颈动脉斑块内钙化分布特征对斑块稳定性的影响

目的探讨颈动脉斑块内钙化分布特征对斑块稳定性的影响。方法选择行颈动脉内膜剥脱术患者49例,且术前通过二维超声及超声造影观察颈动脉斑块回声类型及斑块内造影剂分布情况,记录斑块回声类型、钙化部位、形态、数量及钙化旁有无新生血管,并进行分组,以术后病理结果为金标准,比较各组内不同钙化特征对斑块稳定性的影响。结果不同部位各钙化组、不同形态各钙化组及钙化旁有无新生血管的斑块稳定性比较,差异无统计学意义(χ~2=0. 415,P=0. 813;χ~2=2. 164,P=0. 339;χ~2=3. 352,P=0. 095);不同数量各钙化组的斑块稳定性比较,差异有统计学意义(χ~2=5. 555,P=0. 029)。结论钙化数量对颈动脉斑块稳定性有一定影响,多发钙化可导致斑块不稳定。     

人肝癌裸鼠皮下移植瘤早期血液供应模式的定量研究

目的 定量评估不同时间点人肝癌裸鼠皮下移植瘤内血液供应模式的变化。方法 将1×10⁷/mL的MHCC97-H细胞悬液同一时间接种于40只裸鼠（0.2 mL/鼠）的左侧腹股沟皮下,分别于种瘤后第2、3、4、5周取瘤行HE染色和免疫组化染色（CD34和CD34/PAS双染色）,定量分析血管参数,包括微血管面积（microvascular area,MVA）、微血管密度（microvessel density,MVD）、血管生成拟态（vasculogenic mimicry,VM）,评估肿瘤内血管供应模式的变化。结果 随着肿瘤生长时间的延长,MVA先减小后增大,第3周肿瘤MVA小于第2周[（13 720.8±2 375.6）μm² vs.（28 795.5±3 412.7）μm²,P=0.013],第4周肿瘤MVA大于第3周[（29 221.3±3 958.5）μm² vs.（13 720.8±2 375.6）μm²,P=0.025];VM百分比呈明显升高趋势,第4周肿瘤VM百分比高于第2周（84.2%±15.4% vs.50.1%±14.6%,P=0.015）。结论 在人肝癌裸鼠皮下移植瘤新生血管形成的早期阶段,随着肿瘤生长时间的延长,VM逐渐成为肿瘤的主要血液供应模式。     

Cytochrome P450-generated metabolites derived from ω-3 fatty acids attenuate neovascularization

Ocular neovascularization, including age-related macular degeneration (AMD), is a primary cause of blindness in individuals of industrialized countries. With a projected increase in the prevalence of these blinding neovascular diseases, there is an urgent need for new pharmacological interventions for their treatment or prevention. Increasing evidence has implicated eicosanoid-like metabolites of long-chain polyunsaturated fatty acids (LCPUFAs) in the regulation of neovascular disease. In particular, metabolites generated by the cytochrome P450 (CYP)–epoxygenase pathway have been shown to be potent modulators of angiogenesis, making this pathway a reasonable previously unidentified target for intervention in neovascular ocular disease. Here we show that dietary supplementation with ω-3 LCPUFAs promotes regression of choroidal neovessels in a well-characterized mouse model of neovascular AMD. Leukocyte recruitment and adhesion molecule expression in choroidal neovascular lesions were down-regulated in mice fed ω-3 LCPUFAs. The serum of these mice showed increased levels of anti-inflammatory eicosanoids derived from eicosapentaenoic acid and docosahexaenoic acid. 17,18-epoxyeicosatetraenoic acid and 19,20-epoxydocosapentaenoic acid, the major CYP-generated metabolites of these primary ω-3 LCPUFAs, were identified as key lipid mediators of disease resolution. We conclude that CYP-derived bioactive lipid metabolites from ω-3 LCPUFAs are potent inhibitors of intraocular neovascular disease and show promising therapeutic potential for resolution of neovascular AMD.Angiogenesis plays a central role in many diseases, including age-related macular degeneration (AMD), a leading cause of blindness. Advanced AMD exists in two forms, “atrophic” and “neovascular,” which are defined by the absence or presence of choroidal neovascularization (CNV), respectively (1). Neovascular AMD is characterized by the formation of abnormal blood vessels that grow from the choroidal vasculature, through breaks in Bruch’s membrane, toward the outer retina (1). These vessels generally are immature in nature and leak fluid below or within the retina (2). Although growth factors are thought to play an important role in the late stage of neovascular AMD progression, they likely do not contribute to the underlying cause of the disease. The current standard of care for individuals with neovascular AMD is based on the targeting of VEGF, which promotes both angiogenesis and vascular permeability (3). However, although VEGF-targeted therapy attenuates angiogenesis and vascular permeability, it does not lead to complete vascular regression or disease resolution (3).The ω-3 and ω-6 long-chain polyunsaturated fatty acids (LCPUFAs) are two classes of dietary lipids that are essential fatty acids and have opposing physiological effects. The ω-6 LCPUFA, arachidonic acid (AA), and its cytochrome P450 (CYP)-generated metabolites (epoxyeicosatrienoic acids, EETs) recently have attracted much attention as a result of increasing evidence that they play a role in cancer as well as in cardiovascular disease (4–9). EETs are part of the VEGF-activated signaling cascade leading to angiogenesis (10) and promote tumor growth and metastasis (11). The major dietary ω-3 LCPUFAs are docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), which are highly enriched in the central nervous system including the retina (12). The ω-3 LCPUFAs have antithrombotic, antiangiogenic, and anti-inflammatory properties, and they compete with ω-6 LCPUFAs as substrates for synthesis of downstream metabolites by CYP enzymes, cyclooxygenases (COX), and lipoxygenases (LOX) (6, 13–15). Moreover, dietary enrichment with ω-3 LCPUFAs has been shown to protect against pathological angiogenesis-associated cancer and retinopathy (2, 16–19). Of the three main pathways (COX, LOX, and CYP) involved in eicosanoid biosynthesis, the lipid mediators derived from the CYP branch are the most susceptible to changes in dietary fatty acid composition (20–23). The ω-3 double bond that distinguishes DHA and EPA from their ω-6 counterparts provides a preferred epoxidation site for specific CYP family members (20, 22). In fact, most CYP isoforms can metabolize EPA and DHA with significantly higher catalytic efficiency than AA, making them uniquely susceptible to variations in the availability of these lipids (19–22). CYP epoxygenases target the ω-3 double bond, resulting in an accumulation of 17,18-epoxyeicosatetraenoic acid (17,18-EEQ) derived from EPA and 19,20-epoxydocosapentaenoic acid (19,20-EDP) from DHA (20, 22). Very recently, it was recognized that19,20-EDP inhibits angiogenesis, tumor growth, and metastasis (24). Thus, it appears that the CYP–epoxygenase pathway has the capacity to produce proangiogenic metabolites from ω-6 LCPUFAs (10, 11) and antiangiogenic metabolites from ω-3 LCPUFAs (24). This unique feature of the CYP enzymes may provide a previously unidentified mechanistic link between the ω-6/ω-3 ratio of dietary LCPUFAs and pathological angiogenesis; however, their roles in ocular angiogenesis have been largely unexplored to date.We now show that dietary enrichment with ω-3 LCPUFAs suppresses CNV, vascular leakage, and immune cell recruitment to the lesion site in a mouse model of laser-induced CNV. We characterized the CYP-dependent pathway by which dietary ω-3 LCPUFAs promote resolution of choroidal neovessels in this model and identified CYP-generated metabolites 17,18-EEQ and 19,20-EDP as mediators of disease resolution. Furthermore, we show that expression of adhesion molecules at the CNV site was down-regulated in association with inhibition of leukocyte recruitment in mice receiving ω-3 LCPUFAs.     

Collaborative interplay between FGF-2 and VEGF-C promotes lymphangiogenesis and metastasis

Interplay between various lymphangiogenic factors in promoting lymphangiogenesis and lymphatic metastasis remains poorly understood. Here we show that FGF-2 and VEGF-C, two lymphangiogenic factors, collaboratively promote angiogenesis and lymphangiogenesis in the tumor microenvironment, leading to widespread pulmonary and lymph-node metastases. Coimplantation of dual factors in the mouse cornea resulted in additive angiogenesis and lymphangiogenesis. At the molecular level, we showed that FGFR-1 expressed in lymphatic endothelial cells is a crucial receptor that mediates the FGF-2–induced lymphangiogenesis. Intriguingly, the VEGFR-3–mediated signaling was required for the lymphatic tip cell formation in both FGF-2– and VEGF-C–induced lymphangiogenesis. Consequently, a VEGFR-3–specific neutralizing antibody markedly inhibited FGF-2–induced lymphangiogenesis. Thus, the VEGFR-3–induced lymphatic endothelial cell tip cell formation is a prerequisite for FGF-2–stimulated lymphangiogenesis. In the tumor microenvironment, the reciprocal interplay between FGF-2 and VEGF-C collaboratively stimulated tumor growth, angiogenesis, intratumoral lymphangiogenesis, and metastasis. Thus, intervention and targeting of the FGF-2– and VEGF-C–induced angiogenic and lymphangiogenic synergism could be potentially important approaches for cancer therapy and prevention of metastasis.     

IL-18: a new player in immunotherapy for age-related macular degeneration?

Recent evidence suggests that the pro-inflammatory cytokine IL-18 may have utility as an anti-angiogenic agent in the eye. Numerous laboratories, including our own have demonstrated the ability of murine IL-18 to prevent neovascularization in the retina, choroid and cornea in pathological scenarios. Here, we summarize the potential use of IL-18 as an immunotherapy for wet age-related macular degeneration treatment, describing past and recent findings pertaining to its biological function in the eye.     

IMI Pathologic Myopia

Pathologic myopia is a major cause of visual impairment worldwide. Pathologic myopia is distinctly different from high myopia. High myopia is a high degree of myopic refractive error, whereas pathologic myopia is defined by a presence of typical complications in the fundus (posterior staphyloma or myopic maculopathy equal to or more serious than diffuse choroidal atrophy). Pathologic myopia often occurs in eyes with high myopia, however its complications especially posterior staphyloma can also occur in eyes without high myopia.Owing to a recent advance in ocular imaging, an objective and accurate diagnosis of pathologic myopia has become possible. Especially, optical coherence tomography has revealed novel lesions like dome-shaped macula and myopic traction maculopathy. Wide-field optical coherence tomography has succeeded in visualizing the entire extent of large staphylomas. The effectiveness of new therapies for complications have been shown, such as anti-VEGF therapies for myopic macular neovascularization and vitreoretinal surgery for myopic traction maculopathy.Myopia, especially childhood myopia, has been increasing rapidly in the world. In parallel with an increase in myopia, the prevalence of high myopia has also been increasing. However, it remains unclear whether or not pathologic myopia will increase in parallel with an increase of myopia itself. In addition, it has remained unclear whether genes responsible for pathologic myopia are the same as those for myopia in general, or whether pathologic myopia is genetically different from other myopia.     

Parapapillary Intrachoroidal Cavitation in Glaucoma: Association with Choroidal Microvasculature Dropout

PurposeTo characterize the choroidal microvasculature in glaucomatous eyes with parapapillary intrachoroidal cavitation (PICC) using optical coherence tomography angiography (OCTA) and its association with parapapillary choroidal microvasculature dropout (MvD).MethodsThis study included 47 glaucomatous eyes with PICC, as identified by color fundus photography and optical coherence tomography scanning of the optic nerve head area. Peripapillary choroidal microvasculature was evaluated on en-face OCTA images. Choroidal MvD was defined as a focal sectoral capillary dropout with no visible microvascular network.ResultsPICC was visible as a well-demarcated area with homogeneously reduced vessel density in en-face OCTA images of the choroidal layer. MvD was detected in 42 eyes (89.4%). Although located in the juxtapapillary area adjacent to the PICC, MvD was confined to the area of parapapillary atrophy. MvD observed in OCTA en-face images was distinguished from the area of PICC by the absence of vascular signal. Of the 50 PICCs, 49 (98.0%) had hemifield visual field defects at the location corresponding to the hemispheric location of PICC.ConclusionsPICC was found to have a characteristic microvascular feature in choroidal en-face OCTA images, and to be topographically associated with glaucomatous visual field defect. PICC was frequently accompanied by MvD and was located adjacent to the area of MvD, suggesting that PICC and MvD have similar pathogenesis.     

玻璃体腔注射康柏西普治疗高度近视黄斑脉络膜新生血管的疗效

目的：探究玻璃体腔注射康柏西普治疗高度近视黄斑脉络膜新生血管(CNV)的疗效。

方法：回顾性选取2017-06/2019-12我院眼科收治的因高度近视导致CNV的患者56例56眼作为研究对象,根据治疗方式分为对照组和观察组,对照组28例28眼行玻璃体腔注射雷珠单抗治疗,观察组28例28眼行玻璃体腔注射康柏西普治疗。末次治疗后随访3mo,记录患者眼压、最佳矫正视力(BCVA)及并发症发生情况,采用光学相干断层扫描(OCT)测定黄斑中心凹视网膜厚度(CMT),采用OCT仪水平线性扫描测量CNV面积。

结果：治疗后两组患者BCVA均较治疗前改善,且观察组BCVA优于对照组(均P<0.05)。治疗后3mo两组患者眼压、CNV面积及CMT均较治疗前降低,且观察组改善情况优于对照组(均P<0.05)。随访期间,观察组并发症发生率(4%)低于对照组(18%)。

结论：玻璃体腔注射康柏西普治疗高度近视CNV疗效优于雷珠单抗,可有效改善BCVA,降低CMT,减少术后并发症,提高临床疗效。     

肥厚型脉络膜谱系疾病的研究进展

肥厚型脉络膜谱系疾病包括脉络膜增厚性视网膜色素上皮病变(PPE)、中心性浆液性脉络膜视网膜病变(CSC)、肥厚性脉络膜新生血管病变(PNV)和息肉状脉络膜血管病变(PCV)。PPE指脉络膜厚度永久性异常增加,表现为脉络膜大血管层(Haller层)扩张,压迫其周围的中血管层(Sattler层)和毛细血管层(Choriocapillaris层),导致RPE供血不足,引起一系列色素上皮病变。其余3种疾病可由脉络膜增厚性色素上皮病变进展而来,对于肥厚型脉络膜谱系疾病的发病特征、影像学变化的研究有助于探索该谱系疾病发病机制,为该类疾病的早期临床诊断及预防和治疗提供参考。     

冠心病的“生物搭桥”疗法

冠状动脉旁路移植术(CABG)和经皮冠状动脉腔内成形术(PTCA)是目前治疗冠心病的有效血管重建方法,这些方法主要靠侵入式恢复冠脉血流,存在费用高、术后再狭窄及无组织复流等问题.伴随血管新生分子机制研究的进一步深入,生物因子注射、干细胞移植和中药干预等多种疗法被应用于促进心肌血管再生和冠脉侧支循环的建立上,人们把这种通过生物因子、细胞及药物对血管生成或发生进行调控和干预,以其促进缺血心肌血管新生,增加侧支循环,改善心肌组织血流供应的方法称为“生物搭桥”.目前,治疗性血管新生已成为冠心病研究普遍关注的焦点,为冠心病治疗带来了新的希望.