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101.
Recombinant adeno-associated virus serotype 2 (rAAV2)-based human gene therapy for cystic fibrosis has progressed through a series of preclinical studies and phase I and II clinical trials. This agent has shown an encouraging safety profile, consistent levels of DNA transfer, and positive evidence of short-term clinical improvement in lung function in a prospective, placebo-controlled phase II trial of aerosol administration. Nonetheless, it has been difficult to assess the relationship between its molecular action and the observed clinical improvements, because of the lack of positive results from a highly specific assay for vector mRNA. This issue is further complicated by the fact that the clinical vector utilizes a small cryptic rAAV2 promoter sequence that is less robust for mRNA expression than typical viral promoters. In this paper, we report the results of more sensitive assays performed on primary nasal cells harvested from rAAV2-CFTR gene therapy recipients. These studies demonstrate a correlation between the presence of rAAV2-CFTR vector genomes, CFTR mRNA expression, and cAMP-activated chloride channel function in these cells. The observation of sizeable physiological correction in the face of low mRNA levels may reflect the regulatory role of low levels of CFTR protein as an activator of other chloride channels. 相似文献
102.
胶原-壳聚糖复合材料的制备及生物安全性检测 总被引:4,自引:2,他引:4
目的:制备胶原-壳聚糖复合细胞载体,并对该载体进行系统的生物学性能检测。方法:实验于2003-07/2006-06在天津市医药科学研究所完成。将胶原溶液和壳聚糖溶液按照一定比例(9∶1)混匀,交联后真空冷冻干燥,制成胶原-壳聚糖复合载体,对该载体进行复合材料性状及理化性能检测。并采用急性全身毒性试验、皮内刺激试验、皮肤致敏试验、溶血试验、细胞毒性试验和致突变试验进行生物学性能检测。结果:①胶原-壳聚糖复合材料具有三维立体多孔结构,适合细胞的三维生长,能为新生组织提供良好的支架。②急性全身毒性试验、皮内刺激试验均阴性,致敏率仅为6.25%,细胞毒性为0级,无诱变能力。结论:从仿生学角度出发,制备出可生物降解的胶原-壳聚糖复合材料,经过系统的生物学评价发现,胶原-壳聚糖复合材料具有良好的生物安全性,对机体无毒,不致突变,对细胞有较强的亲和作用,利于细胞生长和分化。 相似文献
103.
Cross‐sectional and longitudinal multimodal structural imaging in prodromal Huntington's disease
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104.
三种移植物关节镜下重建膝关节前交叉韧带效果比较:2年随访 总被引:2,自引:0,他引:2
目的:采用自体骨-髌韧带、自体双股半腱肌腱半膜肌及同种异体跟腱移植重建膝关节前交叉韧带,比较不同移植物的临床疗效。方法:选择1998-06/2003-02中山大学附属第三医院骨科单纯前交叉韧带损伤后行关节镜下重建手术病例96例,患者均签署知情同意书。根据不同移植物分为3组:①自体骨-髌韧带组38例,应用自体中1/3骨-髌韧带-骨移植物。②自体双股半腱肌腱股薄肌腱组22例,应用自体双股半腱肌腱股薄肌腱。③同种异体跟腱组36例,应用同种异体跟腱。术后定期随访,对膝关节活动度、肌力恢复程度、Werner髌股痛评分(最差为0分,最高为55分)、Lysholm评分(0~100分,分数越高膝关节功能恢复越好)、国际膝关节文献委员会评分(按病情严重程度分类分为正常、接近正常、异常、严重异常4个等级)等进行对比观察。结果:①96例患者随访2年,无脱落。②全部患者无感染,未发生髌骨骨折。也未发现关节内粘连、下肢深静脉血栓形成和血管神经损伤等并发症。③膝关节活动度、肌力恢复情况、髌股痛评分:随访结束时3组差异均无显著性意义(P>0.05)。④Lysholm膝关节评分:随访结束时自体骨-髌韧带组由术前(68.2±6.3)分提高至(88.6±6.8)分,自体双股半腱肌腱股薄肌腱组由术前(66.5±6.5)分提高至(86.4±6.6)分,同种异体跟腱组由术前(68.2±6.3)分提高至(86.3±6.2)分,随访结束时各组评分均显著高于术前(P<0.05),3组比较差异无显著性意义(P>0.05)。⑤国际膝关节文献委员会评分(术后活动水平正常或接近正常):随访结束时自体骨-髌韧带组为87%,自体双股半腱肌腱股薄肌腱组为86%,同种异体跟腱组为89%,各组移植术后膝关节功能均有所改善,3组间差异无显著性意义(P>0.05)。结论:关节镜下采用自体骨-髌韧带、自体双股半腱肌腱股薄肌腱和同种异体跟腱移植重建前交叉韧带,均能明显改善膝关节运动功能,3种移植方法的临床疗效无明显差异,提示重建前交叉韧带的术后疗效与移植物种类的相关性不明显。 相似文献
105.
目的:观察咬合垂直距离改变对无牙颌颞下颌关节紊乱病患者两侧颞颌关节髁状突位置的影响。方法:于1994-01/1997-12选择本院口腔修复门诊收治的无牙颌患者中符合颞下颌关节紊乱病诊断标准,同时垂直距离减低的患者48例。实验方案经医院伦理委员会审批,患者均知情同意。将48例无牙颌颞下颌关节紊乱病患者根据垂直距离减低程度的不同分为3组:减低1.8~6.0mm组18例,减低6.1~10.0mm组20例,减低10.1 ̄14.0mm组10例。通过重新制作一副全口义齿的方法治疗,咬合垂直距离恢复在合适的范围内,3组全口义齿的咬合垂直距离恢复前分别平均为63.4,60.6,54.2mm,恢复后咬合垂直距离分别平均为67.8,68.4,66.4mm,平均抬高4.4,7.8,12.2mm。通过拍摄正中颌位时颞下颌关节薛氏位X射线片测量各组前、后、上关节间隙。结果:垂直距离恢复前,减低1.8~6.0mm组关节后间隙,减低6.1~10.0mm组关节前、后间隙、减低10.1 ̄14.0mm组关节上、后间隙左右侧相比较,差异有显著性意义(P<0.05)。垂直距离恢复后,3组关节间隙左右侧差异无显著性意义。结论:无牙颌咬合垂直距离减低后可以导致两侧髁状突位置发生不对称改变。 相似文献
106.
Saadia A. Karim Jennifer A. Barrie Mailis C. Mcculloch Paul Montague Julia M. Edgar Debrah L. Iden Thomas J. Anderson Klaus‐Armin Nave Ian R. Griffiths Mark McLaughlin 《Glia》2010,58(14):1727-1738
The most common cause of Pelizaeus‐Merzbacher (PMD) is due to duplication of the PLP1 gene but it is unclear how increased gene dosage affects PLP turnover and causes dysmyelination. We have studied the dynamics of PLP/DM20 in a transgenic mouse model of PMD with increased gene dosage of the proteolipid protein gene (Plp1). The turnover of PLP/DM20 were investigated using an ex‐vivo brain slice system and cultured oligodendrocytes. Homozygous mice have reduced PLP translation, markedly enhanced PLP degradation, and markedly reduced incorporation of PLP into myelin. Proteasome inhibition (MG132) prevented the enhanced degradation. Numerous autophagic vesicles are present in homozygous transgenic mice that may influence protein dynamics. Surprisingly, promoting autophagy with rapamycin decreases the degradation of nascent PLP suggesting autophagic vacuoles serve as a cellular storage compartment. We suggest that there are multiple subcellular fates of PLP/DM20 when overexpressed: the vast majority being degraded by the proteasome, a proportion sequestered into autophagic vacuoles, probably fused with endolysosomes, and only a small proportion entering the myelin sheath, where its association with lipid rafts is perturbed. Transgenic oligodendrocytes have fewer membrane sheets and this phenotype is improved with siRNA‐mediated knockdown of PLP expression that promotes the formation of MBP+ myelin‐like sheets. This finding suggests that RNAi technology is in principle applicable to improve CNS myelination when compromised by PLP/DM20 overexpression. © 2010 Wiley‐Liss, Inc. 相似文献
107.
108.
Karim SA Barrie JA McCulloch MC Montague P Edgar JM Kirkham D Anderson TJ Nave KA Griffiths IR McLaughlin M 《Glia》2007,55(4):341-351
Duplication of PLP1, an X‐linked gene encoding the major myelin membrane protein of the human CNS, is the most frequent cause of Pelizaeus‐Merzbacher disease (PMD). Transgenic mice with extra copies of the wild type Plp1 gene, a valid model of PMD, also develop a dysmyelinating phenotype dependant on gene dosage. In this study we have examined the effect of increasing Plp1 gene dosage on levels of PLP/DM20 and on other representative myelin proteins. In cultured oligodendrocytes and early myelinating oligodendrocytes in vivo, increased gene dosage leads to elevated levels of PLP/DM20 in the cell body. During myelination, small increases in Plp1 gene dosage (mice hemizygous for the transgene) elevate the level of PLP/DM20 in oligodendrocyte soma but cause only minimal and transient effects on the protein composition and structure of myelin suggesting that cells can regulate the incorporation of proteins into myelin. However, larger increases in dosage (mice homozygous for the transgene) are not well tolerated, leading to hypomyelination and alteration in the cellular distribution of PLP/DM20. A disproportionate amount of PLP/DM20 is retained in the cell soma, probably in autophagic vacuoles and lysosomes whereas the level in myelin is reduced. Increased Plp1 gene dosage affects other myelin proteins, particularly MBP, which is transitorily reduced in hemizygous mice but consistently and markedly lower in homozygotes in both myelin and naïve or early myelinating oligodendrocytes. Whether the reduced MBP is implicated in the pathogenesis of dysmyelination is yet to be established. © 2006 Wiley‐Liss, Inc. 相似文献
109.
Barrie J. Hurwitz 《Annals of Indian Academy of Neurology》2009,12(4):226-230
The diagnosis of multiple sclerosis (MS) requires objective findings referable to the central nervous system. A wide differential diagnosis often has to be considered. Magnetic resonance imaging and electrophysiologic and cerebrospinal fluid studies can all contribute to an early definitive diagnosis. The McDonald diagnostic criteria for MS (2005) are the currently recognized MS diagnostic criteria. The clinical subtypes of MS and their diagnosis are discussed in this article. Being informed of the diagnosis may be a stressful experience for the patient and this is also dealt with. 相似文献
110.
PW Czoty NV Riddick HD Gage M Sandridge SH Nader S Garg M Bounds PK Garg MA Nader 《Neuropsychopharmacology》2009,34(3):548-554
Sex differences have been reported in a variety of affective and neurodegenerative disorders that involve dysfunctional dopamine (DA) neurotransmission. In addition, there is evidence for differences in sensitivity to the abuse-related effects of psychostimulants across the menstrual cycle which may result from effects of ovarian hormones on DA function. The goal of the present study was to extend previous work examining menstrual cycle-related changes in DA D2 receptor availability in humans to drug-naive female cynomolgus monkeys (n=7) using the selective D2-like receptor ligand [(18)F]fluoroclebopride (FCP) and a high-resolution microPET P4 scanner. Menstrual cycle phase was characterized by daily vaginal swabs and measurements of serum progesterone levels. PET studies were conducted once during the luteal phase and once during the follicular phase. Regions of interest in the caudate nucleus, putamen, and cerebellum were defined on coregistered MRIs. Distribution volumes were calculated for FCP in each structure and the distribution volume ratio (DVR) for both brain regions relative to the cerebellum was used as a measure of D2 receptor availability. FCP DVRs were significantly higher in the luteal phase compared to the follicular phase in both the caudate nucleus (11.7% difference, p=0.02) and putamen (11.6% difference, p=0.03). These findings extend earlier work in humans and suggest that changes in DA receptor availability may be involved in the variation in symptoms of various neuropsychiatric disorders across the menstrual cycle, including differences in sensitivity to the abuse-related effects of stimulants. 相似文献