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1.
不同放疗剂量对肌营养不良鼠骨髓干细胞移植的影响   总被引:3,自引:0,他引:3  
目的 使用不同剂量γ射线对Duchenne型肌营养不良鼠 (mdx鼠 )照射 ,研究骨髓干细胞移植后mdx鼠缺失蛋白表达的情况。方法 将 18只 7~ 8周mdx鼠随机平均分为A、B、C 3组 ,依次给予 7Gy、7.5Gy、8Gyγ射线预处理 ;3天后行骨髓干细胞移植。移植骨髓干细胞取自 4~ 5周的C5 7BL/6鼠 ,体外培养 3d ,按 1 2× 10 7个细胞 /每只剂量移植给 3组预处理后的mdx鼠。连续观察受体鼠的移植物抗宿主病 (GVHD)程度 ;移植 12周后 ,检测受体鼠体内抗肌萎缩蛋白表达情况。结果 C组GVHD反应较明显 ;A、B、C 3组的股骨肌肌纤维dystrophin蛋白表达率分别为 8%、9%和 13 %。各组间缺失蛋白表达率有显著差异。结论 对 7~ 8周mdx鼠 ,给予不同剂量的γ射线预处理 ,骨髓干细胞移植后 ,8Gyγ射线表达最多 ,7Gy射线照射表达量最少 ;但 8Gyγ射线照射GVHD反应较明显。  相似文献   

2.
Duchenne肌营养不良模型鼠骨髓移植后dystrophin的表达   总被引:17,自引:1,他引:16  
目的 观察Duchenne型肌营养不良模型鼠 (mdx鼠 )不同成分骨髓细胞移植后dystrophin的表达。方法 用体外培养的C57BL雄鼠的骨髓细胞、骨髓悬浮细胞、骨髓基质细胞分别经鼠尾静脉注射到放疗后的mdx鼠体内 ,动态观察受体雌性mdx鼠骨骼肌dystrophin的表达 ,并取受体mdx雌鼠血 ,用聚合酶链反应进行Sry基因检测。结果 骨髓细胞、悬浮细胞、基质细胞移植后 1~ 2个月 ,较少肌纤维表达dystrophin(<1 % ) ,3~ 4个月分别约有 7%、6 %、4 %的肌纤维表达dystrophin。Sry基因检测均扩增出受体雌鼠Y染色体上 449bp的DNA片段 ,提示供体细胞在受体内存活。结论 骨髓细胞、悬浮细胞、基质细胞分别移植到mdx鼠体内后 ,mdx鼠骨骼肌均有dystrophin的表达  相似文献   

3.
Duchenne 型肌营养不良模型鼠骨髓移植后的行为学观察   总被引:7,自引:0,他引:7  
目的确立Duchenne型肌营养不良模型鼠(mdx鼠)骨髓移植前的有效放疗剂量,观察不同数量、不同成分的骨髓细胞对受体mdx鼠造血功能的重建和保护作用。方法用不同数量的体外培养6~8周C57BL/6雄鼠的骨髓细胞、骨髓基质细胞、骨髓悬浮细胞,经鼠尾静脉注射给不同剂量放疗后的mdx鼠,观察受体鼠的存活率及行为学改变。结果10只mdx鼠移植前3天12Gyγ射线照射,在移植后7天内全部死亡,且注射细胞数较多者,存活时间相对较长,而8Gyγ射线照射的6只mdx鼠,移植后30天5例存活,1例死亡。结论本实验条件下,移植前8Gyγ射线放疗较合理,在有效剂量放疗破坏受体骨髓造血系统后,移植同系鼠的骨髓细胞、基质细胞、悬浮细胞,mdx鼠均能耐受并存活,且以移植细胞数量为1×10  相似文献   

4.
目的观察骨髓移植治疗Duchenne型肌营养不良症(DMD)模型鼠—mdx鼠后,β-dystroglycan和α-sarcoglycan在肌膜上的表达情况。方法以正常C57鼠作为供体,以mdx鼠作为受体进行骨髓移植,在移植后2、4、6个月分别进行mdx鼠骨骼肌的β-dystroglycan和α-sarcoglycan免疫荧光染色,计算阳性细胞的荧光积分光密度,与C57鼠及未移植的mdx鼠进行比较。结果在骨髓移植后2、4、6个月mdx鼠骨骼肌肌膜上β-dystroglycan和α-sarcoglycan的表达量均有随时间的延长逐渐增加的趋势.至移植后6个月时,二者的表达量明显高于未治疗的mdx鼠。结论骨髓移植可使mdx鼠的dystrophin相关蛋白在病损骨骼肌细胞膜上表达增加.其对维持肌膜的稳定性、促进肌肉的恢复有重要意义。  相似文献   

5.
目的研究干细胞在mdx鼠体内较长时间的动态分布以及移植途径对它的影响。方法用3H-TdR掺入标记骨髓基质干细胞,用4×106个/只静脉及腹腔移植放疗mdx鼠各30只,在24h、48h、2周、1个月、2个月、4个月时间点处死小鼠,取血、心、肝、脾、肺、肾、肌、脑、骨髓消化测定放射计数,计算%ID/g值。结果①静脉移植的mdx鼠脑、骨髓在2周才达到它自身的最高水平,心肌、骨骼肌4个月时达到高峰;而每个时间点各器官含量相比早期基本是肺、肝、骨髓分布多,心肌、肌肉2个月后仅次于骨髓。②腹腔移植mdx鼠血、肺、肾、肝、脾脏、脑到达它各自的高峰比静脉注射均有不同时间延迟,早期还是在骨髓、肝、肺分布多,肌肉2个月后仅次于骨髓。③心、肌肉、脑、骨髓含量静脉移植比腹腔移植高,均具有显著的统计学意义(P<0.01)。结论干细胞移植mdx鼠后4个月达高峰,移植途径对干细胞的分布有影响,3H-TdR能长时间动态观察干细胞分布。  相似文献   

6.
目的研究重组腺相关病毒载体(rAAV)介导的人抗肌萎缩蛋白(dystrophin)小基因SMCKA3999对Duchenne肌营养不良(DMD)在病理、肌电图、肌力方面的治疗作用。方法将dystrophin小基因SMCKA3999克隆至rAAV并包装成rAAV SMCKA3999病毒,以5×109病毒颗粒多点注射于DMD模型鼠(mdx鼠)腓肠肌,基因治疗4个月后,以免疫荧光双标法检测肌膜dystrophin基因表达,采用Nicolet肌电及诱发电位仪记录mdx鼠肌电图,基因治疗5个月后以肌肉离体灌注电刺激法测定腓肠肌肌力,观察rAAV SMCKA3999对DMD动物模型鼠的治疗作用。结果rAAVSMCKA3999能有效稳定表达,并使肌膜缺失的dystrophin恢复,明显改善DMD肌电图表现,肌力恢复。结论rAAV SMCKA3999对mdx鼠治疗有效,能显著改善其肌肉功能,应用rAAV介导的dystrophin小基因SMCKA3999基因治疗是临床治疗DMD有希望的方法。  相似文献   

7.
肌营养不良症模型鼠骨骼肌的组织病理学研究   总被引:2,自引:0,他引:2  
目的 比较肌营养不良症模型 (mdx)鼠、C57鼠和Duchenne型肌营养不良症 (DMD)患者骨骼肌的组织病理学改变 ,以及dystrophin在肌细胞膜上的分布。方法 取mdx鼠、C57鼠和DMD患者骨骼肌作常规HE染色 ,比较其组织学改变 ;同时对mdx鼠、C57鼠骨骼肌作dystrophin的免疫组化染色 ,比较dystrophin在肌细胞膜上的分布。结果 mdx鼠骨骼肌肌纤维大小不等 ,轮廓变圆 ,肌间隙增宽 ,少量脂肪、结缔组织增生 ,细胞核中心移位增多 ,部分肌纤维变性坏死 ,而DMD患者骨骼肌的改变和mdx鼠基本一致。mdx鼠肌细胞膜缺乏完整环行棕色条带 ,而C57鼠则呈一完整环行棕色条带 ,提示mdx鼠dystrophin蛋白缺乏。结论 mdx鼠有类似于DMD患者的骨骼肌组织病理学改变  相似文献   

8.
目的利用经杆状病毒基因载体系统进行micro-dystrophin基因修饰后的脂肪干细胞(ADSCs)移植治疗Duchenne型肌营养不良症模型(mdx)鼠,探讨ADSCs移植治疗DMD的安全性及可行性。方法 Mdx鼠60只,分为mdx对照组(30只)和mdx移植组(30只);正常C57小鼠为C57对照组(30只)。体外分离培养小鼠ADSCs,利用杆状病毒基因载体进行micro-dystrophin基因修饰;将基因修饰后的ADSCs经尾静脉移植到mdx鼠体内。于移植后检测mdx鼠的运动功能(采用主动牵引实验和被动转棒实验)、血清CK水平、肌肉病理改变以及肌肉micro-dystrophin表达水平。结果经micro-dystrophin基因修饰的ADSCs移植后,能够重建mdx鼠的micro-dystrophin表达,一定程度上减轻并逆转肌肉的病理损害,进而降低血清CK水平,mdx鼠整体运动功能也有一定改善。结论 ADSCs治疗mdx鼠后,可部分重建模型鼠的dystrophin表达,改善肌肉的病理损害,表明ADSCs是有希望治愈DMD的方法之一。  相似文献   

9.
目的  研究重组腺相关病毒 (rAAV)载体介导的dystrophin小基因SMCKA3999治疗DMD模型鼠mdx ,从病理和功能观察rAAVSMCKA3999治疗对DMD模型小鼠mdx的疗效。方法 以dystrophin小基因SMCK A3999为目的基因 ,将SMCKA3999克隆至rAAV并包装成rAAVSMCKA3999,以 5× 10 10 病毒颗粒单点注射于DMD模型鼠mdx腓肠肌 ,基因治疗后 4个月及 7个月 ,采用免疫荧光、光镜组织病理、肌电图等方法 ,从形态和功能观察rAAVSMCKA3999治疗对DMD模型小鼠mdx的疗效。 结果 rAAVSMCKA3999使肌膜缺失的dys trophin恢复并稳定表达持续 7个月以上 ,肌肉组织病理改变好转 ,肌病肌电图改变明显改善 ,疗效持续 4个月以上。 结论 rAAVSMCKA3999能改善mdx小鼠骨骼肌的病理及功能 ,采用rAAV介导的dystrophin小基因SMC KA3999对Duchenne肌营养不良基因治疗是有希望的治疗方法。  相似文献   

10.
目的探讨自体骨髓间充质干细胞(mMSCs)携带micro-dystrophin基因在移植鼠体内分化为有功能肌细胞的可能性。方法采用脂质体介导micro-dystrophin基因转染mdx小鼠mMSCs,通过尾静脉注射移植治疗mdx鼠,在移植后不同时间点对腓肠肌进行HE染色、计数核中心移位纤维(CNF)比例,并用免疫荧光法检测micro-dystrophin的表达。结果移植后各时间点腓肠肌病理改变较对照组有所改善,CNF比例下降,差异有统计学意义,部分肌细胞膜能表达micro-dystrophin蛋白,并随移植时间延长micro-dystrophin阳性肌纤维比例增加,分别达到3%(8周时)、6%(12周时)和8%(16周时)。结论自体mMSCs可携带外源性micro-dys-trophin基因在受体鼠体内分化为micro-dystrophin阳性肌细胞。  相似文献   

11.
Neuronal migration disorders are the result of disturbed brain development. In such disorders, neurons are abnormally located. In diagnosing these conditions, magnetic resonance imaging is superior to any other imaging technique. This enables us to improve our knowledge of the clinical correlates of neuronal migration. With reference to migrational disorder, a retrospective study of all 303 patients with epileptic seizures referred for magnetic resonance imaging during a 3-year period was performed, 13 patients (aged 12-41, mean age 27) were identified. They represent 4.3% of the entire study group. Of the patients with known epilepsy, 6.7% and of the mentally retarded, 13.7% had migrational disorders. Four patients had schizencephaly as the dominant finding, one was classified as hemimegalencephaly, 2 had isolated heterotopias, and 6 had localized pachy- and/or poly-microgyria. The clinical pictures are complex. Ectopias of grey matter are recognised foci of epilepsy, but from an epileptological and a clinical viewpoint little attention has been given to these disorders. The present study shows that malmigration is not rare in epilepsy patients, especially not in the mentally retarded.  相似文献   

12.
B. J. Wilder 《Epilepsia》1987,28(S2):S1-S7
Summary: The long-standing practice of polypharmacy in treating epilepsy is giving way to use of monotherapy. Monotherapy can improve seizure control as well as reduce the risk of serious idiosyncratic reactions, dose-related side effects, and complex drug interactions. Monotherapy also offers improved compliance and cost-effectiveness. The basis of monotherapy is accurate diagnosis and assessment of the patient's seizure type(s), followed by selection of a single appropriate anticonvulsant drug. Many patients currently treated with multiple anticonvulsants can be successfully converted to monotherapy with a carefully monitored program in which troublesome and redundant drugs are gradually withdrawn from the therapeutic regimen.  相似文献   

13.
Diagnostic Difficulties and Treatment Implications   总被引:1,自引:0,他引:1  
Robert J. Gumnit 《Epilepsia》1987,28(S3):S9-S13
Summary: Differentiation between types of epileptic seizures has been aided in recent years by the introduction of intensive neurodiagnostic techniques and the development of increasingly detailed classification systems. Paradoxically, these developments have not simplified the task of matching the appropriate antiepileptic drug to a particular seizure type. It is reasonable to assume that anticonvulsant drugs will have different effects on different types of seizures, but faulty, circular reasoning can enter the picture if one also assumes that responses of seizures to different drugs signify different seizure types. There are several examples of differential diagnoses that can fall prey to this problem, including the diagnosis between partial seizures with secondary generalization and generalized tonic-clonic seizures, and the diagnosis between complex partial seizures and absence seizures with automatisms, among others. Considerations of etiology in future classification systems can further complicate the problem: should one then choose an anticonvulsant drug on the basis of individual seizure type or on the basis of the type of epilepsy? Ramifications of this issue extend even to the drug approval process. Official sanction is not given for use of a drug for a seizure type not included in the original efficacy studies, even if later scientific evidence shows that seizure type to be related to a type that is included. New trials must be undertaken. These problems arise from how we choose to classify seizures.  相似文献   

14.
Cognitive Dysfunction Associated with Antiepileptic Drug Therapy   总被引:7,自引:5,他引:2  
Eileen P.G. Vining 《Epilepsia》1987,28(S2):S18-S22
Summary: Epilepsy is frequently associated with cognitive dysfunction. However, the reasons for this correlation are unclear. Possible influential factors include patient age; duration, frequency, etiology, and type of seizures; hereditary factors; psychosocial issues; and antiepileptic drug (AED) therapy. Whereas many of these factors are beyond the physician's control, AED therapy is one element that can be addressed in treatment decisions by recognizing the potential cognitive effects of particular AEDs. For example, phenobarbital impairs memory and concentration; phenytoin affects attention, problem solving ability, and performance of visuomotor tasks. In contrast, carbamazepine may affect concentration, while valproate would appear to have minimal effects on cognition. Moreover, cognitive effects of AEDs are amplified with coadministration of multiple anticonvulsants (polytherapy). A review of studies on the cognitive effects of monotherapy with AEDs, as opposed to those of polytherapy, provides evidence that drug-related cognitive dysfunction can be reversed if patients are switched to a simpler therapeutic regimen. Future research should be directed toward developing reliable measures for assessing and monitoring cognition, and understanding the particular cognitive side effects of each AED. Physicians also need to revise their opinions about which side effects are "tolerable" for epileptic patients.  相似文献   

15.
Dextromethorphan: Cellular Effects Reducing Neuronal Hyperactivity   总被引:5,自引:1,他引:4  
G. Trube  R. Netzer 《Epilepsia》1994,35(S5):S62-S67
Summary: Dextromethorphan is a dextrorotary morphinan without affinity for opioid receptors, commonly used as an antitussive medication. During the past 5 years, interest in the compound and its demethylated derivative, dextrorphan, has been revived because additional neuroprotective and an-tiepileptic properties were found in in vitro studies, animal experiments, and a few clinical cases. Both morphinans are able to inhibit N -methyl-D-aspartate (NMDA) receptor channels and voltage-operated calcium and sodium channels with different potencies. The inhibition of the NMDA receptor is believed to be the predominant mechanism of action responsible for the anticonvulsant and neuroprotective properties of the compounds.  相似文献   

16.
Summary: Carbamazepine and phenytoin are drugs of choice in initial monotherapy for adult partial and secondarily generalized tonic-clonic seizures. These designations reflect the results of the Veterans Administration Epilepsy Cooperative Study Group of 1985. An earlier comparative study of carbamazepine and phenytoin by Ramsay and associates found both drugs equally effective in controlling new-onset seizures. Among the advantages of carbamazepine is that it causes relatively few cognitive and dysmorphic side effects. Its disadvantages are its unavailability in parenteral formulation and its metabolic autoinduction. The latter must be compensated for by planned dosage increases to maintain therapeutic plasma steady-state levels during the first 2 or 3 months of treatment. Carbamazepine is judged a drug of choice in the treatment of these secondarily generalized tonic-clonic seizures, and the drug of choice in children, adolescents, and women susceptible to the dysmorphic side effects associated with other anticonvulsant agents.  相似文献   

17.
Summary: Four broad categories of basic phenomena are pertinent to developing ways to prevent epilepsy. These include mechanisms of epileptogenesis, ictal initiation and temporary entrainment by the seizure discharge of normally functioning brain, seizure propagation, and control mechanisms that function both to restrain the cascade of epileptic events culminating in a seizure and to arrest the epileptic event and restore the interictal state. In newborns and children, hypoxia-ischemia is a major factor leading to epileptogenesis, and several schemes are proposed to classify, quantify, and prevent hypoxic-ischemic encephalopathy. Control mechanisms must be better understood in order to develop prophylactic recommendations for epilepsy, and an experimental model of "kindling antagonism" may increase our understanding of these. Programs of prevention of seizures in children will evolve only if basic researchers and clinicians work productively together to develop an adequate understanding of factors important in epileptogenesis and antiepileptogenic control mechanisms.  相似文献   

18.
Hepatic Considerations in the Use of Antiepileptic Drugs   总被引:5,自引:4,他引:1  
Summary: Virtually all of the major antiepileptic drugs (AEDs) can cause hepatotoxicity, although fatal hepatic reactions are rare. The mechanisms, incidences, and risk profiles for such reactions differ from drug to drug. With carbamazepine and phenytoin, hepatotoxicity may be due to drug hypersensitivity. Although the profiles of patients at risk have not been well-defined for these two antiepileptic drugs, it would appear from reports in the literature that older adolescents and adults are at higher risk than children of developing serious or fatal hepatotoxicity. Once hepatotoxicity develops, mortality rates are 10–38% with phenytoin and 25% for carbamazepine. The risk profile for valproate fatal hepatotoxicity has been more clearly defined. Those at primary risk of fatal hepatic dysfunction are children under the age of 2 years who are receiving multiple anticonvulsants and also have significant medical problems in addition to severe epilepsy. The risk is considerably lower for patients over the age of 2 years on valproate monotherapy. In contrast to the risk profile with other AEDs, adults receiving valproate as monotherapy have the lowest risk of hepatotoxicity. Fatal hepatic dysfunction coincident with valproate may be the result of aberrant drug metabolism. Concomitant use of AEDs that induce microsomal P450 enzymes (e.g., phenytoin and phenobarbital) may enhance the production of a toxic metabolite, and hence the greater risk of hepatotoxicity with polypharmacy.  相似文献   

19.
Summary: Vascular malformations (VMs) are associated with epilepsy. The natural history of the various VMs, clinical presentation, and tendency to provoke epilepsy determine treatment strategies. Investigations have probed the mechanisms of epileptogenesis associated with these lesions. Electrophysiologic changes are associated with epileptogenic cortex adjacent to VMs. Putative pathophysiologic mechanisms of epileptogenesis include neuronal cell loss, glial proliferation and abnormal glial physiology, altered neurotransmitter levels, free radical formation, and aberrant second messenger physiology.  相似文献   

20.
Transcranial Electrical Stimulation (tES) encompasses all methods of non-invasive current application to the brain used in research and clinical practice. We present the first comprehensive and technical review, explaining the evolution of tES in both terminology and dosage over the past 100 years of research to present day. Current transcranial Pulsed Current Stimulation (tPCS) approaches such as Cranial Electrotherapy Stimulation (CES) descended from Electrosleep (ES) through Cranial Electro-stimulation Therapy (CET), Transcerebral Electrotherapy (TCET), and NeuroElectric Therapy (NET) while others like Transcutaneous Cranial Electrical Stimulation (TCES) descended from Electroanesthesia (EA) through Limoge, and Interferential Stimulation. Prior to a contemporary resurgence in interest, variations of transcranial Direct Current Stimulation were explored intermittently, including Polarizing current, Galvanic Vestibular Stimulation (GVS), and Transcranial Micropolarization. The development of these approaches alongside Electroconvulsive Therapy (ECT) and pharmacological developments are considered. Both the roots and unique features of contemporary approaches such as transcranial Alternating Current Stimulation (tACS) and transcranial Random Noise Stimulation (tRNS) are discussed. Trends and incremental developments in electrode montage and waveform spanning decades are presented leading to the present day. Commercial devices, seminal conferences, and regulatory decisions are noted. We conclude with six rules on how increasing medical and technological sophistication may now be leveraged for broader success and adoption of tES.  相似文献   

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