including control group,six hours after seizure group,24-hour group,threeday group,one-week group,two-week group,four-week group,and eight-week group.All groups were placed under a pilocarpine-induced epilepsy model except the control group,and all rats were decapitated in different points of time.Brain specimens were taken for quantitative PCR experiments,immunohistochemistry and Western blot experiments.The results of the epilepsy model groups and the control group were compared.Results:There were no significant differences between the six hours after seizure group,the 24-hour group and the control group about the MicroRNA-134 levels.MicroRNA-134 in the hippocampus tissue of the three-day group significantly reduced compared with the control group;same result was observed with the one-week,two-week,four-week and eight-week groups.The CREB and p-CREB levels in the three-day group's rat hippocampus significantly increased compared with the control group;and the high levels of CREB and p-CREB were constantly maintained in the one-week,two-week,four-week and eight-week groups.Conclusions:The MicroRNA-134 level of the epileptic rat hippocampus is significantly lower than normal after three days,and continues to maintain a low level:while CREB and p-CREB levels are rsignificantly increased after three days,and continue to remain at a high level.MicroRNA-134 plays a role in inhibiting synaptic plasticity by inhibiting CREB and p-CREB expressions.
基金supported by the National Natural Science Foundation of China,Nos.81873768 and 81671213(to ZW),81571284 and 81874083(to GL)the Key Research and Development Foundation of Shandong Province of China,No.2017GSF218091(to ZW)+2 种基金the Natural Science Foundation of Shandong Province of China,No.ZR2016HM33(to DXL)the Shandong Medical and Health Science and Technology Development Plan Project of China,No.2017WS068(to QH)the Taishan Scholars of Shandong Province of China,No.ts201511093(to GL)
文摘Hydrogen sulfide,which can be generated in the central nervous system from the sulfhydryl-containing amino acid,L-cysteine,by cystathionine-β-synthase,may exert protective effects in experimental subarachnoid hemorrhage;however,the mechanism underlying this effect is unknown.This study explored the mechanism using a subarachnoid hemorrhage rat model induced by an endovascular perforation technique.Rats were treated with an intraperitoneal injection of 100 mM L-cysteine(30μL)30 minutes after subarachnoid hemorrhage.At 48 hours after subarachnoid hemorrhage,hematoxylin-eosin staining was used to detect changes in prefrontal cortex cells.L-cysteine significantly reduced cell edema.Neurological function was assessed using a modified Garcia score.Brain water content was measured by the wet-dry method.L-cysteine significantly reduced neurological deficits and cerebral edema after subarachnoid hemorrhage.Immunofluorescence was used to detect the number of activated microglia.Reverse transcription-polymerase chain reaction(RT-PCR)was used to detect the levels of interleukin 1β and CD86 mRNA in the prefrontal cortex.L-cysteine inhibited microglial activation in the prefrontal cortex and reduced the mRNA levels of interleukin 1βand CD86.RT-PCR and western blot analysis of the complement system showed that L-cysteine reduced expression of the complement factors,C1q,C3αand its receptor C3aR1,and the deposition of C1q in the prefrontal cortex.Dihydroethidium staining was applied to detect changes in reactive oxygen species,and immunohistochemistry was used to detect the number of NRF2-and HO-1-positive cells.L-cysteine reduced the level of reactive oxygen species in the prefrontal cortex and the number of NRF2-and HO-1-positive cells.Western blot assays and immunohistochemistry were used to detect the protein levels of CHOP and GRP78 in the prefrontal cortex and the number of CHOP-and GRP78-positive cells.L-cysteine reduced CHOP and GRP78 levels and the number of CHOP-and GRP78-positive cells.The cystathionine-β-synthase inhibitor,aminooxyacetic acid,significantly reversed the above neuroprotective effects of L-cysteine.Taken together,L-cysteine can play a neuroprotective role by regulating neuroinflammation,complement deposition,oxidative stress and endoplasmic reticulum stress.The study was approved by the Animals Ethics Committee of Shandong University,China on February 22,2016(approval No.LL-201602022).
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grants from the National Natural Science Foundation of China(No.81671235 and No.81701237)People's Benefit Project of Science and Technology in Qingdao(No.16-6-2-1-nsh)and the Taishan Scholars Program of Shandong Province.
文摘To the Editor:Mitochondrial encephalomyopathy with lactate acidosis and stroke-like episodes(MELAS)is one of the most common multisystem mitochondrial disorders with broad clinical manifestations.[1]It is usually caused by point mutations in the mitochondrial MT-TL1 gene,which accounts for approximately 80%of mutations in individuals with MELAS syndrome.[2]Pathogenic mitochondrial DNA(mtDNA)mutations were first described in 1980[3]and m.l4487T>C is a known pathogenic mtDNA mutation,[4]which has been reported in patients with Leigh syndrome,optic neuropathy,ptosis,dystonia,and encephalomyopathy.We herein report a patient with late-onset MELAS syndrome with the m.l4487T>C mutation for the first time.
文摘Background：The immunopathologic mechanism underlying dermatomyositis （DM） and polymyositis （PM） remains poorly understood.Many cytokines play a pathogenic role in DM and PM.lnterleukin 21 （IL-21） has a pleiotropic effect on inflammation regulation.This study aimed to detect the serum IL-21 level and investigate the expression of IL-21 and IL-21 receptor （IL-21 R） in muscle tissues of patients with DM and PM.Methods：Biopsied muscle samples were obtained from 11 patients with DM,12 with PM,and six controls;mRNA levels of IL-21 and IL-21 R were analyzed by real-time quantitative reverse transcription-polymerase chain reaction;and immunohistochemical staining was used to evaluate the protein expression of IL-21 and IL-21R.Serum samples were obtained from 36 patients with DM,19 with PM,and 20 healthy controls.The serum IL-21 level was detected by enzyme-linked immunosorbent assay.Results：The expression of IL-21 was upregulated in patients with DM and PM.The IL-21 mRNA level was significantly increased in muscle tissues of patients with DM and PM （DM vs.control,P =0.001;PM vs.control,P =0.001）,whereas IL-21R mRNA level in patients with DM/PM was not statistically different from that of healthy controls.Immunohistochemical staining showed both I L-21 and IL-21R were significantly expressed in the inflammatory cells in muscle tissues of patients with DM and PM.The serum IL-21 level was also significantly higher in patients with DM/PM than in controls （DM vs.control,49.12 [45.28,60.07] pg/ml vs.42.54 [38.69,48.85] pg/ml,P =0.00l;PM vs.control,50.77 [44.19,60.62] pg/ml vs.42.54 [38.69,48.85] pg/ml,P =0.005）.Conclusions：IL-21 expression is upregulated in patients with DM and PM in both muscle tissue and serum.In addition,IL-21R protein is highly expressed in affected muscle tissues of patients with DM and PM.IL-21 may play a pathogenic role through IL-21R in patients with DM and PM.
基金supported by grants from the National Natural Science Foundation of China(No.81671235)People's Benefit Project of Science and Technology in Qingdao(No.16-6-2-1-nsh),Natural Science Foundation of Shandong Province(No.ZR2017BH033)the Taishan Scholars Program of Shandong Provinee.
文摘Background:Abnormally activated mechanistic target of rapamycin(mTOR)pathway has been reported in several model animals with inherited metabolic myopathies(IMMs).However,the profiles of mTOR pathway in skeletal muscles from patients are still unknown.This study aimed to analyze the activity of mTOR pathway in IMMs muscles.Methods:We collected muscle samples from 25 patients with mitochondrial myopathy(MM),lipid storage disease(LSD)or Pompe disease(PD).To evaluate the activity of mTOR pathway in muscle specimens,phosphorylation of S6 ribosomal protein(p-S6)and p70S6 kinase(p-p70S6K)were analyzed by Western blotting and immunohistochemistry.Results:Western blotting results showed that p-p70S6K/p70S6K in muscles from LSD and MM was up-regulated when compared with normal controls(NC)(NC vs.LSD,U=2.000,P=0.024;NC vs.MM:U=6.000,P=0.043).Likewise,p-S6/S6 was also upregulated in muscles from all three subgroups of IMMs(NC vs.LSD,U=0.000,P=0.006);NC vs.PD,[7=0.000,P=0.006;NC vs.MM,U=1.000,P=0.007].Immunohistochemical study revealed that p-S6 was mainly expressed in fibers with metabolic defect.In MM muscles,most p-S6 positive fibers showed cytochrome C oxidase(COX)deficiency(U=5.000,P=0.001).In LSD and PD muscles,p-S6 was mainly overexpressed in fibers with intramuscular vacuoles containing lipid droplets(17=0.000,P=0.002)or basophilic materials(U=0.000,P=0.002).Conclusion:The mTOR pathway might be activated in myofibers with various metabolic defects,which might provide evidence for mTOR inhibition therapy in human IMMs.
