正常猕猴与人视网膜血管的比较

目的比较正常猕猴与人视网膜血管的异同,为进一步利用猕猴建立动物模型来研究视网膜血管打下基础。方法取健康成年猕猴眼球6只和人角膜移植供体剩余眼杯8只的视网膜,用ADP酶法进行血管染色,对两者视网膜血管的走行、血管分级、毛细血管分层以及黄斑区血管拱环等进行比较,测量结果进行统计学检验。结果猕猴与人的视网膜铺片经ADP酶法染色后见视网膜血管自穿出视盘后的一级血管逐渐分支变细,直至五级血管即毛细血管;在视盘旁、赤道部、周边部两者血管面积百分比没有差异;视盘旁血管分为多层,赤道部有两层,且深浅层间相互交通,周边部仅见一层毛细血管且较稀疏;两者黄斑区毛细血管均较密集,有形态完整呈不规则状的血管拱环,血管面积百分比以及血管拱环的面积、周长和直径没有差异。结论猕猴与人在视网膜血管走行、分级、毛细血管分层以及黄斑区血管拱环等多方面有良好的相似性,可用作人类视网膜血管、尤其是黄斑区视网膜血管研究的良好动物模型。     

Birdshot retinochoroidopathy

Birdshot retinochoroidopathy is a rare bilateral ocular disorder which typically affects healthy, middle-age caucasians. The typical symptoms are recent onset of bilateral floaters with decreased vision in a white and quiet eye. Minimal anterior chamber reaction, vitreous infiltration without snowballs, and multifocal depigmented lesions in the outer retina and choroid are characteristic of birdshot retinochoroidopathy. Other associated findings include retinal vasculitis, paravascular hemorrhage, vitreous hemorrhage, cystoid macular edema, cellophane maculopathy, posterior subcapsular cataract, optic disc edema, vascular attenuation and tortuosity, optic atrophy and retinal or choroidal neovascularization. Management involves Amsler grid self-assessment and routine funduscopic examinations. A recently documented case of treatment with aromatic retinoids showed improvement while many other commonly prescribed medications are equivocal in effect. Laser photoablation or panretinal photocoagulation are recommended for treatable choroidal or retinal neovascularization, respectively.     

X-linked recessive atrophic macular degeneration from RPGR mutation

We mapped a new X-linked recessive atrophic macular degeneration locus to Xp21.1-p11.4 and show allelic involvement of the gene RPGR, which normally causes severe peripheral retinal degeneration leading to global blindness. Ten affected males whom we examined had primarily macular atrophy causing progressive loss of visual acuity with minimal peripheral visual impairment. One additional male showed extensive macular degeneration plus peripheral loss of retinal pigment epithelium and choriocapillaries. Full-field electroretinograms (ERGs) showed normal cone and rod responses in some affected males despite advanced macular degeneration, emphasizing the dissociation of atrophic macular degeneration from generalized cone degenerations, including X-linked cone dystrophy (COD1). The RPGR gene nonsense mutation G-->T at open reading frame (ORF)15+1164 cosegregated with the disease and may create a donor splice site. Identification of an RPGR mutation in atrophic maculardegeneration expands the phenotypic range associated with this gene and provides a new tool for the dissection of the relationship between clinically different retinal pathologies.     

眼科常用实验动物视网膜血管的比较

目的比较眼科常用实验动物视网膜血管尤其是视网膜毛细血管的情况,为实验时正确选择动物模型提供基础。方法取猕猴、家猪、新西兰大白兔、犬、猫、SD大鼠、C57小鼠以及豚鼠的正常眼球数个,完整剥离整个视网膜,用ADPase法进行血管染色,对视网膜血管进行形态学的比较。结果猕猴视网膜大血管从视盘穿出,分成四支分别供应视网膜四个象限,每条血管逐级分支最后成为毛细血管,其毛细血管呈网状分布,在赤道处分成两层,至周边变成一层,且有发育良好的黄斑区毛细血管拱环结构。家猪视网膜大血管由视盘发出后放射状走行,毛细血管也呈网状分布,无黄斑拱环结构。兔仅视盘两侧部分视网膜可见血管,毛细血管网状不明显。犬的视网膜血管也放射状走行,但迂曲明显,毛细血管不成网状。猫、大鼠、小鼠的视网膜大血管均由视盘发出,猫的分成上、鼻下、颞下三支,大鼠、小鼠的各方向均有,区域性不明显,三者的毛细血管网均发育良好,至周边部仍很密集,呈两层分布。豚鼠视网膜无可见的血管。结论用于研究人视网膜血管尤其是毛细血管时,可选用猕猴、家猪、猫、大鼠和小鼠作为动物模型;但要研究人黄斑区血管时,仅可选用猕猴等灵长类动物。     

Estimated Rates of Retinal Ganglion Cell Loss in Glaucomatous Eyes with and without Optic Disc Hemorrhages

Purpose

To evaluate whether optic disc hemorrhages are associated with faster rates of estimated retinal ganglion cell (RGC) loss in glaucoma.

Methods

A longitudinal observational cohort study of 222 eyes of 122 patients with glaucoma recruited from the Diagnostic Innovations Glaucoma Study (DIGS) followed for an average of 3.74±0.85 years. All subjects had optical coherence tomography and standard automated perimetry during follow up. Optic disc hemorrhages were detected by masked evaluation of stereophotographs. Rates of change in estimated numbers of RGCs were determined using a previously described method. A random coefficients model was used to investigate the relationship between disc hemorrhages and rates of change in estimated RGC counts over time.

Results

19 eyes of 18 subjects had at least one disc hemorrhage during follow up. At baseline, average estimated RGC counts in eyes with and without disc hemorrhages were 677,994 cells and 682,021 cells, respectively (P = 0.929). Eyes with optic disc hemorrhages during follow-up had significantly faster rates of estimated RGC loss than eyes without disc hemorrhages (22,233 cells/year versus 10,704 cells/year, P = 0.020). The effect of disc hemorrhages on the rates of estimated RGC loss remained significant after adjusting for confounding variables.

Conclusion

Eyes with disc hemorrhages showed faster rates of RGC loss compared to eyes without disc hemorrhages. These results provide further evidence that disc hemorrhages should be considered as an indicator of increased risk for faster neural loss in glaucoma.     

不同方向撕除内界膜方式对特发性黄斑裂孔术后视网膜位移的影响

目的:比较玻璃体切割切术中不同方向撕除内界膜对特发性黄斑裂孔愈合后视网膜位移、视功能的影响。方法:纳入特发性黄斑裂孔患者25例(25眼),按照术中内界膜(ILM)撕除方向,以1:1随机分为NS-TI组(13眼)和TI-NS组(12眼)。NS-TI组患者接受内界膜撕除方向为鼻上起瓣,向颞下方向撕除ILM;TI-NS组患者接受内界膜撕除方向为颞下起瓣,向鼻上方向撕除ILM。术前、术后1月、术后3月采集患者自发荧光照相,通过影像学上血管标记点或交叉点的位置计算黄斑视盘距离(FMD)、颞侧血管至视盘距离(T-OD)、鼻侧血管至视盘距离(N-OD)、黄斑区垂直血管距离(VIAD)、黄斑区水平血管距离(HIAD)、黄斑区面积(PMA)。对比两种撕膜方式后术后1月、3月视网膜位移(包括FMD、T-OD、N-OD、VIAD、HIAD、PMA)、裂孔闭合率,术后最佳矫正视力,分析两种撕膜方式的异同。结果:术后1月及3月,两组患者的视网膜皆向视盘方向偏移,表现为FMD、T-OD、N-OD、VIAD、HIAD、PMA五项指标均较术前增大(p 0.05)。术后1月及3月,NS-TI组和TI-NS组FMD、T-OD、N-OD、VIAD、HIAD、PMA、黄斑裂孔愈合率(皆100%)和最佳矫正视力比较差异均无统计学意义(P0.05)。结论:不同方向撕除内界膜不是特发性黄斑裂孔术后视网膜位移的影响因素。     

Visual loss as initial presentation of chronic myelogenous leukemia

A previously healthy 17-year old girl presented with sudden visual loss in both eyes. Visual acuity on the right eye was 0.3 and on the left eye 0.1. Fundoscopic examination showed bilateral optic disc edema, retinal venous tortuousity and dilatation, retinal blot and flame-shaped hemorrhages, Roth spots and on the left eye dark blot preretinal hemorrhage covering the fovea. Laboratory evaluation showed white blood cell count of 455 x 10(9) L. Bone marrow biopsy confirmed the diagnosis of chronic myelogenous leukemia. Chemotherapy was initiated and led to the improvement of visual acuity. Fundus changes had resolved except for the preretinal hemorrhage on left eye which decreased in size. Preretinal hemorrhage in fovea caused maculopathy on the left eye. Three months after admisson visual acuity was 1.0 on the right eye and 0.3 on the left eye. Leukemia should always be included in the differential diagnosis of optic disc edema and retinal hemorrhages.     

Unilateral optical nerve hypoplasia in a Beagle dog

Unilateral (left eye) optic nerve hypoplasia was detected in a six-month-old male Beagle dog. Vision testing indicated that the left eye had poor vision and testing the pupillary light reflex showed the left eye to have an absence of the afferent pathway of the reflex but it had a normal efferent pathway. Ophthalmoscopy revealed a small-sized optic disc, winding retinal artery and dilated retinal vasculature in the left globe. Electroretinography showed no abnormal findings even in the left globe. Histopathologically, the left optic nerve was markedly hypoplastic and was composed of sparse neural elements and a moderate amount of connective and glial tissues. In the retina of the left globe, the nerve fibre layer and the ganglion cell layer were reduced in thickness, although a small number of ganglion cells were still present. There were no abnormal findings detected in the right globe and the right optic nerve. The brain appeared normal macroscopically.     

Advances in repairing the degenerate retina by rod photoreceptor transplantation

Despite very different aetiologies, age-related macular degeneration (AMD) and most inherited retinal disorders culminate in the same final common pathway, loss of the light-sensitive photoreceptors. There are few clinical treatments and none can reverse the loss of vision. Photoreceptor replacement by transplantation is proposed as a broad treatment strategy applicable to all degenerations. The past decade has seen a number of landmark achievements in this field, which together provide strong justification for continuing investigation into photoreceptor replacement strategies. These include proof of principle for restoring vision by rod-photoreceptor transplantation in mice with congenital stationary night blindness and advances in stem cell biology, which have led to the generation of complete optic structures in vitro from embryonic stem cells. The latter represents enormous potential for generating suitable and renewable donor cells with which to achieve the former. However, there are still challenges presented by the degenerating recipient retinal environment that must be addressed as we move to translating these technologies towards clinical application.     

Familial early onset macular degeneration in cynomolgus monkeys (Macaca fascicularis)

The mode of inheritance of macular degeneration was determined with 45 cynomolgus monkeys (18 females and 27 males) who were the offspring of one breeding male with typical macular degeneration. In the first generation, 27 offspring (10 females and 17 males) were born from mating between the macular degeneration-affected founder male and 5 normal female breeders. Among them, 18 monkeys (9 females and 9 males) were judged as having macular degeneration (affected). Next, the distribution of affected offspring was examined with 18 offspring who were born from 3 different mating pairs, normal vs normal, affected vs normal and affected vs affected, when they became 2 years old. All of the 9 monkeys (4 females and 5 males) obtained from the 2 pairs of normal vs normal were normal. On the other hand, 6 affected monkeys (3 females and 3 males) were detected in 8 offspring from the mating pair of affected vs normal, and the single offspring produced by the mating pair of affected vs affected was affected. These results showed that this degeneration must be early onset familial macular degeneration controlled by autosomal dominant gene(s).     

Dyslipidemia and eye diseases in the adult Chinese population: the Beijing eye study

To determine associations between dyslipidemia and ocular diseases, the population-based Beijing Eye Study 2006 examined 3251 subjects (age≥45 years) who underwent a detailed ophthalmic examination and biochemical blood analysis. Dyslipidemia was defined as any of the following: hypercholesterolemia (total cholesterol concentration≥5.72 mmol/L (220 mg/dL)) or hypertriglyceridemia (triglyceride concentration≥1.70 mmol/L (150 mg/dL)) or low high-density lipoprotein-cholesterol (HDL-C concentration≤0.91 mmol/L (35 mg/dL)). Biochemical blood examinations were available for 2945 (90.6%) subjects. After adjustment for age, gender, habitation region, body mass index, self reported income, blood glucose concentration, diastolic blood pressure and smoking, dyslipidemia was significantly associated with higher intraocular pressure (P<0.001) and beta zone of parapapillary atrophy (P = 0.03). Dyslipidemia was not significantly associated with the prevalence of glaucoma (P = 0.99), retinal vein occlusions (P = 0.92), diabetic retinopathy (P = 0.49),presence of retinal vascular abnormalities such as focal or general arteriolar narrowing, age-related macular degeneration(P = 0.27), nuclear cataract (P = 0.14), cortical cataract (P = 0.93), and subcapsular cataract (P = 0.67). The results make one conclude that, controlled for systemic and socioeconomic parameters, dyslipidemia was not associated with common ophthalmic disorders including glaucoma and age-related macular degeneration.     

Ophthalmoscopic observations of ocular fundus in colony-born cynomolgus monkeys aged from 0 day to 90 days

Apparently healthy 242 colony-born cynomolgus monkeys (Macaca fascicularis) aged from 0 day to 90 days were examined for the findings of ocular fundus by using ophthalmoscope. One drop of mixed solution of 0.5% tropicamide and 0.5% phenylephrine hydrochloride was instilled into each eye of the monkey. Then, those monkeys were anesthetized with ketamine-HC1 at the dose level of 10mg/kg B. W. Regular and fluorescein photographs were taken with Kowa RC-II ophthalmoscope-camera by using daylight typed color film. Following findings were obtained in each age class: Retinal color was salmon pink with 0 to 3-days-old neonates, salmon pink and blue to green with 7 days to 14-days-old animals and blue to green with 60-days to 90-days-old monkeys. As regards optic disc, 0- to 14-days-old animals were observed to be light orange in color, and the infant aged more than 28-days showed orange color. Retinal arteries and veins were lightly reddish in color with every age class. Macular color was salmon pink in 0-day-old cases, slightly dark in 3-days-old neonates and very dark after 14-days of age. Lightly retinal reflex was noted in 0- and 7-days-old animals. The reflex was observable in 14-days-old animals without any case of exception. Retinal hemorrhages were recorded in 22 (67%) of 36 neonates born in natural condition and 10 (33%) of 30 neonates born by cesarean section. These findings will be useful as the criteria for ophthalmoscopic observations of the cynomolgus monkeys as laboratory use.     

Optic nerve histopathology in a case of Wolfram Syndrome: A mitochondrial pattern of axonal loss

Mitochondrial dysfunction in Wolfram Syndrome (WS) is controversial and optic neuropathy, a cardinal clinical manifestation, is poorly characterized. We here describe the histopathological features in postmortem retinas and optic nerves (ONs) from one patient with WS, testing the hypothesis that mitochondrial dysfunction underlies the pathology. Eyes and retrobulbar ONs were obtained at autopsy from a WS patient, and compared with those of a Leber hereditary optic neuropathy (LHON) patient and one healthy control. Retinas were stained with hematoxylin & eosin for general morphology and ONs were immunostained for myelin basic protein (MBP). Immunostained ONs were examined in four “quadrants”: superior, inferior, nasal, and temporal. The WS retinas displayed a severe loss of retinal ganglion cells in the macular region similar to the LHON retina, but not in the control. The WS ONs, immunostained for MBP, revealed a zone of degeneration in the temporal and inferior quadrants. This pattern was similar to that seen in the LHON ONs but not in the control. Thus, the WS patient displayed a distinct pattern of optic atrophy observed bilaterally in the temporal and inferior quadrants of the ONs. This arrangement of axonal degeneration, involving primarily the papillomacular bundle, closely resembled LHON and other mitochondrial optic neuropathies, supporting that mitochondrial dysfunction underlies its pathogenesis.     

Visual function of cynomolgus monkeys with macula degeneration and peripheral retinal degeneration

Using the simplified method for judging visual function of the cynomolgus monkey that was established by the present authors (Suzuki et al., 1988), forty-four cynomolgus monkeys with normal ophthalmoscopic findings, eleven monkeys with macula degeneration and thirteen monkeys with peripheral retinal degeneration were examined for their visual function. It was demonstrated that the monkeys with macula degeneration were inferior in their visual function to the monkeys with normal fundus. In addition, the degree of visual function varied with the degree of macula degeneration. The monkeys with peripheral retinal degeneration showed about the same degree in their visual function as the monkeys with normal fundus.     

A Comparison of Some Organizational Characteristics of the Mouse Central Retina and the Human Macula

Mouse models have greatly assisted our understanding of retinal degenerations. However, the mouse retina does not have a macula, leading to the question of whether the mouse is a relevant model for macular degeneration. In the present study, a quantitative comparison between the organization of the central mouse retina and the human macula was made, focusing on some structural characteristics that have been suggested to be important in predisposing the macula to stresses leading to degeneration: photoreceptor density, phagocytic load on the RPE, and the relative thinness of Bruch’s membrane. Light and electron microscopy measurements from retinas of two strains of mice, together with published data on human retinas, were used for calculations and subsequent comparisons. As in the human retina, the central region of the mouse retina possesses a higher photoreceptor cell density and a thinner Bruch’s membrane than in the periphery; however, the magnitudes of these periphery to center gradients are larger in the human. Of potentially greater relevance is the actual photoreceptor cell density, which is much greater in the mouse central retina than in the human macula, underlying a higher phagocytic load for the mouse RPE. Moreover, at eccentricities that correspond to the peripheral half of the human macula, the rod to cone ratio is similar between mouse and human. Hence, with respect to photoreceptor density and phagocytic load of the RPE, the central mouse retina models at least the more peripheral part of the macula, where macular degeneration is often first evident.     

Retinal cone and rod photoreceptor cells exhibit differential susceptibility to light-induced damage

All-trans-retinal and its condensation-products can cause retinal degeneration in a light-dependent manner and contribute to the pathogenesis of human macular diseases such as Stargardt's disease and age-related macular degeneration. Although these toxic retinoid by-products originate from rod and cone photoreceptor cells, the contribution of each cell type to light-induced retinal degeneration is unknown. In this study, the primary objective was to learn whether rods or cones are more susceptible to light-induced, all-trans-retinal-mediated damage. Previously, we reported that mice lacking enzymes that clear all-trans-retinal from the retina, ATP-binding cassette transporter 4 and retinol dehydrogenase 8, manifested light-induced retinal dystrophy. We first examined early-stage age-related macular degeneration patients and found retinal degenerative changes in rod-rich rather than cone-rich regions of the macula. We then evaluated transgenic mice with rod-only and cone-like-only retinas in addition to progenies of such mice inbred with Rdh8(-/-) Abca4(-/-) mice. Of all these strains, Rdh8(-/-) Abca4(-/-) mice with a mixed rod-cone population showed the most severe retinal degeneration under regular cyclic light conditions. Intense light exposure induced acute retinal damage in Rdh8(-/-) Abca4(-/-) and rod-only mice but not cone-like-only mice. These findings suggest that progression of retinal degeneration in Rdh8(-/-) Abca4(-/-) mice is affected by differential vulnerability of rods and cones to light.     

Progressive cone–rod dystrophy

Inherited macular dystrophies present with varying clinical signs. They possess significant overlap with other inherited retinal dystrophies and with several acquired retinal degenerations. A classification system for diagnostic purposes is crucial. This paper includes a case report of an extremely unusual presentation of a cone–rod dystrophy. Its challenge lies in the difficulty to differentiate it from not only inherited dystrophies of the photoreceptors and retinal pigment epithelium, but also from acquired degenerations of the macula and retina. This paper reviews the differential diagnoses and management considerations of cone–rod dystrophy.     

Illusory contours over pathological retinal scotomas

Our visual percepts are not fully determined by physical stimulus inputs. Thus, in visual illusions such as the Kanizsa figure, inducers presented at the corners allow one to perceive the bounding contours of the figure in the absence of luminance-defined borders. We examined the discrimination of the curvature of these illusory contours that pass across retinal scotomas caused by macular degeneration. In contrast with previous studies with normal-sighted subjects that showed no perception of these illusory contours in the region of physiological scotomas at the optic nerve head, we demonstrated perfect discrimination of the curvature of the illusory contours over the pathological retinal scotoma. The illusion occurred despite the large scar around the macular lesion, strongly reducing discrimination of whether the inducer openings were acute or obtuse and suggesting that the coarse information in the inducers (low spatial frequency) sufficed. The result that subjective contours can pass through the pathological retinal scotoma suggests that the visual cortex, despite the loss of bottom-up input, can use low-spatial frequency information from the inducers to form a neural representation of new complex geometrical shapes inside the scotoma.     

Increased expression of glial cell line-derived neurotrophic factor protects against oxidative damage-induced retinal degeneration

Oxidative damage contributes to retinal cell death in patients with age-related macular degeneration or retinitis pigmentosa. One approach to treatment is to identify and eliminate the sources of oxidative damage. Another approach is to identify treatments that protect cells from multiple sources of oxidative damage. In this study, we investigated the effect of increased expression of glial cell line-derived neurotrophic factor (GDNF) in three models of oxidative damage-induced retinal degeneration. Double transgenic mice with doxycycline-inducible expression of GDNF in the retina were exposed to paraquat, FeSO(4), or hyperoxia, all sources of oxidative damage and retinal cell death. Compared to controls, mice with increased expression of GDNF in the retina showed significant preservation of retinal function measured by electroretinograms, reduced thinning of retinal cell layers, and fewer TUNEL-positive cells indicating less retinal cell death. Mice over-expressing GDNF also showed less staining for acrolein, nitrotyrosine, and 8-hydroxydeoxyguanosine, indicating less oxidative damage to lipids, proteins, and DNA. This suggests that GDNF did not act solely to allow cells to tolerate higher levels of oxidative damage before initiation of apoptosis, but also reduced damage from oxidative stress to critical macromolecules. These data suggest that gene transfer of Gdnf should be considered as a component of therapy for retinal degenerations in which oxidative damage plays a role.     

Pathways to photoreceptor cell death in inherited retinal degenerations.

The mutations that cause many forms of inherited retinal degenerations have been identified, yet the mechanisms by which these mutations lead to death of photoreceptor cells of the retina are not completely understood. Investigations of the pathways from mutation to retinal degeneration have focused on spontaneous and engineered animal models of disease. Based on the studies performed to date, four major categories of degeneration mechanism can be identified. These include disruption of photoreceptor outer segment morphogenesis, metabolic overload, dysfunction of retinal pigment epithelial cells, and chronic activation of phototransduction. Future investigations will likely identify additional mechanisms of photoreceptor damage. This review will summarize what has been learned from studying animal models of non-syndromic inherited retinal degenerations.