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1.
目的 使用磁共振扩散张量成像技术(DTI)研究视网膜色素变性(RP)患者的视神经改变及其与视野检查的相关性。方法 46例RP患者(RP组)和46例健康对照志愿者(对照组)进行了前瞻性研究。所有受试者进行3.0T MRI-DTI扫描检测,使用简化的小视野扩散张量成像(rFOV-DTI)序列推导出单个视神经的各向异性(FA)、平均弥散系数 (MD)、平行扩散系数(λ//)、垂直扩散系数(λ⊥),获得平均分数FA、平均扩散率和特征值图,用于定量分析。进一步分析视野平均偏差(MDVF)与患者的分数FA、平均扩散率、λ//及λ⊥的相关性。结果 RP组与对照组受试者间年龄和体质量等差异均无统计学意义(均为P>0.05),而两组之间最佳矫正视力和MDVF差异均具有统计学意义(均为P=0.000)。与对照组相比,RP组患者视神经FA降低,MD、λ//、λ⊥升高,两组之间差异有统计学意义(P<0.001)。RP组患者两侧视神经的FA、MD、λ//和λ⊥与MDVF行相关性分析,视神经FA及λ⊥与MDVF有显著相关性(右侧:r=-0.864、0.719,均为P<0.001;左侧:r=-0 .997、r=0.830,均为P<0.001);MD与MDVF不相关(右侧:r=-0.026,P=0.866;左侧:r=-0.115,P=0.445)。结论 rFOV-DTI测量值可用于RP患者视神经轴突和髓鞘病变的早期诊断。  相似文献   
2.
Because retinitis pigmentosa (RP) has been shown to cause degenerative changes in the entire visual pathway, there is an urgent need to perform longitudinal assessments of RP-induced degeneration and identify imaging protocols to detect this degeneration as early as possible. In this study, we assessed a transgenic rat model of RP by using complementary noninvasive magnetic resonance imaging techniques, namely, proton magnetic resonance spectroscopy (1H-MRS), to investigate the metabolic changes in RP. Our study demonstrated decreased concentrations and ratios to creatine (Cr) of N-acetylaspartate (NAA), glutamate (Glu), γ-aminobutyric acid (GABA), and taurine (Tau), whereas myo-inositol (Ins) and choline (Cho) were increased in the visual cortex of Royal College of Surgeons (RCS) rats compared with control rats (p < 0.05). Furthermore, with the progression of RP, the concentrations of NAA, Glu, GABA, and Tau, and the ratios of GABA/Cr and Tau/Cr significantly decreased over time, whereas the concentrations of Ins and Cho and the ratio of Ins/Cr significantly increased over time (p < 0.05). In addition, in RCS rats, NAA/Cr decreased significantly from 3 to 4 months postnatal (p < 0.001), and Cho/Cr increased significantly from 4 to 5 months postnatal (p = 0.005). Meanwhile, the 1H-MRS indicators in 5-month postnatal RCS rats could be confirmed by immunohistochemical staining. In conclusion, with the progression of RP, the metabolic alterations in the visual cortex indicated progressive reprogramming with the decrease of neurons and axons, accompanied by the proliferation of gliocytes.  相似文献   
3.
视网膜色素变性(retinitis pigmentosa,RP)的治疗目前仍处于探索阶段。胶质细胞源性神经营养因子(glial cell line-derived neurotrophic factor,GDNF)是目前研究中重要的神经营养因子,但其传统给药方式生物利用度相对较低。近年来GDNF安全有效的给药方式成为研究热点,包括经病毒载体或非病毒载体的基因工程法释药技术、经聚合物释放系统释药技术、经细胞移植释药技术、小分子触发器诱导产生GDNF等。本文就GDNF干预RP的给药方式进行综述。  相似文献   
4.
ABSTRACT

Background: Gene editing has shown huge potential in correcting aberrant splicing and Cas13 has been identified as being particularly suitable for targeting RNA. It has therefore become increasingly important to highlight new splice site mutations that may be correctable, particularly in genes that are too large to be encoded by AAV vectors. About 20% of Usher Type 1 cases are caused by mutations in CDH23.

Purpose: To report a novel splice site mutation of CDH23 associated with Usher Type 1D.

Materials and Methods: Case report.

Results: A 35-year-old Caucasian female who is congenitally deaf with vestibular dysfunction presented with visual acuity of 6/12 in both eyes. Fundus examination revealed findings typical of retinitis pigmentosa with foveal preservation of photoreceptor layer. Next generation sequencing analysis revealed a novel homozygous variant, c.9319 + 1G>T in CDH23 consistent with the diagnosis of Usher Syndrome Type 1D. The c.9319 + 1G>T variant is predicted to affect splicing at the exon 65/intron 65 boundary, which highly likely leads to complete skipping of exon 65.

Conclusions: We describe a case of a typical Usher Syndrome Type 1D caused by a novel splice site variant in CDH23. Currently there are no treatments for CDH23 related retinal degeneration, partly because the cDNA size of 10kb is too large for AAV vector gene augmentation therapy. Alternative strategies include CRISPR-Cas9 adenine base editors and RNA editing with CRISPR-Cas13. Single-nucleotide editing represents a promising approach for targeting this variant in CDH23 to restore the wildtype splice donor site at this position.  相似文献   
5.
目的 分析原发性视网膜色素变性(retinitis pigmentosa,RP)患者并发白内障行超声乳化联合人工晶状体植入术后视力的影响因素并探讨频域光学相干断层扫描(spectral domain optical coherence tomography,SD-OCT)在评估视力预后中的作用。方法 回顾性系列病例研究。收集RP并发白内障患者38例(58眼),均行白内障手术治疗。根据SD-OCT下黄斑区椭圆体带的形态将患者分为3组,A组:黄斑区椭圆体带缺失(19眼),B组:黄斑区椭圆体带可见但不连续(18眼),C组:黄斑区椭圆体带完整(21眼)。比较所有患者手术前后最佳矫正视力(best corrected visual acuity,BCVA)、组内手术前后BCVA和组间手术前后BCVA;利用Pearson相关分析,分析SD-OCT检测指标的临床意义;并进一步对术后BCVA与黄斑中心凹厚度之间关系进行分析。结果 逐步回归分析结果表明,术前BCVA和黄斑区椭圆体带长度是影响术后视力的主要因素。手术前后BCVA之间、术后BCVA与黄斑区椭圆体带长度之间均呈直线相关(r=0.855、-0.622,均为P<0.01)。A组、B组和C组术前BCVA分别为(2.41±1.05)logMAR、(1.17±0.64)logMAR和(0.83±0.59)logMAR,术后第1天BCVA分别为(1.16±0.90)logMAR、(0.52±0.27)logMAR和(0.21±0.19)logMAR。各组患眼术后第1天BCVA均好于其术前视力(t=5.246、4.632、6.198,均为P<0.01)。3组患眼术后第1天BCVA比较,差异有统计学意义(F=32.760,P<0.01)。A组、B组和C组黄斑区椭圆体带长度分别为(0.00±0.00)mm、(1.16±0.57)mm和(4.04±1.26)mm,黄斑中心凹厚度分别为(100.84±45.49)μm、(203.44±33.33)μm和(248.19±37.79)μm。术后BCVA与黄斑中心凹厚度之间呈直线正相关(r=-0.754,P<0.01)。结论 白内障超声乳化吸出联合人工晶状体植入术治疗RP并发白内障可有效改善视功能。术前视力差、黄斑区椭圆体带结构的破坏以及黄斑中心凹厚度变薄是患者手术后视力不良的指征,SD-OCT对评估视力预后具有一定临床意义。  相似文献   
6.
Inherited retinal dystrophies are a group of monogenic disorders that, as a whole, contribute significantly to the burden of ocular disease in both pediatric and adult patients. In their syndromic forms, retinal dystrophies can be observed in association with intellectual disability, frequently alongside other systemic manifestations. There are now over 80 genes implicated in syndromic retinal dystrophies with intellectual disability. Identifying and accurately characterizing these disorders allows the clinician to narrow the differential diagnosis, evaluate for relevant associated features, arrive at a timely and accurate diagnosis, and address both sight‐threatening ocular manifestations and morbidity‐causing systemic manifestations. The co‐occurrence of retinal dystrophy and intellectual disability in an individual can be challenging to investigate, diagnose, and counsel given the considerable phenotypic and genotypic heterogeneity that exists within this broad group of disorders. We performed a review of the current literature and propose an algorithm to facilitate the evaluation, and clinical and mechanistic classification, of these individuals.  相似文献   
7.
视网膜色素变性(retinitis pigmentosa,RP)是一类由视杆细胞首先受累为主的进行性遗传性视网膜变性疾病。初期以视杆细胞功能异常为主,同时或随后可合并视锥细胞功能异常。随着疾病的进展,视功能进行性受损,直至全盲,眼底出现以色素异常为主的多种形态的视网膜变性改变。RP具有高度的遗传异质性和表型多样性。已发现的致病基因有90个。本指南从RP的病因与发病机制、疾病诊断、临床咨询等方面进行总结,旨在规范其临床诊疗,供临床医师参考。  相似文献   
8.
目的:研究不同血清型腺相关病毒 (adeno-associated virus,AAV) 载体介导的外源基因在视网膜中的表达效率, 同时比较AAV载体和两种眼科常用启动子组合后转染小鼠视网膜的表达效率高低,为视网膜色素变性基因治疗选择合适的AAV载体与启动子提供依据。方法:AAV病毒根据衣壳蛋白不同可分为不同血清型,本课题选取视网膜疾病基因治疗中常用的AAV2/2、AAV2/5、AAV2/8和AAV2/9四种血清型AAV载体,并以绿色荧光蛋白 (green fluorescent protein, GFP) 作为报告基因,用GFP的表达强度判断AAV载体介导的外源基因在视网膜中的表达效率。AAV载体纯化后滴度为1.00×10 13 mg/L,注射1 μL至C57BL/6J小鼠视网膜下腔, 于2周取眼球做成冰冻切片,在共聚焦显微镜下观察 GFP在小鼠视网膜各层的表达情况。选取在感光细胞内特异性表达最强的AAV2/8于第4周取眼球冰冻切片继续观察是否能持续稳定表达。随后选取眼科基因治疗最常用的广谱启动子CMV和由CMV增强子与鸡β-肌动蛋白启动子组成的CAG启动子,并构建AAV2/8-GFP-CMV和AAV2/8-GFP-CAG两种不同启动子的病毒载体注射至视网膜下腔,于2周取眼球做成冰冻切片,在共聚焦显微镜下观察不同启动子的AAV2/8在小鼠视网膜各层的表达情况。结果: 注射AAV-GFP后未见典型的术后细菌感染及明显免疫反应。AAV2/2、AAV2/5、AAV2/8和AAV2/9四种血清型AAV载体视网膜下腔注射2周后,AAV2/8和AAV2/9在小鼠视网膜的GFP绿色荧光明显,说明这两种AAV载体转染小鼠视网膜后的表达效率高,而在这两种血清型中,AAV2/8的GFP绿色荧光主要集中在感光细胞内,AAV2/9 在视网膜全层均有表达,说明AAV2/8对视网膜感光细胞特异性更强。对AAV2/8的进一步实验表明在视网膜下腔注射4周后小鼠视网膜的GFP绿色荧光明显,说明AAV2/8载体介导的外源基因能在体内稳定表达。使用CMV启动子时GFP在感光细胞与视网膜色素上皮细胞均有表达,而使用CAG启动子时GFP主要在感光细胞表达。结论:视网膜下腔注射AAV病毒载体可在视网膜细胞内稳定表达报告基因;AAV2/2、AAV2/5、AAV2/8和AAV2/9四种血清型AAV载体中,AAV2/8和AAV2/9在视网膜表达能力最强,AAV2/8对视网膜感光细胞特异性最好;CMV和CAG两种启动子,CAG启动子对感光细胞特异性更高。  相似文献   
9.
ABSTRACT

Background: Retinitis pigmentosa (RP) is a heterogeneous group of ocular dystrophy. It is challenging to identify the underlying genetic defect in individuals with RP due to huge genetic heterogeneity. This study was designed to delineate the genetic defect(s) underlying RP in extended Saudi families and to describe the possible disease mechanism.

Materials and Methods: Fundus photography and a high definition optical coherence tomography (HD-OCT) were performed in order to detect the earlier stages of macular degeneration. Genomic DNA was extracted followed by genome-wide SNP genotyping and whole exome sequencing (WES). Exome data was filtered to identify the genetic variant(s) of interest.

Results: Clinical examination showed that affected individuals manifest key features of RP. The fundus exam shows pale optic disc and bone spicules at the periphery. OCT shows macular degeneration as early as at the age of 4 years. Whole genome scan by SNPs identified multiple homozygous regions. WES identified a 10 bps novel insertion mutation (c.3544_3545insAGAAAAGCTG; p.Ala1182fs) in the RP1 gene in both affected individuals of family A. Affected individual from family B showed a large insertion of 48 nucleotides in the coding part of the RP1L1 gene (c.3955_3956insGGACTAAAGTAATAGAAGGGCTGCAAGAAGAGAGGGTGCAGTTAGAGG; p.Ala1319fs). Sanger sequencing validates the autosomal recessive inheritance of the mutations.

Conclusion: The results strongly suggest that the insertion mutations in the RP1 and RP1L1 genes are responsible for the retinal phenotype in affected individuals from two families. Heterozygous individuals are asymptomatic carriers. We propose that the protective allele in other homozygous regions in heterozygous carriers contribute to the phenotypic variability in asymptomatic individuals.  相似文献   
10.
Cytomegalovirus (CMV) retinitis in hematologic malignancies in the absence of hematopoietic cell transplant (HCT) is uncommon. We report a case of a 54‐year‐old woman with peripheral T‐cell lymphoma who develops CMV retinitis and subsequently undergoes an autologous HCT, with eventual development of immune reconstitution uveitis. We further reviewed the PubMed literature on CMV retinitis in patients with lymphoma. We describe that CMV retinitis in patients with lymphoma has variable clinical presentations, may occur at any time during the course of the disease and chemotherapy, and is associated with significant morbidity.  相似文献   
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