Two types of photoreceptors, rods and cones, coexist in the vertebrate retina. An in-depth analysis of the retinal circuitry that transmits rod and cone signals has been hampered by the presence of intimate physical and functional connections between rod and cone pathways. By deleting the cyclic nucleotide-gated channel CNG3 we have generated a mouse lacking any cone-mediated photoresponse. In contrast, the rod pathway is completely intact in CNG3-deficient mice. The functional loss of cone function correlates with a progressive degeneration of cone photoreceptors but not of other retinal cell types. CNG3-deficient mice provide an animal model to dissect unequivocally the contribution of rod and cone pathways for normal retinal function.
Deleterious mutations in RS1 encoding retinoschisin are associated with X-linked juvenile retinoschisis (RS), a common form of macular degeneration in males. The disorder is characterized by a negative electroretinogram pattern and by a splitting of the inner retina. To gain further insight into the function of the retinoschisin protein and its role in the cellular pathology of RS, we have generated knockout mice deficient in Rs1h, the murine ortholog of the human RS1 gene. We show that pathologic changes in hemizygous Rs1h(-/Y) male mice are evenly distributed across the retina, apparently contrasting with the macula-dominated features in human. Similar functional anomalies in human and Rs1h(-/Y) mice, however, suggest that both conditions are a disease of the entire retina affecting the organization of the retinal cell layers as well as structural properties of the retinal synapse.
Leber congenital amaurosis (LCA) is the most serious form of the autosomal recessive childhood-onset retinal dystrophies. Mutations in the gene encoding RPE65, a protein vital for regeneration of the visual pigment rhodopsin in the retinal pigment epithelium, account for 10-15% of LCA cases. Whereas previous studies of RPE65 deficiency in both animal models and patients attributed remaining visual function to cones, we show here that light-evoked retinal responses in fact originate from rods. For this purpose, we selectively impaired either rod or cone function in Rpe65-/- mice by generating double- mutant mice with models of pure cone function (rhodopsin-deficient mice; Rho-/-) and pure rod function (cyclic nucleotide-gated channel alpha3-deficient mice; Cnga3-/-). The electroretinograms (ERGs) of Rpe65-/- and Rpe65-/-Cnga3-/- mice were almost identical, whereas there was no assessable response in Rpe65-/-Rho-/- mice. Thus, we conclude that the rod system is the source of vision in RPE65 deficiency. Furthermore, we found that lack of RPE65 enables rods to mimic cone function by responding under normally cone-isolating lighting conditions. We propose as a mechanism decreased rod sensitivity due to a reduction in rhodopsin content to less than 1%. In general, the dissection of pathophysiological processes in animal models through the introduction of additional, selective mutations is a promising concept in functional genetics.
Melanosomes within the retinal pigment epithelium (RPE) of mammals have long been thought to exhibit no movement in response to light, unlike fish and amphibian RPE. Here we show that the distribution of melanosomes within the mouse RPE undergoes modest but significant changes with the light cycle. Two hours after light onset, there is a threefold increase in the number of melanosomes in the apical processes that surround adjacent photoreceptors. In skin melanocytes, melanosomes are motile and evenly distributed throughout the cell periphery. This distribution is due to the interaction with the cortical actin cytoskeleton mediated by a tripartite complex of Rab27a, melanophilin, and myosin Va. In ashen (Rab27a null) mice RPE, melanosomes are unable to move beyond the adherens junction axis and do not enter apical processes, suggesting that Rab27a regulates melanosome distribution in the RPE. Unlike skin melanocytes, the effects of Rab27a are mediated through myosin VIIa in the RPE, as evidenced by the similar melanosome distribution phenotype observed in shaker-1 mice, defective in myosin VIIa. Rab27a and myosin VIIa are likely to be required for association with and movement through the apical actin cytoskeleton, which is a prerequisite for entry into the apical processes.
The presented Z-suture is a simple, rapid and safe knotless technique that facilitates transscleral suture fixation of various intraocular implants in the ciliary sulcus like sutured intraocular lenses, artificial iris prostheses, and iris diaphragms. As the knotless approach reliably avoids suture erosion, external fixation can be performed without any protecting scleral flaps or lamellar grooves. The needle is simply passed through the sulcus, and the emerging polypropylene suture is secured in the sclera using a zigzag shaped intrascleral suture (Zsuture). Each pass starts directly adjacent to the exiting site. Five passes are sufficient to reliably fix the suture resisting even maximum tractive forces. Once this procedure is done, the suture can be cut without any knot. By avoiding suture knots, and hence the necessity for intrascleral flaps, this knotless approach may help to reduce suture-related complications such as scleral atrophy, suture erosion and infections.
Repetitive intravitreal bevacizumab injections result in a significant long-term improvement of VA and CRT. The number of re-injections necessary to maintain this effect declined over time. However, the treatment seems to be only slightly better than grid laser photocoagulation.
BackgroundTo identify predictive factors for improvement of visual acuity and central retinal thickness by intravitreal bevacizumab for the treatment of macular edema (ME) due to branch retinal vein occlusion (BRVO).MethodsTwo hundred and five eyes from 204 patients with ME secondary to BRVO were retrospectively included at six sites. All eyes received intravitreal bevacizumab therapy (1.25 mg/0.05 ml). The mean follow-up was 36.8 ± 12.7 weeks (range, 18 to 54 weeks). Measurement of ETDRS best-corrected visual acuity (BCVA, in all eyes) and optical coherence tomography (OCT, in 87% of eyes) were performed at baseline and at follow-up examinations every 12 weeks. Using fluorescein angiography, the perfusion status of the macula at baseline could be assessed in 84% of the eyes. The main outcome measures were changes in BCVA and central retinal thickness (CRT). For analysis of predictive factors, the results at 24 weeks were used.ResultsThe median BCVA was 0.6 LogMAR at baseline and improved to 0.4 LogMAR at 24 and 48 weeks. This visual improvement was associated by a significant reduction in CRT, decreasing from a baseline of 454 μm to 267 μm and 248 μm after 24 and 48 weeks respectively. Eyes with ME and intact (perfused) or interrupted (ischemic) foveal capillary ring showed a 2-line increase of median BCVA [45 eyes (22%) and 128 eyes (62%) respectively]. However, the final median BCVA was significantly worse in eyes with ischemic ME (0.6 versus 0.3 logMAR in perfused ME). Other factors for visual improvement were absence of previous treatments of the ME, age younger than 60 years and low baseline BCVA (≥0.6 logMAR) (2, 3, and 2 median BCVA lines increase respectively). Furthermore, eyes with duration of the ME of less than 12 months responded with a 3-line increase of the median BCVA. Final CRT only showed minor differences between the subgroups. During the entire follow-up, retreatments were performed in 85% of the eyes, with a median number of injections of three (mean 3.2; range, 1 to 10) and a median time-interval between injections of 11.6 weeks (mean 14.6 weeks).ConclusionsIntravitreal injection of bevacizumab resulted in a significant improvement of BCVA and reduction of ME in BRVO. Baseline BCVA, patient’s age, and duration of BRVO were found to be of prognostic relevance for visual improvement. A less favorable outcome of the bevacizumab therapy in eyes with longstanding BRVO would advocate initiation of treatment within 12 months after onset.
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