目的：探讨基因多态性与2型糖尿病(type 2 diabetes mellitus，T2DM)患者发生增生性糖尿病性视网膜病变(proliferative diabetic retinopathy，PDR)的相关性。方法：2019年1月至2020年9月桂林医学院附属医院收治的700名T2DM患者，分为无糖尿病性视网膜病变(non-diabetic retinopathy，NDR)组(n=386)与PDR组(n=314)。收集临床基本资料，抽取患者外周血，使用竞争性等位基因特异性聚合酶链反应(kompetitive allele specific polymerase chain reaction，KASP)基因分型检测法检测两组患者血清中的内皮素-1(endothelin 1，EDN1)基因的rs5370位点和补体因子H(complement factor H，CFH)基因的rs800292位点基因型。用logistic回归分析这2个基因位点的多态性与广西汉族T2DM患PDR的关系。结果：收缩压、使用胰岛素治疗以及肾小球滤过率(glomerular filtration rate，GFR)的分析结果显示两组间差异有统计学意义(P收缩压=0.025，P胰岛素=0.001，PGFR=0.013)。排除以上混杂因素后，EDN1基因的rs5370位点上TT基因型与PDR易感性呈正相关(P=0.03，OR=2.973；adj.P=0.011，OR=2.718)；CFH基因的rs800292位点上AA基因型与PDR易感性呈正相关(P=0.037，OR=1.949；adj.P=0.044，OR=2.058)。结论：收缩压增高、GFR降低可能与T2DM患者发生PDR相关。EDN1基因的rs5370位点与CFH基因的rs800292位点的多态性与广西汉族人群的PDR易感性显著相关。
Objective: To investigate the relationship between gene-polymorphisms and proliferative diabetic retinopathy in patients who have type 2 diabetes mellitus (T2DM). Method: A total of 700 hospitalized T2DM patients were included in this study from January 2019 to September 2020. They were divided into two groups: the no-diabetic retinopathy (NDR) group (n=386) and the proliferative diabetic retinopathy (PDR) group (n=314). Basic clinical data were collected, and clinical indexes affecting diabetic retinopathy were analyzed. Two tag SNPs rs5370 in endothelin 1 (EDN1) and rs800292 in complement factor H (CFH) were examined using kompetitive allele-specific polymerase chain reaction (KASP) genotyping assays. Logistic regression was used to analyse the relationship between the polymorphisms of these two SNPs and PDR in a Guangxi Han population with T2DM. Results: Significant differences were found through the analysis of the systolic blood pressure—whether using insulin or not—and the glomerular filtration rate (GFR) between the two groups (Psystolic blood pressure=0.025, Pinsulin=0.001, PGFR=0.013) The TT genotype of rs5370 was determined to be associated with an increased risk of PDR (P=0.03, OR=2.973; adj.P=0.011, OR=2.718). The AA genotype of rs800292 was also determined to be associated with an increased risk of PDR (P=0.037, OR=1.949; adj.P=0.044, OR=2.058). Conclusion: Increased systolic blood pressure and decreased GFR may be associated with PDR in patients with T2DM. The rs5370 polymorphism of the EDN1 gene and the rs800292 polymorphism of the CFH gene are significantly associated with the risk of PDR in Guangxi’s Han population.
目的：探讨2型糖尿病(type 2 diabetes mellitus，T2DM)患者二甲双胍治疗与糖尿病性视网膜病变(diabetic retinopathy，DR)的相关性。方法：回顾2015年9月至2020年8月在中日友好医院眼科就诊的1 891例T2DM患者的临床资料，对病程≥10年的324例T2DM患者的一般资料、内科疾病史、糖尿病治疗史、眼科检查和实验室血生化指标进行回顾性病例研究。根据是否接受二甲双胍治疗分为二甲双胍治疗组与非二甲双胍治疗组，根据眼底检查结果同时结合DR临床诊断标准，将DR分为无明显DR、非增生性DR及增生性DR。采用logistic多因素回归分析判断年龄、性别、糖尿病发病年龄、糖尿病病程、高血压病程、高血脂病程、吸烟年数、体重指数、胰岛素治疗及空腹血糖、糖化血红蛋白、总胆固醇、三酰甘油、尿酸和血肌酐水平对结局变量的影响。结果：在DR的发病风险方面，二甲双胍治疗组与非二甲双胍治疗组的差异无统计学意义(P>0.05)。对T2DM患者DR发生及不同分期的相关变量行单因素及多因素分析，结果显示吸烟年数、空腹血糖及肌酐均与DR发病呈正相关(均P<0.05)，而年龄与DR发病呈负相关(P<0.01)，糖尿病发病年龄与DR发生呈显著负相关(OR=0.95，95%CI：0.92~0.98，P=0.0003)。在二甲双胍治疗的T2DM患者中，二甲双胍的疗程(OR=1.02，95%CI：0.96~1.08，P>0.05)及平均剂量(OR=1.50，95%CI：0.79~2.84，P>0.05)与DR的发生与进展均无显著相关性；女性DR发生与进展的风险较男性低(P<0.05)；合并胰岛素治疗与DR发生呈明显正相关(OR=3.11，95%CI：1.59~6.07，P<0.01)；吸烟年数长、糖化血红蛋白及尿酸水平高于正常范围均与DR的发生与进展呈正相关(P<0.05)。在口服二甲双胍患者中，未使用胰岛素治疗组和联合使用胰岛素组的DR发病风险有显著差异(P<0.01)；而未口服二甲双胍患者中，胰岛素治疗与DR发生呈正相关(OR=12.43，95%CI：3.75~41.19，P<0.0001)。结论：病程10年以上T2DM患者中，二甲双胍治疗与DR发生与进展均无显著相关性。
Objective: To investigate the correlation between metformin therapy and diabetic retinopathy (DR) in patients with type 2 diabetes mellitus (T2DM). Methods: The clinical data of 1 891 patients with type 2 diabetes mellitus attending the ophthalmology department of China-Japan Friendship Hospital from September 2015 to August 2020 were reviewed. A retrospective study was performed on 324 cases of these T2DM patients with disease duration ≥10 years. Medical records of all patients including general information, history of medical disease, diabetes treatment, ophthalmologic examination and blood biochemical indices were collected. According to whether metformin treatment was received or not, the patients were divided into a metformin-treated and a non-metformin-treated groups. DR is classified into non-obvious DR, non-proliferative DR and proliferative DR according to the fundus examination and the clinical diagnostic criteria of DR. Logistic multiple regression analysis was used to determine the effects of age, sex, age of DM onset, duration of DM, duration of hypertension,duration of hyperlipidemia, years of smoking, body mass index, insulin treatment and fasting glucose, glycated hemoglobin, total cholesterol, triglycerides, uric acid and blood creatinine levels on DR. Results: There was no statistically significant difference in the risk of developing DR between the metformin-treated and non-metformin-treated groups (P>0.05). Univariate and multifactorial analyses of variables related to the occurrence and different stages of DR in patients with T2DM showed that years of smoking, fasting glucose and creatinine were positively associated with DR (P<0.05), while age was negatively associated with DR (P<0.01), and age of DM onset was significantly negatively associated with DR (OR=0.95, 95%CI: 0.92 to 0.98, P=0.0003). In T2DM patients treated with metformin, neither the duration of metformin (OR=1.02, 95%CI: 0.96 to 1.08, P>0.05) nor the mean dose(OR=1.50, 95%CI: 0.79 to 2.84, P>0.05) was significantly associated with developing DR. The risk of developing DR was lower in women than in men (P<0.05); combined insulin therapy was significantly positively correlated with the risk of DR (OR=3.11, 95%CI: 1.59 to 6.07, P<0.01); long-term smoking, glycosylated hemoglobin and uric acid levels higher than normal were positively associated with DR (P<0.05). In metformin users, there was a significant difference in the risk of developing DR between the no-insulin treatment group and the combined insulin group (P<0.01); and among patients not using metformin, insulin therapy was positively associated with the occurrence of DR (OR=12.43, 95%CI: 3.75 to 41.19, P<0.0001). Conclusion: There was no significant association between metformin treatment and DR among patients with T2DM for >10 years.
视网膜退行性疾病的种类繁多、患病人口基数大，该病特征为终末期严重的视网膜细胞丢失。视网膜类器官(retinal organoid，RO)可通过3D干细胞体外分化培养技术大量获取，并拥有完整的各亚型视网膜细胞和经典的视网膜分层结构。因此，RO可作为最佳的视网膜退行性疾病建模方法之一，以便于发现潜在致病机制。目前，RO衍生物已被广泛用于视网膜细胞替代治疗的动物实验和临床研究，具体的成效参差不齐，可能的影响因素包括移植细胞数量、移植时间窗、移植工具等。随着RO相关研究的快速发展，视网膜退行性疾病在分子和个体上的诊断和治疗将进一步完善。
Retinal degenerative diseases, characterized by severe retinal cell loss at the end stage, are of various kinds and haunt vast amounts of patients. Retinal organoid (RO) with complete retinal cell subtypes and classic retinal stratification structures can be obtained in large quantities through stem cells in vitro 3D differentiation and culture method. Therefore, RO can serve as one of the best ways for retinal degenerative disease modeling to facilitate the decipherment of underlying pathogenic mechanisms. At present, RO derivatives have been widely used in animal experiments and clinical studies of retinal cell replacement therapy with varying results possibly affected by cell quantity, time window, or tools in terms of transplantation. With the booming progress of RO-related research, the diagnosis and treatment on molecular and individual level for retinal degenerative diseases will be further improved.
目的：建立能驱动GFP在视网膜神经节细胞(retinal ganglion cell，RGC)中特异性表达的小鼠胚胎干细胞系。方法：通过同源重组的方式建立Brn3b-GFP敲入的小鼠胚胎干细胞系(Brn3b-GFP ESC)，利用3D培养将其诱导成视网膜类器官检测GFP表达的细胞特异性，再用流式细胞分选富集GFP阳性RGC，采用玻璃体腔注射的方式将GFP阳性RGC移植到健康小鼠和NMDA损伤模型小鼠眼中探索该细胞的应用价值。结果：Brn3b-GFP ESC经3D视网膜诱导培养后在RGC中特异性表达GFP，将这些GFP阳性RGC移植到两种小鼠中2周后能在所有视网膜内观察到GFP阳性细胞存活，且均能观察到有供体RGC整合到宿主视网膜RGC层。结论：本研究建立了RGC特异的报告基因干细胞系Brn3b-GFP ESC，通过将该细胞系诱导成视网膜类器官进而获得的GFP阳性RGC移植后能够整合进宿主视网膜。该细胞系的建立将为青光眼及相关疾病提供重要的研究手段和工具。
Objective: This study was designed to establish a mouse embryonic stem cell line that can drive GFP expression specifically in retinal ganglion cells (RGCs). Methods: In this study, we established a Brn3b-GFP knock-in embryonic stem cell line (Brn3b-GFP ESC) by homologous recombination. By 3D culture, we induced these cells into retinal organoids to investigate the cell-specificity of GFP expression. GFP-positive RGCs were then enriched by flow cytometry and transplanted by intravitreal injection into the eyes of healthy mice and NMDA injury model mice to explore the feasibility of a potential clinical application. Results: GFP was specifically expressed in RGCs following induction of Brn3b-GFP ESCs into 3D retinal organoids. Two weeks after these GFP-positive RGCs were transplanted into the control and injured mice, GFP-positive cells were observed in all transplanted retinas, and donor RGCs were seen to integrate into the RGC layer of the host retina. Conclusion: This study has established a retinal ganglion cell-specific reporter stem cell line Brn3b-GFP ESC. The GFP-positive RGCs obtained by inducing the cell line into retinal organoids can be integrated into the host retina after transplantation. The establishment of such a cell line will provide an important research tool for glaucoma and related diseases.
视网膜静脉阻塞(retinal vein occlusion，RVO)是发生率仅次于糖尿病性视网膜病变的视网膜血管病。RVO后导致视网膜血管损伤进而引起血管闭塞，造成视网膜缺血从而促进异常视网膜新生血管(retinal neovascularization，RNV)的增生，晚期发生玻璃体积血、新生血管性青光眼等并发症，积极治疗可以稳定患者的眼部情况，避免并发症的发生。本文报告了1例患有高血压病的23岁年轻女性患者发生视网膜分支静脉阻塞并发新生血管增殖膜的病例，给予病变区视网膜激光光凝治疗，10年后随访发现RNV膜机化萎缩。
Retinal vein occlusion (RVO) is the second most common retinal vascular disease after diabetic retinopathy. Retinal vascular damage after RVO leads to venous occlusion, which further causes retinal ischemia and promotes abnormal retinal neovascularization (RNV). Later complications such as vitreous hemorrhage and neovascular glaucoma occur. Active treatment can stabilize the ocular condition of patients and avoid the occurrence of complications. This paper reports a case of a 23-year-old young female patient with hypertension who developed branch RVO complicated by neovascularization membrane. The lesion area was treated with laser photocoagulation. The RNV was found to be mechanized and atrophied after 10 years of follow-up.
目的：探讨光学相干断层扫描血管成像(optical coherence tomography angiography，OCTA)在糖尿病性视网膜病变中的应用。方法：选取2021年中山大学附属第七医院眼科63例糖尿病患者为研究对象，分为无糖尿病性视网膜病变(T0，21眼)、轻度非增殖期(T1，21眼)、中重度非增殖期(T2，14眼)及增殖期(T3，7眼)。收集各组生化指标，包括空腹血糖、糖化血红蛋白、谷丙转氨酶、谷草转氨酶、碱性磷酸酶、血清尿素氮、肌酐、尿素氮肌酐比值，及OCTA数据，即中心视网膜厚度、Angiography3×3及Angiography6×6血管线性密度及血管灌注密度等。采用单因素方差分析比较各组间差异。结果：T2组、T3组与T0组相比，T3组与T1组相比，糖尿病病程延长；T3组与其他各组相比，尿素氮升高；T1组、T2组、T3组与T0组相比，T3组与T1组相比，6 mm ×6 mm外层血流线性密度减少；与T0组相比，T1组、T2组及T3组6 mm ×6 mm完整血流线性密度减少；与T0相比，T2组、T3组6 mm ×6 mm外层血流灌注密度减少；与T0组相比，T3组6 mm ×6 mm完整血流灌注密度减少；T2组、T3组与T0组相比，T3与T1相比，3 mm ×3 mm内层血流线性密度明显减少；T3组与T0组及T1组相比，3 mm ×3 mm完整血流线性密度减少。结论：随着糖尿病性视网膜病变的进展，患者的尿素氮及肌酐逐渐升高，OCTA的血流线性密度及血流灌注密度逐渐减少。与血流灌注密度相比，血流线性密度对于早期糖尿病性视网膜病变筛查可能更为敏感。而利用Angiography6×6模式可能可以更早地发现糖尿病性视网膜病变的视网膜血流变化。
Objective: To explore the applications of optical coherence tomography angiography (OCTA) in diabetic retinopathy. Methods: A total of 63 diabetic patients in the Department of Ophthalmology, Seventh Affiliated Hospital of Sun Yat-sen University in 2021 were divided into 4 groups: the patients without diabetic retinopathy (T0, n=21), mild non-proliferative diabetic retinopathy (T1, n=21), moderate-to-severe non-proliferative diabetic retinopathy (T2, n=14) and proliferative diabetic retinopathy (T3, n=7). Biochemical Indicators were collected in all patients, such as fasting plasma glucose (FPG), glycated hemoglobin A1c (HbA1c), alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), the blood urea nitrogen (BUN), creatinine (CRE) and the ratio of blood urea nitrogen and creatinine (BUN/CRE). The Macular Cube 521×128, Angiography3×3, and Angiography6×6 models of OCTA were used to obtain central retinal thickness (CRT), vascular density (VD) and perfusion density (PD) of each group. The data of all subjects was applied to do one-way ANOVA. Results: Prolonged duration of diabetes in T2 and T3 compared to T0 and in T3 compared to T1. Elevated BUN in T3 compared to all other groups. When T1, T2 and T3 were compared to T0, and T3 was compared to T1, the VD of the 6 mm ×6 mm outer layer decreased. Reduced VD of intact 6 mm ×6 mm region in T1, T2 and T3 compared to T0. Declining PD of the 6 mm ×6 mm outer layer in T2 and T3 compared to T0. Diminished PD of whole 6 mm ×6 mm area at T3 compared to T0. The VD of 3 mm ×3 mm inner layer was significantly reduced in T3 compared to T0 and T1. The VD of 3 mm ×3 mm intact area gradually dwindled in T3 compared with T0 and T1 (P<0.05). Conclusion: With the progression of diabetic retinopathy, the levels of BUN and CRE gradually increased, and the OCTA-derived vascular density and perfusion density gradually decrease. Vascular density may be more sensitive for early diabetic retinopathy screening than perfusion density.The use of the Angiography6×6 model may result in an earlier detection of changes in retinal blood flow in diabetic retinopathy.
报道1例人类免疫缺陷病毒(human immunodeficiency virus，HIV)眼部巨细胞病毒性视网膜炎(cytomegalovirus retinitis，CMVR)合并脉络膜结核瘤感染患者，主因双眼视物模糊2周就诊。经眼部检查发现右眼底颞侧视网膜广泛黄白色颗粒样病变，病灶边界可见黄白色奶酪样渗出，左眼下方视网膜大片黄白色渗出伴出血。在随访半年后发现左眼视网膜脉络膜隆起病灶，根据其全身及眼部临床特征，诊断为双眼CMVR伴左眼脉络膜结核瘤，予全身抗病毒及结核治疗后随访1年余，全身情况及眼部病灶稳定。
A case of human immunodeficiency virus (HIV) cytomegalovirus retinitis (CMVR) complicated with choroidal tuberculoma infection was reported. The patient visited hospital due to bilateral blurred vision for 2 weeks. Ocular examination showed extensive yellowish-white granular lesions in the temporal retina of the right fundus, with yellowish-white cheese-like exudation at the border of the lesion, and a large yellowish-white exudation with hemorrhage at the lower part of the left eye’s retina. After six months of follow-up, the patient was found to have a retinal choroid hump in the left eye. Based on her systemic and ocular clinical features, the patient was diagnosed as bilateral CMVR with choroidal tuberculoma of the left eye. The patient had her follow up check-up a year after her systemic antiviral and anti-tuberculosis treatment with her general condition stable and ocular lesions treated.
本文根据上海鹰瞳医疗科技有限公司的创新产品《糖尿病视网膜病变眼底图像辅助诊断软件》在国家药品监督管理局(NMPA，原CFDA)历时两年半的上市前创新申报与注册申报经历，介绍了人工智能类医疗器械产品的产品研发、注册申报流程及相关重点难点，并且列明了在整个过程中需要遵循和参考的法律法规，为此类产品的上市前注册工作提供参考。
Based on the NMPA premarket application through two and a half years for the computer aided diagnosis software using fundus images of diabetic retinopathy, which is an innovative medical device of Shanghai EagleVision Medical Technology Co., Ltd. (Airdoc), this article introduced the development process, the premarket application, and the key points in the application of this artificial intelligence device, also lists the related regulations and guidelines as references to provide some ideas for the follow-up premarketing application of such kind of products.
目的：分析高度近视有晶状体眼后房型人工晶状体植入术后孔源性视网膜脱离的临床特征及预后。方法：回顾分析2012年4月至2021年6月中山眼科中心收治的9例(9只眼)行后房型人工晶状体植入术后孔源性视网膜脱离患者的临床特征、手术方式及疗效，随访(4.96±4.78)个月。结果：患者年龄(30.44±20.11)岁，屈光手术至发病时间(32.10±17.80)个月。4例(44.4%)马蹄形裂孔，1例(11.1%)萎缩性裂孔，4例(44.4%)巨大裂孔；9眼裂孔均位于赤道部前，除2眼(22.2%)为单个巨大裂孔，1眼(11.1%)单个马蹄孔，余6眼(66.7%)均有视网膜周边变性区存在；视网膜脱离范围(3.0±1.12)个象限，8例累及黄斑；增殖性玻璃体视网膜病变C级以上4眼。视网膜初始复位率为77.8%，最终视网膜复位率100%。末次随访最佳矫正视力优于术前(P<0.05)。随访期间，2例硅油填充眼发生并发性白内障，4眼发生术后早期高眼压。结论：有晶状体眼后房型人工晶状体植入术前存在的视网膜变性或术后玻璃体牵引的存在可能是孔源性视网膜脱离发生的危险因素。
Objective: To analyze the clinical presentation, surgical management, and outcomes of rhegmatogenous retinal detachment (RRD) in patients with high-myopia corrected by posterior chamber phakic (PCP) intraocular lens (IOL) implantation. Methods: Nine eyes of 9 patients in whom RRD developed after PCPIOL implantation from April 2012 to June 2021 in Zhongshan Ophthalmic Center were retrospectively studied. Mean follow-up after retinal detachment surgery was (4.96±4.78)months. Results: Mean patient age was (30.44±20.11) years old. RRD occurred (32.10±17.80) months after PCPIOL implantation. Four (44.4%) breaks were horseshoe tear, 1 (11.1%) was atrophic hole and 4 participants (44.4%) had a giant retinal tear. Nine cases had causative breaks located anterior to the equator while peripheral retina lattice degeneration was found in 6 eyes. RRD extended from 1 to 4 quadrants (3.0±1.12 quadrants) and 8 cases were macula-off retinal detachments. Four eyes’ proliferative vitreoretinopathy were more severe than level C. Initial reattachment rate was 77.80%. Final retinal reattachment was 100%. Final follow-up BCVA was significantly better than baseline (P<0.05). Furthermore, concurrent cataract occurred in 2 eyes in which silicone oil was used as tamponade. Ocular hypertension was detected in 4 eyes after surgery. Conclusion: The existed lattice degeneration and postoperative vitreous traction may be risk factors for RRD after PCPIOL implantation.
脂质代谢异常是糖尿病性视网膜病变可能的危险因素。糖尿病性视网膜病变被认为是致盲的主要原因。近年来研究认为总胆固醇、三酰甘油等血脂与糖尿病性视网膜病变及糖尿病黄斑水肿的进展有关，降脂药物的应用能够延缓糖尿病性视网膜病变进展。随着色谱分离和质谱分析等脂质组学分析方法的发展，除了常规的血清脂质标志物以外的各种脂质成分也被发现可能与糖尿病性视网膜病变进展有关。现总结脂质及其衍生物在糖尿病性视网膜病变发病机制中的作用，阐述糖尿病性视网膜病变脂质代谢治疗的潜在靶点和前景。
Abstract Abnormal lipid metabolism is a possible risk factor for diabetic retinopathy. Diabetic retinopathy is considered to be the main cause of blindness. In recent years, studies have shown that serum lipids, such as total cholesterol, triglycerides, are related to the progress of diabetic retinopathy and diabetic macular edema, and lipid-lowering drugs can delay the progress of diabetic retinopathy. With the development of lipidomics analysis methods such as chromatographic separation and mass spectrometry, lipid components other than conventional serum lipid markers have also been found to be related to the progression of diabetic retinopathy. The review summarizes the role of lipids and their derivatives in the pathogenesis of diabetic retinopathy, and highlights the potential targets and prospects of lipid metabolism treatment for diabetic retinopathy.
