湿性年龄相关性黄斑变性药物遗传学的研究进展

年龄相关性黄斑变性(age-related macular degeneration,ARMD)是一种多因素疾病,其中遗传因素在它的发病机制中起着重要的作用。目前抗血管内皮生长因子药物的眼内注射是湿性ARMD的首选治疗手段,但疗效却存在个体差异。本文概括总结了血管内皮生长因子(vascular endothelial growth factor,VEGF)基因、补体因子H(complement factor H,CFH)基因、年龄相关性黄斑病变易感因子2(age-related maculopathy susceptibility 2,ARMS2)基因和高温需求蛋白A-1(high-temperature requirement A-1,HTRA1)基因的单核苷酸多态性(single-nucleotide polymorphisms,SNP)在湿性ARMD药物遗传学方面的研究,以期进一步了解疾病的遗传机制,为临床个体化精准治疗及预测预后提供依据。     

Toxicity and detoxification of lipid-derived aldehydes in cultured retinal pigmented epithelial cells

Age-related macular degeneration (ARMD) is the leading cause of blindness in the developed world and yet its pathogenesis remains poorly understood. Retina has high levels of polyunsaturated fatty acids (PUFAs) and functions under conditions of oxidative stress. To investigate whether peroxidative products of PUFAs induce apoptosis in retinal pigmented epithelial (RPE) cells and possibly contribute to ARMD, human retinal pigmented epithelial cells (ARPE-19) were exposed to micromolar concentrations of H2O2, 4-hydroxynonenal (HNE) and 4-hydroxyhexenal (HHE). A concentration- and time-dependent increase in H2O2-, HNE-, and HHE-induced apoptosis was observed when monitored by quantifying DNA fragmentation as determined by ELISA, flow cytometry, and Hoechst staining. The broad-spectrum inhibitor of apoptosis Z-VAD inhibited apoptosis. Treatment of RPE cells with a thionein peptide prior to exposure to H2O2 or HNE reduced the formation of protein-HNE adducts as well as alteration in mitochondrial membrane potential and apoptosis. Using 3H-HNE, various metabolic pathways to detoxify HNE by ARPE-19 cells were studied. The metabolites were separated by HPLC and characterized by ElectroSpray Ionization-Mass Spectrometry (ESI-MS) and gas chromatography-MS. Three main metabolic routes of HNE detoxification were detected: (1) conjugation with glutathione (GSH) to form GS-HNE, catalyzed by glutathione-S-transferase (GST), (2) reduction of GS-HNE catalyzed by aldose reductase, and (3) oxidation of HNE catalyzed by aldehyde dehydrogenase (ALDH). Preventing HNE formation by a combined strategy of antioxidants, scavenging HNE by thionein peptide, and inhibiting apoptosis by caspase inhibitors may offer a potential therapy to limit retinal degeneration in ARMD.     

经瞳温热疗法治疗湿性年龄相关黄斑变性的疗效观察

目的：探讨经瞳温热疗法（transpupillary thermotherapy,TTT）治疗湿性年龄相关黄斑变性（age-related macular degeneration,ARMD）的初步疗效.方法：对9例14眼经眼底检查、荧光素眼底血管造影（fundus fluorescein angiography,FFA）和吲哚菁绿眼底血管造影（indocyanine green angiography,ICGA）确诊为湿性ARMD（12眼为隐匿型、2眼为经典型）的患眼行TTT治疗.根据脉络膜新生血管膜（choroidal neovascular membrane,CNV）的范围选择不同的光斑大小和能量,术后对眼底改变、视力、眼底血管造影复查,随访1～22（平均11.67）mo,以观察疗效.结果：经TTT治疗后,至末次复查时11眼（79%）出血、水肿、渗出消失、病灶斑痕化,3眼（21%）的出血、水肿、渗出明显减轻.5位患者的8眼患眼有TTT后的FFA及ICGA复查,显示其中6眼的原病灶渗漏消失、CNV消退,2眼的渗漏明显减轻.治疗后视力提高的有4眼（29%）,稳定的有7眼（50%）,下降的有3眼（21%）.除2位患者的2只患眼（14%）分别在第一次治疗后的第4和第5mo经造影复查后,接受了原病灶的再次TTT外,其余患眼（86%）均只进行了一次TTT.结论：TTT对湿性ARMD有较明确的疗效,经济安全,其远期疗效需更多病例观察.     

Evidence of hematopoietic differentiation, vasculogenesis and angiogenesis in the formation of human choroidal blood vessels

Human fetal eyes 8–40 weeks gestation (WG) were examined using markers to hematopoietic stem cells (HSC), vascular precursor cells (VPC), monocytes/macrophages and endothelial cells (EC). Electron microscopy and bromo-deoxyuridene labeling were undertaken to confirm the existence of solid vascular cords and to demonstrate vasculogenesis and angiogenesis in developing choroidal tissue. Our results demonstrated that the earliest incipient choroid consisted of vimentin⁺ mesenchymal precursor cells which downregulated vimentin expression with maturation. Our observations lead us to conclude that these vimentin⁻/CD34⁺/CD44⁺/CD133⁺ HSCs then differentiated into three distinct lineages: single isolated CD34⁻/CD39⁺ VPCs that formed solid vascular cords which lumenized and became lined with CD34⁺ vascular ECs; CD34⁻⁻⁺/CD14⁺/CD68⁺ monocytes that differentiated into tissue macrophages; and CD133⁺/CD34⁻⁻⁺/α-smooth muscle actin⁺ mural precursor cells that matured into smooth muscle cells and pericytes. Blood vessel formation occurred throughout the whole choroid simultaneously, indicative of in situ differentiation. Vasculogenesis, as evidenced by lumenization of solid vascular cords, was responsible for the formation of the entire choroidal area with angiogenesis, in all three layers of the choroid, only adding to vascular density. These results suggest that formation of the human choroid involves three processes: HSC differentiation, vasculogenesis and angiogenesis. Since vasculogenesis takes place independently of VEGF₁₆₅, further insights regarding the molecular mechanisms of vasculogenesis are required to better inform future treatments of choroidal neovascularization.     

SCARB1 rs5888 is associated with the risk of age-related macular degeneration susceptibility and an impaired macular area

Background: Age-related macular degeneration (ARMD), a progressive retinal disease, is responsible for an impaired central vision in about 180 million people worldwide. Current options for ARMD prevention and treatment are limited due to an incomplete understanding of disease etiopathogenesis. We aimed to test the hypothesis that the single nucleotide polymorphism rs5888 of SCARB1 gene reflecting lipid and antioxidant micronutrient metabolism pathways is associated with ARMD susceptibility and to evaluate if there is any relation between SCARB1 rs5888 and the macular lesion area.

Materials and methods: The prospective case-control study included patients with ARMD (n = 215) and the reference group (n = 238) drawn from a random sample of the Lithuanian population (n = 1436). The genotyping test of SCARB1 rs5888 was carried out using the real-time polymerase chain reaction method.

Results: Regression analysis adjusted by gender and age demonstrated that SCARB1 rs5888 TT genotype significantly decreased the odds for ARMD development (OR: 0.61, 95%; CI: 0.380–0.981, p = 0.04). A smoking habit and leading an outdoor life are associated with larger macular lesion areas in ARMD patients (0.54 (0.00–39.06) vs. 3.09 (0.02–19.30) and 0.27 (0.00–34.57) vs. 0.75 (0.00–39.06), respectively). In late stage ARMD subjects with CT genotype, the macular lesion area was larger than in TT carriers (7.64 (0.49–39.06) mm² vs. 5.02 (0.03–37.06) mm², p = 0.006).

Conclusions: SCARB1 rs5888 and environmental oxidative stress have a prominent role in ARMD susceptibility, early ARMD progression to advanced stage disease and even in the outcome of the disease—an area of macular lesion.     

玻璃体腔内注射Bevacizumab治疗年龄相关性黄斑变性视野改变

目的 观察玻璃体腔内注射Bevacizumab(Avastin)治疗湿性年龄相关性黄斑变性(ARMD)术后各时间段的视野变化情况.方法 采用单中心随机临床研究方法.收集经间接眼底镜、荧光素眼底血管造影(FFA)以及光学相干断层扫描(OCT)检查确诊存在黄斑中心凹下脉络膜新生血管(CNV)的ARMD患者13例(15只眼),患眼最佳矫正视力均>0.1.患眼行Bevacizumab玻璃体腔内注射1.25mg(0.05ml),注射次数为6次,间隔6周至3个月,治疗后随访3～12个月,记录并分析术前及术后6周,3月,6月,12月的平均视觉敏感度(mean visual sensitivity,MS),平均缺损(mean defect,MD),缺损变异度(lose variance,Lv)的变化.结果 以0周注射为基准,第24周及48周MS值与注射前MS值相比有显著性差异(t值分别为2.91、3.69,P值均<0.05));第48周MD值与注射前MD值(7.97±3.97)dB差异有统计学意义(t值为1.35,P<0.05);各组LV值与注射前LV值比较差异无统计学意义.结论 多次玻璃体腔内注射Bevacizumab有利于改善湿性ARMD患者黄斑区视功能,主要体现在对视网膜平均敏感度以及平均缺损的改善上;重复4-6次注射后绝大多数湿性ARMD患者的视功能得到改善.     

Is significant relevant? Validity and patient benefit of randomized controlled clinical trials on age-related macular degeneration

A large variety of new treatment options for different forms of age-related macular degeneration (ARMD) are becoming available. Not all new therapies may meet the expectations of patients and ophthalmologists. Despite the given statistical significant priority of treatment investigations, the endpoints may not be relevant to the patient's requirements. Therefore, questions inevitably arise regarding patient's benefit and the validity of the randomized controlled trials. The randomized controlled trial is regarded as the "gold standard" in terms of evaluating the effectiveness of interventions. The external validity of randomized controlled trials may be compromised, if, for example, patients assigned to the study group are unrepresentative of the reference population. This review aims to analyze problems with external validity in the randomized controlled trials on ARMD and surveys the endpoints of clinical studies with respect to the patient benefit.     

Multivariate use of MRI biomarkers to classify histologically confirmed necrosis in symptomatic total hip arthroplasty

The failure of total hip arthroplasty (THA) is commonly associated with the necrosis of the periprosthetic tissue. To date, there is no established method to noninvasively quantify the progression of such necrosis. Magnetic resonance imaging (MRI) of soft tissues near implants has undergone a recent renaissance due to the development of multispectral metal-artifact reduction techniques. Advanced analysis of multispectral MRI has been shown capable of detecting small magnetism effects of metallic debris in periprosthetic tissue. The purpose of this study is to demonstrate the diagnostic utility of these MRI-based tissue-magnetism signatures. Together with morphological MRI metrics, such as synovial volume and thickness, these measurements are utilized as biomarkers to noninvasively detect soft-tissue necrosis in symptomatic THA patients (). All subjects underwent an advanced MRI scan before revision surgery and tissue biopsies utilized for necrosis grading. Statistical analyses demonstrated a weak, but significant positive correlation (P = .04) between MRI magnetism signatures and necrosis scores, while indicating no meaningful association between the latter and serum cobalt and chromium ion levels. Receiver-operating characteristic (ROC) analyses were then performed based on uni- and multivariate logistic regression models utilizing the measured MRI biomarkers as predictors of severe necrosis. The area under the curve of the ROC plots for MRI biomarkers as combined predictors were found to be 0.70 and 0.84 for cross-validation and precision-recall tests, respectively.     

Revision Total Hip Arthroplasty Using the Modular Proximal Stem Modified for Asians: Medium-Term Clinical Results and Perioperative Complications

BackgroundThis study aimed to examine the medium-term clinical and radiological outcomes of revision THA using the S-ROM-A stem, a modification of the S-ROM stem intended for Asians.MethodsFemoral reconstruction using the S-ROM-A stem was performed in 126 hips that underwent revision THA. All patients were followed for perioperative complications. In addition, clinical and radiographic outcomes at a mean of 8 (range 5-14) years postoperatively were evaluated in 96 hips of 86 patients (76%).ResultsThe most common perioperative complication was a femoral fracture, occurring in 16 hips (13%), including 11 intraoperative and 5 postoperative fractures. Dislocation occurred in five hips (4.0%), infection in three hips (2.4%), and trunnionosis in two hips (1.6%), including late complications. The total second stem revision was performed in two hips while stem only second revision preserving the bone ingrown sleeve was performed in four hips. With a second revision for aseptic loosening as the endpoint, the 13-year stem survival rate was 100%. Hip function as assessed by the Japanese Orthopedic Association score improved from a mean of 48 points preoperatively to 87 points 8 years postoperatively (P < .05). Radiological evaluation at the final follow-up showed that 95 hips (99%) achieved bone ingrowth fixation and one hip (1%) achieved fibrous stable status.ConclusionRevision THA using the S-ROM-A stem resulted in good medium-term outcomes. Although modifications of the stem length and shape may be effective in preventing fractures in Asians with relatively small body sizes, attention should be paid to the occurrence of trunnionosis, which may be associated with the decreased taper size.