雷珠单抗治疗湿性年龄相关性黄斑变性的疗效观察及其对患者血浆miRNA-126、VEGF-A表达的影响

目的 探讨玻璃体腔注射雷珠单抗治疗湿性年龄相关性黄斑变性(wAMD)的临床疗效,及其对患者血浆中微小RNA(miRNA)-126、血管内皮生长因子(VEGF)-A的表达水平的影响。方法 前瞻性研究。纳入2018年6月-2019年6月蚌埠医学院第一附属医院眼科收治40例(40只眼)wAMD患者为wAMD组,其中男17例、女23例,年龄50~86岁。纳入同期在蚌埠医学院第一附属医院体检中心进行健康体检的中老年人为对照组(40人),其中男18人、女22人,年龄53~81岁。wAMD组患者均接受单次玻璃体腔注射雷珠单抗0.05 mL治疗。采用实时荧光定量PCR(qPCR)法检测对照组和wAMD组治疗前及治疗后1个月血浆miRNA-126相对表达水平,酶联免疫吸附试验检测血浆中VEGF-A水平。(1)比较对照组、wAMD组治疗前miRNA-126及VEGF-A的表达水平。(2)比较wAMD组治疗前、治疗后1个月血浆miRNA-126、VEGF-A表达水平,以及最佳矫正视力(BCVA)、黄斑中央区视网膜厚度(CMT)、脉络膜新生血管(CNV)面积的变化情况。(3)分析wAMD组患者治疗前、治疗后1个月血浆miRNA-126的相对表达量与VEGF-A水平、CMT、CNV面积的相关性。结果 (1)wAMD组患者的miRNA-126相对表达量(0.86±0.11)低于对照组(1.04±0.10),VEGF-A水平(329.09±17.58)pg/mL高于对照组(295.74±14.80)pg/mL,差异均有统计学意义(t=8.010、9.179,P值均＜0.01)。(2)wAMD组治疗后1个月miRNA-126相对表达量(1.47±0.27)较治疗前(0.86±0.11)增加,VEGF-A水平(315.36±15.44)pg/mL较治疗前(329.09±17.58)pg/mL降低,差异均有统计学意义(t=19.410、8.048,P值均＜0.01);BCVA(0.45±0.11)较治疗前(0.83±0.16)增加,CMT与CNV面积分别为(296.53±21.52)μm,(0.58±0.18)mm²,较治疗前的(311.88±37.25)μm、(0.70±0.17)mm²均降低,差异均有统计学意义(t=12.667、3.602、4.906,P值均＜0.01)。(3)wAMD组患者治疗前及治疗后1个月血浆miRNA-126相对表达水平与VEGF-A、CMT、CNV面积均呈显著负相关(r_治疗前=-0.706、-0.723、-0.552,r_{治疗后1个月}=-0.783、-0.709、-0.620, P值均＜0.01)。治疗前拟合VEGF-A、CMT、CNV面积与miRNA-126相对表达量之间的线性回归方程分别为:$\hat{Y}$_VEGF-A=-112X_miRNA-126+426,$\hat{Y}$_CMT=-243X_miRNA-126+522,$\hat{Y}$_CNV=-0.84X_miRNA-126+1.42;治疗后线性回归方程分别为:$\hat{Y}$_VEGF-A=-45.64X_miRNA-126+382,$\hat{Y}$_CMT=-57.53X_miRNA-126+381,$\hat{Y}$_CNV=-0.41X_miRNA-126+1.18。结论 雷珠单抗可通过降低VEGF-A的表达,减少CMT及CNV面积,有效改善BCVA。雷珠单抗在取得临床疗效的同时,可能通过增强miRNA-126基因表达活性而延缓wAMD的进展。     

年龄相关性黄斑变性与单核甘酸多态性相关性的研究进展

年龄相关性黄斑变性(AMD)是发达国家老年人致盲的首要疾病.遗传因素在AMD的发生、发展中起重要作用.近几年研究发现,一些单核甘酸多态性(SNP)与AMD的发病明显相关.因而对补体因子H(CFH)基因,补体因子B(CFB)基因,补体因子2(C2)基因,补体因子3(C3)基因,CX3C趋化因子受体1(CX3CR1)基因,三磷酸腺苷结合盒转运体基因亚家族A第4成员(ABCA4)在AMD形成过程中的研究具有重要意义.     

年龄相关性黄斑变性的分子遗传流行病学研究进展

年龄相关性黄斑变性是发达国家老年人致盲的主要原因,它是一种具有高度遗传异质性的疾病.随着分子生物学和分子遗传学的发展,已经发现多个潜在的致病基因.现就年龄相关性黄斑变性的易感基因和遗传流行病学的研究进展进行综述.     

玻璃体腔注射雷珠单抗辅助治疗黄斑水肿的临床观察

目的:研究玻璃体腔注射雷珠单抗辅助治疗黄斑水肿的临床效果.方法:回顾分析2018年1月至2021年1月于我院治疗的80例ME患者病例资料,将所有患者随机分为对照组和观察组,各40例.对照组采用常规的激光光凝治疗,观察组在术前7d玻璃体腔注射雷珠单抗液辅助常规的激光光凝治疗.比较两组患者治疗的不良反应和治疗总有效率;比较两组患者不同治疗阶段的眼压、黄斑中心凹厚度(Macular thickness,MT)、黄斑中心视网膜厚度(Central Macular Thickness,CMT)以及最佳矫正视力(Best Corrected Visual Acuity,BCVA).比较两组患者治疗前、治疗90d后的光感受器内外节交界完整性、患者生活质量、和心理状况评分.结果:治疗后各组不同治疗时间段的MT、CMT均明显降低,BCVA均明显增加(P<0.05),其中观察组MT、CMT更低,BCVA更高(P<0.05).治疗总有效率、光感受器内外节交界完整性、生活质量观察组更高(P<0.05),心理状况评分均观察组更低(P<0.05).两组眼压变化、不良反应发生率无明显差异(P>0.05).结论:激光治疗黄斑水肿前对患者玻璃体腔注射雷珠单抗可有效提高治疗效果,安全性高.     

七个全基因组关联分析提示的易感位点与汉族人群年龄相关性黄斑变性的相关性分析

目的验证全基因组关联分析所发现的7个单核苷酸多态性(single nucleotide polymorphisms, SNPs), 包括rs13278062(TNFRSF10A)、rs3750846(ARMS2-HTRA1)、rs429358(APOE)、rs5817082(CEPT)、rs2043085(LIPC)、rs1626340(TGFBR1)以及rs8135665(SLC16A8)与四川汉族人群年龄相关性黄斑变性(age-related macular degeneration, AMD)的相关性。方法采用病例-对照研究, 用飞行质谱对576例湿性AMD患者和572例健康对照进行SNPs分型并通过Sanger测序进行验证。在两组各SNP位点基因型分布均满足Hardy-Weinberg平衡的前提下, 分析各位点的遗传模式, 并比较其等位基因与基因型频率的分布。结果 TNFRSF10A rs13278062在杂合子模型(P=0.000, OR=1.529, 95%CI=1.196-1.954)和显性模型(P=0.002, OR=1.459, 95%CI=1.154-1.865)下...     

玻璃体腔连续注射康柏西普治疗湿性年龄相关性黄斑变性短期疗效观察

目的 观察玻璃体腔连续注射新型抗血管内皮生长因子(VEGF)药物康柏西普治疗湿性年龄相关性黄斑变性(wAMD)的短期疗效。方法 前瞻性纳入2015年2月—2017年9月蚌埠医学院第一附属医院眼科38例(47只眼)wAMD患者,每月予以玻璃体腔注射康柏西普0.05 mL 1次,连续3个月,于首次注射前及注射后1、2、3个月,检查术眼最佳矫正视力(BCVA)、黄斑中心凹视网膜厚度(CFT)、黄斑容积(CV)。结果 患者注射前基线视力为1.07±0.51,注射后3个月视力为0.84±0.53,较注射前明显提高(P＜0.05)。患者注射前基线CFT为(298.15±53.76) μm,注射后3个月CFT为(258.62±37.25) μm,较注射前明显降低(P＜0.05)。患者注射前基线CV为(8.43±1.51) mm³,注射后3个月CV为(7.39±0.92) mm³,较注射前明显减小(P＜0.05),注射后出现轻微异物感7只眼、结膜下出血5只眼,均自愈;无一例发生感染、白内障及视网膜剥脱等严重并发症。结论 玻璃体腔内注射新型抗VEGF药物康柏西普治疗wAMD,可短期内快速提高患者视力,减轻视网膜水肿,使黄斑区结构恢复,且安全性高,无严重并发症发生。     

Proteomic Profiling of Aqueous Humor Exosomes from Age-related Macular Degeneration Patients

Purpose: The alteration of the exosomal proteins in the aqueous humor (AH) is linked to the development of eye diseases. The goal of this study was to examine the exosomal protein profile of patients with age-related macular degeneration (AMD) to better understand their role in the pathogenesis of AMD.Methods: Exosomes were isolated from the AH of 28 AMD and 25 control eyes. The quality, concentration, and size distribution of exosomes were measured using a nanoparticle tracking analysis system (NTA). Total exosomal proteins from each sample were purified and digested with trypsin for liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis.Results: Based on LC-MS/MS analysis, we got 105 exosomal peptides from AMD and control patients. Gene ontology (GO) analysis in the biology process revealed that exosomal proteins of AMD were enriched in the lipoprotein metabolic process. T-test analysis revealed six exosomal proteins in patients with AMD were significantly different from controls. Comparing the exosomal protein profile of AMD patients who were receiving anti-VEGF therapy, we observed the amount of two proteins decreased with the duration of the anti-VEGF treatment time.Conclusions: In this study, we successfully isolated and purified AH exosomes. Our results provide pioneering findings for the exosomal protein profile in AMD development and under therapy. These unique proteins could be the new targets for drug discovery or biological markers for evaluating therapeutic efficacy.     

Chemokine Receptor Profiles of T Cells in Patients with Age-Related Macular Degeneration

PurposeTo evaluate the expression of multiple chemokine receptors in peripheral blood T cells from patients with age-related macular degeneration (AMD).Materials and MethodsPeripheral blood mononuclear cells and/or aqueous humor were obtained from 24 AMD patients and 24 age- and sex-matched healthy controls. Chemokine receptor expression on T cells from peripheral blood was determined by multicolor flow cytometry. The levels of chemokines and cytokines in the aqueous humor from 12 AMD patients and six healthy controls were assessed.ResultsAMD patients had increased expressions of CCR4 in CD4⁺ T cells (p=0.007) and CRTh2 in CD8⁺ T cells (p=0.002), and decreased expressions of CXCR3 in CD4⁺ T cells (p=0.029) and CXCR3, CCR5, and CX₃CR1 in CD8⁺ T cells (p=0.005, 0.019, and 0.007, respectively). Monocyte chemoattractant protein-1 levels were increased in the aqueous humor from AMD patients (p=0.018), while the levels of interleukin (IL)-4 and IL-22 were significantly decreased compared to controls (p=0.018 and 0.041, respectively).ConclusionThe chemokine receptor profiles of T cells are altered in AMD patients compared to healthy controls without noticeable associations with chemokine levels in the aqueous humor. Further evaluation is needed to clarify the role of these alterations in AMD pathogenesis.     

Clinical and Morphological Characteristics of Chorioretinal Degeneration in Early Aging OXYS Rats

OXYS rats are characterized by early development of cataract and chorioretinal degeneration with clinical manifestations similar to those observed in senile cataract and ageassociated macular degeneration in humans. According to fundoscopy findings, the incidence of chorioretinal degeneration sharply increases in OXYS rats by the age of 4.5 months, when all animals develop signs of fundus oculi pathology. Morphological analysis of semithin sections of the posterior wall of the eye in OXYS rats aged 5 months showed that choroid vessels, pigmented epithelium, and radial glia were most vulnerable to injury. Retinal hypoxia and destruction of the pigmented epithelium associated with circulatory disorders in the choroid vessels presumably lead to injuries of the neurosensory cells (mainly the external segments) and a 3.5-fold increase in the percent of photoreceptors with nuclear pyknosis in comparison with the control. These results indicate that OXYS rats represent an adequate model of age-associated macular degeneration and can be used for studies of the pathogenesis of this condition and development of methods for its treatment and prevention. Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 146, No. 10, pp. 435-438, October, 2008     

Analysis of Single Nucleotide Polymorphisms in the NOS2A Gene and Interaction with Smoking in Age‐Related Macular Degeneration

Age‐related macular degeneration (AMD) is a complex degenerative retinal disease influenced by both genetic and environmental risk factors. We assessed whether single nucleotide polymorphisms (SNPs) in the NOS2A gene increase risk and modulate the effect of smoking in AMD. 998 Caucasian subjects (712 AMD cases and 286 controls) were genotyped for 17 SNPs in NOS2A. Multivariable logistic regression models containing SNP genotypes, age, sex, smoking status and genotype/smoking interaction were constructed. SNP rs8072199 was significantly associated with AMD (OR = 1.3; 95% CI : 1.02, 1.65; P= 0.035). A significant interaction with smoking was detected at rs2248814 (P= 0.037). Stratified data by genotypes demonstrated that the association between AMD and smoking was stronger in carriers of AA genotypes (OR = 35.98; 95% CI: 3.19, 405.98) than in carriers of the AG genotype (OR = 3.05; 95% CI: 1.36, 6.74) or GG genotype (OR = 2.1; 95% CI: 0.91, 4.84). The results suggest a possible synergistic interaction of AA genotype with smoking, although the result bears replication in larger samples. Our data suggests that SNPs in the NOS2A gene are associated with increased risk for AMD and might modulate the effect of smoking on AMD.     

Correlation of complement factor H gene polymorphisms with exudative age-related macular degeneration in a Chinese cohort

To evaluate the association between complement factor H (CFH) gene polymorphism and the risk of exudative age-related macular degeneration (AMD) in a case-control study in a Chinese cohort. One hundred and thirty-six exudative AMD patients and 140 age- and sex-matched control subjects were recruited. We genotyped 3 common single nucleotide polymorphisms (SNPs), namely, -257C>T (rs3753394), Y402H (rs1061170) and IVS15 (rs1329428), genetic analyses were performed on all available genotype data. All the possible haplotypes of these 3 SNPs were detected. Polymerase chain reaction (PCR) and allele-specific restriction endonuclease digestion were performed, some PCR products of these 3 SNPs were sequenced. The risk alleles (T, C or G) of the 3 SNPs conferred 1.72-fold, 3.14-fold, and 1.79-fold of increased likelihood of the disease, respectively (P<0.05). The heterozygous genotype in rs1061170 (TC) revealed significant association, meanwhile rs3753394 and rs1329428 had a slight association with the disease, respectively. Significant differences were shown in the risk alleles in the 3 SNPs among different Chinese cohort. Low linkage disequilibrium was found among the 3 SNPs. The haplotypes TCG and CTG revealed as risk factors, whereas the protective haplotype CTA was over-represented in controls. We found significant association between risk alleles (T, C or G) of the 3 SNPs and the disease. The genetic divergence across multiple populations within Chinese existed. Risk haplotypes and protective haplotype were found in this study.     

玻璃体腔内注射曲安奈德治疗湿性年龄相关性黄斑病变与眼压升高的关系

目的：明确玻璃体腔内注射小剂量曲安奈德治疗年龄相关性渗出性黄斑病变和眼压升高的关系。方法通过眼底血管造影确诊99例具有视网膜下新生血管的年龄相关性渗出性黄斑病变患者,均接受玻璃体腔内注射曲安奈德4mg,监测患者注射后眼压变化情况。结果有31%的患者的眼压比原来基础眼压升高(≥5mmHg)。结论玻璃体腔注射曲安奈德可导致眼压升高,接受这种方法的治疗的患者,应充分告知眼压升高风险。     

CFH基因R1210C突变与中国人老年黄斑变性的相关性研究

目的 补体因子H(complement factor H,CFH)基因R1210C突变与高加索人老年黄斑变性(age-related macular degeneration,AMD)显著相关.我们通过对中国大陆汉族人群进行病例-对照研究,评估CFH基因R1210C突变与中国人老年黄斑变性的相关性.方法 收集258例中国汉族人湿性AMD患者作为病例组,同时收集来自同一地区426名正常中国汉族人作为对照,应用直接测序法检测CFH基因中R1210C的突变情况,并比较病例组和对照组的差异.结果 258例中国人AMD患者和426名正常中国人的CFH基因中未发现R1210C突变.结论 中国人老年黄斑变性与CFH基因R1210C突变可能无关.     

Baseline Predictors of Visual Acuity and Retinal Thickness in Patients with Retinal Vein Occlusion

This study investigated the baseline predictors of best corrected visual acuity (BCVA) and central retinal thickness (CRT) at 6 months in patients with treatment-naïve branch retinal vein occlusion (BRVO) and central retinal vein occlusion (CRVO). This multicenter, interventional case series included 208 BRVO and 123 CRVO patients with follow-up period of 6 months or more. Outcome measures of BCVA (logMAR) included absolute change from baseline and a gain or loss of ≥ 0.3 from baseline. Outcome measures of CRT included absolute change from baseline and a measurement of ≤ 250 µm or ≥ 400 µm at 6 months. Univariate and multiple regression analyses were done to find baseline predictors. For BRVO, younger age, worse baseline BCVA, and shorter duration of symptom were associated with more gain in BCVA. For CRVO, worse baseline BCVA was associated with more gain in BCVA. For CRT outcomes, higher baseline CRT predicted greater decrease at 6 months in both BRVO and CRVO. Younger age and better baseline BCVA were associated with an increased likelihood of measurement of a ≤ 250 µm outcome for BRVO and CRVO, respectively. For CRVO, smoking was associated with greater decrease from baseline and decreased likelihood of measurement of a CRT ≥ 400 µm at 6 months. In conclusion, several baseline factors including age, symptom duration, and baseline BCVA and CRT are associated with BCVA and CRT outcomes at 6 months, which may help to predict disease course for RVO patients.

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