目的：通过高通量测序分析进行基因诊断，鉴别视网膜病变中的神经纤维瘤病，为其早诊早治提供重要依据。方法：回顾性分析眼遗传病高通量测序数据库中的NF1和NF2基因变异，根据ACMG/AMP指南解析变异致病性；进一步结合患者的临床表型、家族史以及其他检查结果，综合判断明确是否患有神经纤维瘤病，同时进行疾病的进展和随访的研究分析。结果：通过分析不同眼部表型家系的高通量测序结果，共在11例先证者中发现NF1和NF2基因的10个可能致病变异，包括7个NF1变异和3个NF2变异。这11例先证者的初始诊断包括家族性渗出性玻璃体视网膜病变、黄斑/视网膜发育不良、斜视、视网膜色素变性、Coats病和牵牛花综合征等。其中，在1例初诊为家族性渗出性玻璃体视网膜病变的患儿中，检测到3个基因的致病变异，即NF2: c.122G>A/p.(W41*)、RS1: c.520C>T/p.(R174W)和NYX: c.1027C>T/p.(R343C)。随访检查发现，该患儿的复杂眼部表型符合NF2、RS1和NYX致病变异的临床改变，且MRI检查发现双侧前庭神经鞘瘤、脊髓室管膜瘤和多发性神经鞘瘤改变。除该患者外，还有4例患者在随访中发现存在牛奶咖啡斑或雀斑样色素沉着等皮肤改变，1 例合并小脑神经纤维瘤浸润。结论: 高通量测序分析能有效检测出神经纤维瘤病相关基因的变异，有助于筛选非典型表现的神经纤维瘤病，为疾病的早期诊断，尤其是对严重中枢神经系统病变的早期筛查和及时干预，提供了重要依据。
Objective: To identify neurofibromatosis in retinopathy through high-throughput sequencing analysis and provide important indicators for early diagnosis and treatment. Methods: Variants in NF1 and NF2 were selected from in-house high-throughput sequencing, including targeted exome sequencing, exome sequencing and whole genome sequencing, of individuals with different eye conditions. Pathogenic or likely pathogenic variants were assessed according to ACMG/AMP criteria. All the available clinical data, including clinical manifestation, family history and other examination results, were summarized and further analyzed to determine whether neurofibromatosis. Results: Based on the results of in-house high-throughput sequencing, a total of ten pathogenic or likely pathogenic variants in NF1 and NF2 were identified in 11 unrelated cases with various eye conditions, including three NF2 variants in four cases and seven NF1 variants in seven cases. The unrelated cases with NF1 and NF2 variants had initial clinical manifestation similar to familial exudative vitreoretinopathy (FEVR), macular or retinal dystrophy, strabismus, retinitis pigmentosa, Coats disease, or morning glory syndrome. In one of these cases, who was diagnosed as FEVR at the initial visit, three pathogenic variants of three different genes were identified, namely NF2: c.122G>A/p.(W41*), RS1: c.520C>T/p.(R174W) and NYX: c.1027C>T/p.(R343C). Follow-up examination on this case revealed a complex retinopathy, which were consistent with clinical presentations due to pathogenic variants in NF2, RS1, and NYX, as well as bilateral vestibular schwannomas, spinal ependymoma and multiple schwannomas by MRI. In addition to this patient, a follow-up examination on four of the seven cases present Café-au-lait macules or freckling, which could be easily neglected if neurofibromatosis is not realized on the initial visit, while one had neurofibromatosis in cerebellum. Conclusions: Complex retinopathy may present as the initial sign of neurofibromatosis, and high-throughput sequencing analysis for neurofibromatosis related genes contribute to early diagnosis of neurofibromatosis and facilitating early identification of vital systemic complication.
糖尿病视网膜病变(diabetic retinopathy,DR)是世界范围内劳动年龄人口视力损伤的主要原因。糖尿病前期和DR临床前期患者作为罹患DR的高危人群，在该阶段可发现视网膜神经元形态功能及视网膜微小血管的改变。视网膜及神经纤维层厚度的变化可部分反映视网膜神经元结构改变；色觉、对比敏感度、视野及视觉电生理等变化可反映视网膜神经元功能改变。随着光学相关断层扫描血管成像技术的发展，临床可以检测出DR之前视网膜微血管的改变。此外，许多生物标志物也可以预测和评估DR。由于目前还没有方法可以阻止DR的发生与进展，临床可以通过观察以上视网膜的改变更为及时地发现DR，以降低其患病率，最大限度地减少DR带来的视力损伤。
Diabetes retinopathy (DR) is the main cause of visual impairment in the working population worldwide. Patients with pre-diabetes and pre-clinic diabetic retinopathy are regarded as in high risk group of DR. The changes in morphology and function of renal neurons and retinal micro-vessels can be found in these patients at this stage. The changes of retinal nerve structure can be partly reflected by changes in the thickness of retina and nerve fiber layer. The changes in function of retinal neurons can be reflected by changes in color vision, contrast sensitivity, visual field and visual electrophysiology.With the development of optical coherence tomography angiography, changes in retinal micro-vessels can be observed prior to clinical detection of DR. In addition, many biomarker can also predict and evaluate DR. Since there is no way to prevent the occurrence and progress of DR at present, more attention should be paid in DR by observing the changes inthe retina mentioned above timely, to reduce its incidence and minimize the visual damage caused by DR.
糖尿病视网膜病变(diabetes retinopathy, DR)是糖尿病常见的眼部并发症，其病理过程复杂，涉及多种细胞及炎症因子。Müller细胞作为视网膜主要支持细胞，在DR中不仅产生白介素-17(interleukin-17, IL-17)，还作为其主要靶点发挥作用，通过谷氨酸代谢异常、血管内皮生长因子(vascular endothelial growth factor, VEGF)分泌增加及调控参与DR的病理过程，加重炎症反应。IL-17主要由辅助性T细胞17(T helper cell 17, Th17)分泌，通过促进多种炎症介质(如细胞因子、趋化因子和金属蛋白酶)的分泌，增强炎症反应，导致视网膜微血管损害和神经元凋亡，促进DR的发展。高糖环境下，Müller细胞功能受损，IL-17进一步加剧其功能障碍形成恶性循环。研究表明，阻断IL-17及核因子-κB激活剂1(Nuclear factor-kappa B activator 1, Act1)/肿瘤坏死因子受体关联因子6(tumor necrosis factor receptor associated factor 6, TRAF6)/核因子-κB(Nuclear factor-kappa B, NF-κB)信号通路可减轻DR的病理改变，为DR的治疗提供了新的思路。因此，深入研究IL-17与Müller细胞在DR中的相互作用机制，对于研究该疾病的发病机制及开发精准有效的治疗策略具有重要意义。
Diabetes retinopathy (DR) is a common ocular complication of diabetes, characterized by a complex pathological process involving multiple cells and inflammatory factors. Müller cells, as the primary supporting cells of the retina, not only produce interleukin-17 (IL-17) but also serve as a primary target in DR. They participate in the pathological process of DR by contributing to abnormal glutamate metabolism, increased secretion of vascular endothelial growth factor (VEGF), and regulatory functions, thereby exacerbating the inflammatory response. IL-17 is primarily secreted by T helper cell 17 (Th17) cells and enhances the inflammatory response by promoting the secretion of various inflammatory mediators (such as cytokines, chemokines, and metalloproteinases), leading to retinal microvascular damage and neuronal apoptosis, which accelerates the progression of DR. In a high-glucose environment, Müller cell function is impaired, and IL-17 further exacerbates this dysfunction, creating a vicious cycle. Studies have shown that blocking the IL-17 and Act1/TRAF6/NF-κB signaling pathways can mitigate the pathological changes associated with DR, providing new insights for the treatment of this disease. Therefore, conducting in-depth research on the interaction mechanism between IL-17 and Müller cells in DR is of great significance for exploring the pathogenesis of this disease and developing precise and effective treatment strategies.
糖尿病视网膜病变是最为常见的糖尿病微血管并发症，主要由糖尿病引起的机体代谢紊乱导致。而然在临床工作中发现，部分患者通过单纯控制血糖以延缓糖尿病视网膜病变进展，所取得效果不甚理想，一些其他因素对于糖尿病视网膜病变的发生、发展，也起到不可忽视的作用。研究表明，在并发高脂血症的糖尿病视网膜病变患者中，胆固醇代谢异常是诱发视网膜病变的主要原因之一。胆固醇代谢异常通过减弱肝脏X受体，导致胆固醇在视网膜上不断积累，降低视网膜血管内皮功能，从而造成视网膜缺血、缺氧环境的形成，又可通过增加炎症因子和细胞黏附分子-1的表达，使原本病态的糖尿病视网膜血管变得更加脆弱，该文总结了糖尿病视网膜病变的病理因素，对比分析当前糖尿病视网膜病变的主要治疗手段，通过分析胆固醇逆向转运(cholesterol reverse transport,RCT)途径转运对糖尿病视网膜病变发生、发展的影响，发现降低高血脂可提高糖尿病视网膜病变的治愈率，这将为糖尿病视网膜病变的临床防治工作提供新思路。
Diabetic retinopathy is the most common diabetic microvascular complication, which is mainly caused by metabolic disorders caused by diabetes. However, in clinical work, it is found that some patients do not achieve satisfactory results in delaying the progress of diabetic retinopathy by simply controlling blood sugar, and some other factors contribute to the occurrence and development of diabetic retinopathy. Also played a role that can not be ignored. Studies have shown that abnormal cholesterol metabolism is one of the main causes of retinopathy in diabetic retinopathy patients with hyperlipidemia. Abnormal cholesterol metabolism leads to the accumulation of cholesterol in the retina and the decrease of retinal vascular endothelial function by weakening the X receptor in the liver, resulting in the formation of retinal ischemia and hypoxia environment. it can also increase the expression of inflammatory cytokines and cell adhesion molecule-1 to make the originally morbid retinal vessels more fragile. This paper summarizes the pathological factors of diabetic retinopathy. By comparing and analyzing the main treatment methods of diabetic retinopathy at present, and by analyzing the influence of cholesterol reverse transport (cholesterolreversetransport,RCT) pathway on the occurrence and development of diabetic retinopathy, it is found that reducing hyperlipidemia can improve the cure rate of diabetic retinopathy, which will provide new ideas for the clinical prevention and treatment of diabetic retinopathy.
糖尿病视网膜病变是糖尿病引起的微血管病变之一，是不可逆性致盲的眼病。根据其病程可分为根据其病程可分为非增殖期和增殖期，其中还包括糖尿病性黄斑水肿。全科医师需要检测量裸眼视力、矫正视力和眼压，通过裂隙灯显微镜评估眼前节以及眼底检查来评估眼部整体情况。控制血糖、血压、血脂对改善预后很重要。需要重视餐前、餐后血糖，糖化血红蛋白和代谢记忆，一线降血压药物包括血管紧张素转化酶抑制剂和血管紧张素Ⅱ受体阻断剂，调脂药物首选他汀类，而非诺贝特有额外的视网膜保护作用。干预生活方式，宣教，早期发现也同样重要。全科医师需要进行眼底筛查和评分，及时转诊至眼科治疗。眼科治疗包括全视网膜激光光凝术、经平坦部玻璃体切除术、玻璃体抗血管内皮生长因子药物注射术。
Diabetic retinopathy is one of the microvascular diseases caused by diabetes, it is an irreversible blindness eye disease. According to its course, it can be divided into non-proliferative diabetic retinopathy and proliferative diabetic retinopathy, including diabetic macular edema. Te general practitioner needs to measure the uncorrected visual acuity, corrected visual acuity intraocular pressure, use the slit lamp microscope to exam the anterior segment and fundus to evaluate the overall condition of the eye. Controlling blood glucose, blood pressure and blood lipid is very important to improve the prognosis. Attach importance to pre- and postprandial blood glucose, glycosylated hemoglobin and metabolic memory should be carried out. The first-line antihypertensive drugs are angiotensin converting enzyme inhibitors and angiotensin II receptor blockers. Statins are the first choice for lipid-lowering drugs, fenofibrate has additional protective efect of retinal. Intervention in lifestyle, education and early detection are is important. Te general practitioner needs to perform fundus screening and scoring, timely refer to ophthalmology department for treatment. Ophthalmic treatment includes panretinal laser photocoagulation, pars plana vitrectomy, and intravitreal injection of anti-vascular endothelial growth factor drugs.
3位国际视网膜专家在中山眼科中心(Zhongshan Ophthalmic Center，ZOC)眼底病中心进行临床查房并讨论了4例具有挑战性且不寻常的视网膜病例：1)VHL病合并视网膜血管母细胞瘤的11年 随访观察；2)半剂量光动力疗法(photodynamic therapy，PDT)或微脉冲激光光凝治疗中心性浆液性视网膜病变(central serous chorioretinopathy，CSC)的观察；3)视神经缺陷儿童的诊断与治疗；4)合并虹膜晶状体脉络膜缺损的视网膜脱离(retinal detachment，RD)的治疗选择。通过讨论有助于我们更好地了解这四例视网膜疾病的发病机制和治疗方法，及其与全身疾病的关系。
目的：检测 2 型糖尿病患者眼房水中血管内皮生长因子（Vascular endothelial growth factor, VEGF）和白细胞介素-6（Interleukin-6, IL-6）的含量，并探讨其临床意义
方法：在白内障手术过程中获取 66 例 2 型糖尿病患者的房水，采用双抗体夹心酶联免疫吸附（ELISA）法测定 VEGF 和 IL-6 的含量。根据手术后散瞳眼底检查和眼底荧光素血管造影检查确定糖尿病视网膜病变的分期。实验组分为：无糖尿病视网膜病变组（NDR）21 例、单纯型糖尿病性视网膜病变组（BDR）26 例、增生型糖尿病性视网膜病变组（PDR）19 例，正常对照组为健康的老年性白内障患者 20 例。
结果：NDR 组、BDR 组、PDR 组的房水 VEGF 含量分别为（240.30 ± 26.15）pg/ml、（292.27 ± 58.91）pg/ml、（477.41 ± 91.01）pg/ml，IL-6 含量分别为（160.83 ± 33.41）pg/ml、（238.60 ± 62.23）pg/ml、（389.13 ± 90.35）pg/ml，对照组房水 VEGF 含量为（140.58 ± 26.27）pg/ml、IL-6 含量为（82.72 ± 21.53）pg/ml，对照组与实验组比较差异均有统计学意义（F = 113.67，P < 0.01；F = 106.53，P < 0.01）。实验组房水中的 VEGF 与 IL-6 含量有相关性（r = 0.995，P < 0.01）；糖尿病患者的病程与房水中 VEGF（r = 0.792，0.826，0.841 均 P < 0.01）、IL-6（r = 0.829，0.817，0.896 均 P < 0.01）含量有相关性。
结论：VEGF、IL-6 在糖尿病视网膜病变的形成过程中有重要作用，且两者之间有相关性。
Purpose: To explore the role of vascular endothelial growth factor (VEGF) and interleukin-6 (IL-6) in the aqueous humor in the pathogenesis of diabetic retinopathy (DR).
Methods: Aqueous humor samples were collected in type 2 diabetic patients during cataract surgery. The classification of DR was assigned based on the fundus examination and fluorescein angiography after cataract surgery. The experiment group included non-diabetic retinopathy (NDR, 21 cases), background diabetic retinopathy (BDR, 26 cases), and proliferative diabetic retinopathy (PDR, 19 cases). The control group was the healthy cataract patients (20 cases). The levels of VEGF and IL-6 in the aqueous humor were assessed using the ELISA technique.
Results: The level of VEGF in NDR, BDR, and PDR cases were (240.30 ± 26.15) pg/ml, (292.27 ± 58.91) pg/ml, and (477.41 ± 91.01) pg/ml, respectively. The level of IL-6 in NDR, BDR, and PDR cases were (160.83 ± 33.41) pg/ml, (238.60 ± 62.23) pg/ml, and (389.13 ± 90.35) pg/ml, respectively. The levels of VEGF and IL-6 in the aqueous humor from the control group were (140.58 ± 26.27) pg/ml, (82.72 ± 21.53) pg/ml. The levels of VEGF and IL-6 were significantly different in experiment and control groups (F = 113.67, P < 0.01; F = 106.53, P < 0.01). In the aqueous humor of diabetic patients increased significantly (P < 0.1). The levels of VEGF and IL-6 were significantly correlated with each other in the experiment group (r = 0.995, P < 0.01). The levels of VEGF (r = 0.792, 0.826, 0.841, P < 0.01) and IL-6 ((r = 0.829, 0.817, 0.896, P < 0.01) were also significantly correlated with the duration of DR.
Conclusion: VEGF and IL-6 play important roles in the development of DR. The levels of these two factors are correlated with each other in DR patients.
目的：探讨全视网膜光凝及术后应用羟苯磺酸钙治疗糖尿病视网膜病变的疗效。方法：选取96例患者，共175只眼，随机分为对照组(48例，86只眼)和研究组(48例，89只眼)。两组均予全视网膜激光光凝治疗，其中研究组术后再予羟苯磺酸钙继续12周治疗。12周后，观察两组患者治疗前后视力、血液流变学的变化。结果：治疗后研究组在视力>1.0范围的患者明显多于对照组(χ2=6.779，P=0.009)， 而2组在视力≤0.4，0.4~0.6，0.7~1.0范围患者视力差异比较分别为( χ2=0.003，P=0.955)，(χ2=1.640，P=0.200)，(χ2=2.148，P=0.143)。治疗后研究组患者的血浆粘度、红细胞压积、红细胞变形指数、纤维蛋白原改善均优于对照组(P<0.05)。研究组总有效率89.9%，对照组75.6%，两组差异比较(χ2 =6.302，P=0.012)。结论：全视网膜激光光凝及术后应用羟苯磺酸钙治疗糖尿病性视网膜病，能有效提高视力及临床疗效，可能与改善患者血液流变相关。
Objective: To investigate the curative effect of the postoperative retinal laser photocoagulation and calcium dobesilate in the treatment of diabetic retinopathy. Methods: Selected 96 patients, 175 eyes, randomly divided into control group (48 cases, 86 eyes) and study group (48 cases, 89 eyes). Two groups were all given retinal laser photocoagulation treatment, while the study group continued to receive calcium dobesilate for 12 weeks after treatment. After 12 weeks, observed the eyesight, change of blood rheology of the two groups. Results: After the treatment, the patients with vision >1.0 in the study group were significantly more than the control group (χ2 =6.779, P=0.009), in the vision range of ≤0.4, 0.4~0.6, 0.7~1.0, the difference between the two groups was (χ2 =0.003, P=0.955), (χ2 =1.640, P=0.200), (χ2=2.148, P=0.143), respectively. After treatment, plasma viscosity, erythrocyte deposited, erythrocyte deformation index, fibrinogen in the study group were better than those in the control group (P<0.05). The total effectiveness in the study group was 89.9%, in the control group was 75.6%, the difference was statistically significant (χ2=6.302, P=0.012). Conclusion: The whole retinal laser photocoagulation and postoperative application of calcium dobesilate in treating the diabetic retinopathy can effectively improve eyesight and clinical curative effect, which may be associated with improving blood rheology.
目的：探讨基质金属蛋白酶-3(matrix metalloproteinases-3，MMP-3)基因多态位点与承德地区人群2型糖尿病视网膜病变的遗传易感性的关系。方法：应用病例对照研究方法，选取195例糖尿病视网膜病变患者(DR组)，其中非增殖性糖尿病视网膜病变(non-proliferative diabetic retinopathy，NPDR)组(n=152)和增殖性糖尿病视网膜病变(proliferative diabetic retinopathy，PDR)组(n=43)，205例单纯糖尿病患者(DM组)和261例正常对照组(Control组)，采用限制性片段长度多态性(restrictive fragment length polymorphism，RFLP)-聚合酶链反应(polymerase chain reaction，PCR)方法检测MMP-3的基因多态性。结果：MMP-3-1171 5A/6A的等位基因及基因型频率分布在Control组，DM组和DR组之间差异无显著性(P=0.474和P=0.407)。MMP-3-1171 5A/6A的等位基因及基因型频率分布在NPDR和PDR组之间差异无显著性(P=0.724和P=0.820)。结论：MMP-3-1171 5A/6A基因多态性与2型糖尿病视网膜病变的遗传易感性无关。
目的：探讨基质金属蛋白酶-3(matrix metalloproteinases-3，MMP-3)基因多态位点与承德地区人群2型糖尿病视网膜病变的遗传易感性的关系。方法：应用病例对照研究方法，选取195例糖尿病视网膜病变患者(DR组)，其中非增殖性糖尿病视网膜病变(non-proliferative diabetic retinopathy，NPDR)组(n=152)和增殖性糖尿病视网膜病变(proliferative diabetic retinopathy，PDR)组(n=43)，205例单纯糖尿病患者(DM组)和261例正常对照组(Control组)，采用限制性片段长度多态性(restrictive fragment length polymorphism，RFLP)-聚合酶链反应(polymerase chain reaction，PCR)方法检测MMP-3的基因多态性。结果：MMP-3-1171 5A/6A的等位基因及基因型频率分布在Control组，DM组和DR组之间差异无显著性(P=0.474和P=0.407)。MMP-3-1171 5A/6A的等位基因及基因型频率分布在NPDR和PDR组之间差异无显著性(P=0.724和P=0.820)。结论：MMP-3-1171 5A/6A基因多态性与2型糖尿病视网膜病变的遗传易感性无关。
目的:研究增殖性糖尿病视网膜病变患者玻璃体基质细胞衍生因子(Strmalcell-derivedfactor-1, SDF-1)和血管内皮生长因子(Vascular endothelial growth factor, VECF)的浓度,及其相互作用关系。方法:酶联免疫吸附法(Enzyme-linked immunosorbent assay, ELISA)检测玻璃体内 SDF-1 和 VEGF 的含量,每个标本重复3次。实验组为增性糖尿病视网膜病变(Proliferalive diabeticretinopathy, PDR)的住院患者30例,对照组为同期行玻璃体切除术的特发性黄斑裂孔患者12例。结果: PDR 患者玻璃体 VECF 的平均浓度为(2865.87+387.85) pg/ml,明显高于特发性黄斑裂孔组[(142.42+21.03) pg/ml，P < 0.0001]。增殖性糖尿病视网膜病变患者玻璃体 SDF-1的含量平均为(298.40+24.57) pg/ml,对照组为(86.91+15.89) pg/ml,两组的差异具有统计学意义(P < 0.0001)。在30例PDR患者玻璃体内 VEGF 和 SDF-1 的含量表现为正相关(Peanson相关系数 r=0.62，P < 0.001)。结论:增殖性糖尿病患者玻璃体 SDF-1 和 VECF 的含量均高于非糖尿病患者,提示 SDF-1 和 VEGF 共同参与了增殖性糖尿病视网膜病变患者病理性新生血管的形成过程。
Purpose: To investigate the levels of stromal cell-derived factor-1(SDF-1) andvascular endothelial growth factor (VEGF) in the vitreous of patients with proliferativediabetic retinopathy.
Methods: The levels of $DF-1 and VEGF in the vitreous of 30 eyes of 30 patients withproliferative diabetic retinopathy(PDR)and 12 eyes of 12 patients with idiopathicmacular hole (MH) were measured by enzyme-linked immunosorbent assay. Vitreousfluid samples were obtained by vitrectomy.
Resuls: The vitreous concentration of VEGF was signifcantly higher in eyes with PDR(2 865.87+387.85 pg/ml) than in eyes with idiopathic macular hole (142.42+21.03 Pgml, P< 0.000 1). The vitreous level of SDF-1 was also significantly higher in eyes withPDR (298.40+24.57 pg/ml ) than in eyes with idiopathic macular hole (86.91+15.89Pg/ml, P<0.000 1 ). The vitreous concentration of SDF-1 correlated significantly with that of VEGF in eyes with PDR( [correlation coefficient]r=0.62,P<0 .001)
Conclution: Vitreous levels of both SDF-1 and VEGF in patients with PDR aresignificantly higher than those of nondiabetic patients. SDF-1 may be correlated withVEGF in angiogenesis in PDR.
