Retinal detachment in morning glory syndrome with large hole in the excavated disc.

PURPOSE: To present a case of morning glory syndrome (MGS) associated with retinal detachment and to discuss the pathogenesis of retinal tear. METHODS: A 2-year-old-girl had a MGS with a large hole in the excavated disc and retinal detachment. The visual acuity was 4/200 in the affected eye. The excavated disc and retinal detachment were confirmed by echogram. Optical coherence tomography demonstrated that the large hole was connected to the subretinal space. The excavated lesion did not show contractions. The detachment area and the volume of subretinal fluid rose and fell between initial examinations, but ultimately increased. After 2 years of observations, surgery was performed as the retinal detachment had enlarged to include the macula. RESULTS: Surgery included triamcinolone-assisted vitrectomy, subretinal fluid drainage through the large hole in the excavated disc, retinal photocoagulation along the excavated disc, and long-acting gas tamponade. One month later, the retina was redetached due to incomplete closure of the hole. A second operation was performed using silicone oil tamponade. Ultimately, the retina was reattached after silicone oil-fluid exchange surgery. CONCLUSIONS: One possible reason for a large hole in an excavated disc is origination of the tear from a congenital defect, such as an optic pit. The retinal detachment in patients with MGS with a large hole in the disc can be treated with triamcinolone-assisted pars plana vitrectomy and retinal photocoagulation along the excavated disc. This case has shown that one critical component for a high success rate is the tamponade agent used in the vitreous.

Reiterative membranous proliferation with giant-cell deposits on hydrophobic acrylic intraocular lenses after triple procedures in eyes with cataracts and uveitis.

PURPOSE: To report 2 cases of reiterative membranous proliferation with giant-cell deposits on hydrophobic acrylic intraocular lenses (IOLs) after a triple procedure of vitrectomy, phacoemulsification, and IOL implantation in uveitic eyes with cataracts and vitreous opacity. METHODS: A 72-year-old Japanese woman and a 67-year-old Japanese man underwent AcrySof IOL (SA60AT) implantation in their eyes (both eyes in the first case and the left eye in the second case) for the treatment of cataract and vitreous opacity with uveitis. Although intraocular inflammation seemed to be successfully controlled, the number of giant-cell deposits on the posterior surface of the posterior capsule was gradually increased with the development of posterior capsular opacification in 5 and 9 months, respectively, and neodymium-doped yttrium-aluminum-garnet (Nd:YAG) laser capsulotomy was required. RESULTS: After the treatment, Nd:YAG laser membranotomy (4 and 5 times) was required because of repeated membranous proliferation with giant-cell deposits occurring on the posterior surface of the IOL monthly, although postoperative intraocular inflammation seemed to be controlled. CONCLUSIONS: The possibility of development of this undesirable complication, which is believed to be limited in cases with hydrophobic acrylic IOL implantation, should be kept in mind. Also, Nd:YAG laser membranotomy for the proliferative membrane is an available option for recovery of vision.

Ocular hypotony after the use of indocyanine green for epiretinal membrane surgery.

PURPOSE: To report the occurrence of transient ocular hypotony after indocyanine green (ICG)-assisted macular surgery for removal of the epiretinal membrane (ERM). MATERIALS AND METHODS: This was a retrospective review of 122 eyes of 118 patients who underwent vitrectomy for idiopathic ERM. The ICG staining technique was used in 71 eyes without fluid-air exchange (FAX) and in 15 eyes with FAX. Detailed eye examinations, including intraocular pressure (IOP) measurement, were performed before and after surgery. RESULTS: We observed postoperative transient ocular hypotony with choroidal detachment in 8 of 71 eyes (11%) in the ICG (+)/FAX (-) group, and no ocular hypotony was seen in the ICG (+)/FAX (+) group (15 eyes) or in the ICG (-) group (36 eyes). The median best corrected visual acuity (BCVA) in the ICG(-)group was only significantly better than in the ICG (+)/FAX (-) with hypotony at 1 week after surgery (p = 0.046). However, there was no statistically significant difference in BCVA at 3 and 6 months after surgery among the groups (p > 0.05). CONCLUSION: ICG staining of the internal limiting membrane (ILM) supports complete ERM removal because of enhanced visualization of the border between the ILM and the ERM. However, it should be cautioned that postoperative ocular hypotony may occur in some cases of ICG-assisted macular surgery. Therefore, informed consent with careful follow-up is required when ICG-assisted surgery is performed.

Inhibition of posterior capsule opacification by a capsular adhesion-preventing ring.

OBJECTIVE: To assess the inhibitory effect of a capsular adhesion-preventing ring (CAPR) that facilitates aqueous humor circulation into the capsular bag on posterior capsule opacification (PCO) formation after cataract surgery. METHODS: After phacoemulsification, a polymethyl methacrylate intraocular lens with (n=5) or without (n=5) a CAPR was implanted in rabbit eyes. The inhibitory effect of the CAPR on PCO formation was assessed by stereoscopic microscopy and histologic examination 8 weeks after surgery. RESULTS: All eyes in which a CAPR was implanted demonstrated remarkably less PCO than the control eyes. Neither anteroposterior capsular adhesion nor regeneration of lens fiber occurred in 2 eyes in the CAPR group. The remaining 3 eyes with a CAPR showed partial capsular adhesion and limited lens fiber regeneration in the resultant closed capsular space. CONCLUSIONS: The CAPR appears to prevent PCO formation by separating the anterior and posterior capsules and allowing circulation of aqueous humor, including growth inhibitory factors, into the equatorial space of the capsule through the holes and grooves in the ring. CLINICAL RELEVANCE: A CAPR may be useful for preventing PCO in the clinical setting.

Angiotensin II upregulates RAGE expression on podocytes: role of AT2 receptors.

BACKGROUND: Advanced glycation end products (AGEs) play an important role in diabetic nephropathy. The receptor for AGEs, called RAGE, is present on podocytes. We investigated whether angiotensin II (ANG II) modulates RAGE expression on cultured differentiated podocytes. RESULTS: Cultured podocytes expressed AT1 and AT2 receptors. Surprisingly, ANG II induced RAGE mRNA and protein expression through AT2 receptors. ANG II had no influence on proliferation or protein content of podocytes. The increase in RAGE expression depended on stimulated transcriptional activity. Using various mutant reporter constructs of the RAGE promoter region, it was shown that a NF-kappaB binding site at -1519 was essential for ANG II-induced transcriptional activity. Preincubation with ANG II increased the expression of tumor necrosis factor-alpha mRNA and protein expression induced by AGE, indicating that the ANG II-mediated upregulation of RAGE has functional consequences. AGE-BSA was incorporated into cells as measured by Western blots for N epsilon-carboxymethyllysine, but ANG II did not influence this process. ANG II in the absence or presence of AGE-BSA did not induce apoptosis of podocytes. CONCLUSION: Our study revealed aninteraction between the renin-angiotensin system and the AGE/RAGE axis in podocytes. Since intraglomerular ANG II levels are increased in diabetic nephropathy, this interaction may have pathophysiological consequences for podocyte injury and inflammation associated with the development of diabetic nephropathy.

Restoration of visual function in retinal degeneration mice by ectopic expression of melanopsin.

The rod and cone cells of the mammalian retina are the principal photoreceptors for image-forming vision. They transmit information by means of a chain of intermediate cells to the retinal ganglion cells, which in turn send signals from the retina to the brain. Loss of photoreceptor cells, as happens in a number of human diseases, leads to irreversible blindness. In a mouse model (rd/rd) of photoreceptor degeneration, we used a viral vector to express in a large number of retinal ganglion cells the light sensitive protein melanopsin, normally present in only a specialized subset of the cells. Whole-cell patch-clamp recording showed photoresponses in these cells even after degeneration of the photoreceptors and additional pharmacological or Cd(2+) block of synaptic function. Interestingly, similar responses were observed across a wide variety of diverse types of ganglion cell of the retina. The newly melanopsin-expressing ganglion cells provided an enhancement of visual function in rd/rd mice: the pupillary light reflex (PLR) returned almost to normal; the mice showed behavioral avoidance of light in an open-field test, and they could discriminate a light stimulus from a dark one in a two-choice visual discrimination alley. Recovery of the PLR was stable for at least 11 months. It has recently been shown that ectopic retinal expression of a light sensitive bacterial protein, channelrhodopsin-2, can restore neuronal responsiveness and simple visual abilities in rd/rd mice. For therapy in human photodegenerations, channelrhodopsin-2 and melanopsin have different advantages and disadvantages; both proteins (or modifications of them) should be candidates.

Inducible ablation of melanopsin-expressing retinal ganglion cells reveals their central role in non-image forming visual responses.

Rod/cone photoreceptors of the outer retina and the melanopsin-expressing retinal ganglion cells (mRGCs) of the inner retina mediate non-image forming visual responses including entrainment of the circadian clock to the ambient light, the pupillary light reflex (PLR), and light modulation of activity. Targeted deletion of the melanopsin gene attenuates these adaptive responses with no apparent change in the development and morphology of the mRGCs. Comprehensive identification of mRGCs and knowledge of their specific roles in image-forming and non-image forming photoresponses are currently lacking. We used a Cre-dependent GFP expression strategy in mice to genetically label the mRGCs. This revealed that only a subset of mRGCs express enough immunocytochemically detectable levels of melanopsin. We also used a Cre-inducible diphtheria toxin receptor (iDTR) expression approach to express the DTR in mRGCs. mRGCs develop normally, but can be acutely ablated upon diphtheria toxin administration. The mRGC-ablated mice exhibited normal outer retinal function. However, they completely lacked non-image forming visual responses such as circadian photoentrainment, light modulation of activity, and PLR. These results point to the mRGCs as the site of functional integration of the rod/cone and melanopsin phototransduction pathways and as the primary anatomical site for the divergence of image-forming and non-image forming photoresponses in mammals.

Reciprocity between phase shifts and amplitude changes in the mammalian circadian clock.

Circadian rhythms help organisms adapt to predictable daily changes in their environment. Light resets the phase of the underlying oscillator to maintain the organism in sync with its surroundings. Light also affects the amplitude of overt rhythms. At a critical phase during the night, when phase shifts are maximal, light can reduce rhythm amplitude to nearly zero, whereas in the subjective day, when phase shifts are minimal, it can boost amplitude substantially. To explore the cellular basis for this reciprocal relationship between phase shift and amplitude change, we generated a photoentrainable, cell-based system in mammalian fibroblasts that shares several key features of suprachiasmatic nucleus light entrainment. Upon light stimulation, these cells exhibit calcium/cyclic AMP responsive element-binding (CREB) protein phosphorylation, leading to temporally gated acute induction of the Per2 gene, followed by phase-dependent changes in phase and/or amplitude of the PER2 circadian rhythm. At phases near the PER2 peak, photic stimulation causes little phase shift but enhanced rhythm amplitude. At phases near the PER2 nadir, on the other hand, the same stimuli cause large phase shifts but dampen rhythm amplitude. Real-time monitoring of PER2 oscillations in single cells reveals that changes in both synchrony and amplitude of individual oscillators underlie these phenomena.

Unfolding characteristics of a new hydrophobic acrylic intraocular lens, and possible association with complications in triple procedures.

BACKGROUND: To evaluate the relationship between complications observed in triple procedures and the unfolding characteristics of the HOYA AF-1 lens. METHODS: Intraoperative and postoperative complications of 242 eyes undergoing vitrectomy, phacoemulsification and intraocular lens (IOL) implantation were reviewed. Ninety eyes were implanted with the AF-1 lens (VA60BB), 100 eyes with a polymethylmethacrylate lens (824C) and 52 eyes with an AcrySof lens (SA60AT). The unfolding characteristics of the VA60BB and SA60AT were also experimentally examined. RESULTS: Intraoperative iatrogenic posterior capsular holes caused by the vitreous cutter were observed in two eyes with the VA60BB, in three eyes with the 824C, and in one eye with the SA60AT. Significant rotation of the curled IOL in the capsular bag during implantation, with dislocation of the IOL into the vitreous cavity through the hole occurred in the two eyes with the VA60BB. Postoperatively, posterior synechia of the iris occurred more frequently in the VA60BB group (seven eyes) than in the 824C group (one eye) or the SA60AT group (one eye). In the experimental study, the unfolding time of the VA60BB lens was longer than that of the SA60AT lens. The overall diameter of the VA60BB lens after unfolding remained shorter than that before folding. CONCLUSION: Incomplete unfolding of the VA60BB appears to cause intraoperative rotation of the IOL in the capsular bag, resulting in IOL dislocation into the vitreous cavity in the presence of a posterior capsular hole. This lens also appears to be associated with higher rate of postoperative complications in triple procedures.

Bilateral subretinal haemorrhage with Terson's syndrome.

PURPOSE: To present a case of Terson's syndrome with bilateral subretinal haemorrhage emanated from peripapilla, resulting in Mariotte blind spot enlargement. METHODS: Preoperative CT scan and postoperative eye examinations, including funduscopy, fluorescein angiography, optical coherence tomography (OCT), and Goldmann perimetry. RESULTS: A 41-year-old Japanese man had suffered a subarachnoid haemorrhage. Three months later, he recovered from disturbance of consciousness and was referred for decreased vision in both eyes. A CT scan, obtained on the day after the event, had revealed bilateral vitreous hemorrhage. The patient underwent a standard pars plana vitrectomy to clear vitreous haemorrhage. Surprisingly we found bilateral subretinal haemorrhage around peripapilla during surgery. Although subretinal haemorrhage was almost absorbed at six months after the operation, Mariotte blind spot enlargement corresponding to the area of subretinal haemorrhage was detected in both eyes. CONCLUSIONS: In some population of the patients with Terson's syndrome, it was demonstrated that the disturbance of peripapillary structure, presumably due to intracranial hypertension, causes subretinal haemorrhage, resulting in irreversible visual field defect.

Choroidal neovascularization in transgenic mice expressing prokineticin 1: an animal model for age-related macular degeneration.

The prognosis of choroidal neovascularization (CNV) in age-related macular degeneration (AMD) is poor and existing treatments are limited in retarding the progression of disease. The development of an animal model for AMD will be beneficial for finding potential treatments, including gene therapy. Recently prokineticin 1 (hPK1) was identified as a mitogen of fenestrated endothelium. We hypothesized that hPK1 could induce CNV, a hallmark of the exudative or wet form of AMD, since the endothelium of the choriocapillaris, but not retinal endothelium, has fenestration. We generated transgenic mice expressing hPK1 in the retina using the rhodopsin promoter. In these transgenic mice, an enlarged vascular bed of choroid resembling CNV was observed without any morphological changes in the retinal vasculature. In addition, the major fluorophore of lipofuscin, N-retinylidene-N-retinylethanolamine, which has several potential cytotoxic effects on the RPE, was accumulated approximately twice as much in the transgenic mouse eyes compared to controls. hPK1 could be one of the causative factors of AMD and the transgenic mouse exhibiting CNV may be useful to establish treatments for the wet form of AMD.

Elevated intraocular pressure in secondary piggyback intraocular lens implantation.

We report 2 cases of postoperative intraocular pressure (IOP) elevation in secondary piggyback intraocular lens (IOL) implantation without history of glaucoma or ocular hypertension. A 74-year-old woman with myopic pseudophakia and a 68-year-old man with hyperopic pseudophakia received secondary piggyback AcrySof IOL implantation in their left eyes. In both patients, the left IOP gradually increased and sustained around 30 mm Hg for about 1 year. In the first, IOP continued elevating despite topical and systemic medications. There was an episode of pupillary block in the second. Gonioscopically, heavier trabecular meshwork pigmentation in their left eyes was observed. Because of this, the 2 IOLs implanted were removed and replaced by an adequate IOL and trabeculotomy was performed in the former. The AcrySof IOL has a truncated optic edge, which increases the risk for chafing the iris, resulting in pigment dispersion syndrome; thus, it would be a poor choice for a sulcus-placed piggyback implantation.

Generation of transgenic mice using lentiviral vectors: a novel preclinical assessment of lentiviral vectors for gene therapy.

Lentiviral vectors have become attractive delivery vehicles for gene therapy investigators. Specifically, the ability of lentiviral vectors to integrate into nondividing cells and provide stable and long-term gene expression in vivo is a desirable attribute of gene therapy approaches. We report here a simple method for generating transgenic mice using lentiviral vectors, which could be useful models for gene therapy. After removal of the zona pellucida, fertilized eggs were co-incubated with oncoretroviral or lentiviral vectors. The resulting blastocysts were transferred into uteri of pseudo-pregnant females. In both cases, around 60-70% of founder pups were transgenic as determined by PCR analysis. Southern blot analysis revealed that the transgenes were integrated at different genetic loci and transmitted through the germ line. Most of the transgenes delivered by lentiviral vectors were expressed in transgenic mice, although those delivered by oncoretroviral vectors were completely silenced. When the upstream sequences of the rhodopsin gene and the red pigment gene were used as tissue-specific promoters, consistent enhanced green fluorescent protein (EGFP) expression was observed in rod and cone photoreceptor cells, respectively, in retina. However, mice generated with the corneal epithelium-specific keratin-12 promoter displayed EGFP expression not only in cornea but also in other tissues of the mouse. We conclude that the generation of transgenic mice using lentiviral vectors is a simple and robust method to evaluate the promoter specificity in lentiviral vectors in vivo prior to undertaking a gene therapy strategy.

The AGE-RAGE system and diabetic nephropathy.

As is diabetes itself, diabetic vasculopathy is a multifactor disease. Studies revealed advanced glycation end products (AGE) as the major environmental account for vascular cell derangement characteristic of diabetes and the receptor for AGE (RAGE) as the major genic factor that responds to them. AGE fractions that caused the vascular derangement were proved to be RAGE ligands. When made diabetic, RAGE transgenic mice exhibited the exacerbation of the indices of nephropathy and retinopathy, and this was prevented by the inhibition of AGE formation. Extracellular signals and nuclear factors that induce the transcription of human RAGE gene were also identified, which would be regarded as risk factors of diabetic complications. Through an analysis of vascular polysomal poly(A)(+)RNA, a novel splice variant coding for a soluble RAGE protein was found and was named endogenous secretory RAGE. Endogenous secretory RAGE was able to capture AGE ligands and to neutralize the AGE action on endothelial cells, suggesting that this variant has a potential to protect blood vessels from diabetes-induced injury. The AGE-RAGE system, therefore, should be a candidate molecular target for overcoming this life- and quality-of-life-threatening disease.