Treatment History as a Predictor for Change in Visual Acuity After Surgical Correction of Diabetic Retinal Traction Detachment.

Introduction: Tractional retinal detachment remains a leading cause of severe, persistent vision loss in those with diabetic retinopathy. The purpose of this study was to investigate factors in treatment history associated with outcomes of surgical repair for diabetic tractional retinal detachments. Methods: A retrospective, cohort study design was used. Data on 64 eyes that underwent surgical correction for diabetic tractional retinal detachment were analyzed. For eyes that received any treatment within three months of surgery, the entire treatment history was recorded and analyzed. Eyes with no recorded treatment or only remote treatment outside of three months prior to surgery were considered treatment naïve. Results: Of all eyes, 56% (n = 36) had received treatment for proliferative diabetic retinopathy in the three months prior to surgery. Among those treated, 50% (n = 18) of eyes had both laser and bevacizumab treatments and 44% (n = 16) had only bevacizumab injections. Average best corrected visual acuity (BCVA) for all eyes improved from 1.68 LogMAR (20/1,000) pre-operatively to 1.34 (20/400) post-operatively, p = 0.0017. Average BCVA in eyes with pre-operative treatment history improved from 1.73 (20/1,000) pre-operatively to 1.09 (20/250) post-operatively, p = 0.0006. Average BCVA in treatment-naïve eyes was 1.60 (20/800) pre-operatively and 1.66 (20/1,000) post-operatively, p = 0.638. Eyes treated only with intravitreal injections had an improvement in BCVA from 1.81 (20/1,200) pre-operatively to 0.91 (20/160) post-operatively, p = 0.006. There was no difference between tamponade agents when comparing mean change in BCVA, p = 0.944. Conclusions: There was a relationship between intravitreal injection treatment history and a large improvement in BCVA, and a similar association between combined laser and injection treatment history and improvement in BCVA. These relationships, however, were not present when controlling for confounders in multivariate analysis. There were likely other factors in the patient's treatment history such as timing, quantity, and order of treatments that played a role in the bivariate association observed in this study.

In vitro generation of early-born neurons from late retinal progenitors.

Evidence suggests that, as development ensues, the competence of neural progenitors is progressively altered, such that they become fated to give rise to neurons of a particular stage. Here, we demonstrate that late retinal progenitors can give rise to retinal ganglion cells (RGCs), an example of an early-born cell type in the retina. A subset of late retinal progenitors in vitro responds to cues that favor RGC differentiation by displaying markers characteristic of RGCs. In addition, mechanisms used during normal RGC differentiation are recruited by these cells toward their differentiation along RGC lineage. Our observations suggest that late neural progenitors may not be irreversibly fated but may appear as such under the constraints dictated by epigenetic cues.

Transplantation of ocular stem cells: the role of injury in incorporation and differentiation of grafted cells in the retina.

The incorporation of transplanted cells into the host retina is one of the prerequisites for successful cell replacement therapy to treat retinal degeneration. To test the hypothesis that injury promotes cell incorporation, stem cells/progenitors were isolated from the retina, ciliary epithelium or limbal epithelium and transplanted into the eyes of rats with retinal injury. Different stem cell/progenitor populations incorporated into traumatized or diseased retina but not into the normal retina. The proportion of cells incorporated into the inner retina was consistently higher than in the outer retina. The transplanted cells expressed markers specific to cells of the lamina into which they were incorporated suggesting that cues for specific differentiation are localized within the inner and outer retina. These findings demonstrate that injury-induced cues play a significant role in promoting the incorporation of ocular stem cells/progenitors regardless of their origin or their differentiation along specific retinal sublineage.

Lysophosphatidic acid receptor signaling in mammalian retinal pigment epithelial cells.

PURPOSE: Lysophosphatidic acid (LPA) is a phospholipid growth factor that stimulates proliferation, chemotaxis, cation currents, and K(+) currents in retinal pigment epithelial (RPE) cells. LPA receptor transduction was analyzed in human and rat RPE cells. METHODS: Cells were cultured with standard methods, and signaling pathways were analyzed with a variety of approaches, including whole-cell recording, calcium imaging, and second-messenger assays. RESULTS: LPA-activated nonselective cation currents in rat RPE were blocked by the protein tyrosine kinase (PTK) inhibitor genistein, by the MAP kinase kinase (MEK) inhibitor PD98059, and by loading cells with antibodies to G(alpha(i)/o/t/z). LPA activated the MAP kinase and extracellular signal-related kinase (ERK)-1, and produced a dose-dependent inhibition of cAMP production. LPA stimulated a dose-dependent increase in [Ca(2+)](i) that persisted in Ca(2+)-free medium and was reduced by pretreatment with thapsigargin, suggesting it involves release from intracellular stores. The [Ca(2+)](i) increase was not blocked by ryanodine or the phospholipase C inhibitor U73122. LPA did not stimulate inositol phosphate production. Similar to the cation current, LPA-evoked [Ca(2+)](i) increases were blocked by PD98059 and by loading cells with antibodies to G(alpha(i)/o/t/z). RT-PCR experiments showed the presence of RNA for three LPA receptor subtypes (Edg2, -4, and -7); RNase protection assays showed the strongest expression for Edg2 receptor RNA. CONCLUSIONS: LPA receptors in RPE cells activate pertussis toxin (PTx)-sensitive G proteins that inhibit cAMP accumulation; stimulate MAP kinase which activates a cation current and probably contributes to mitogenesis; and stimulate release of Ca(2+) from intracellular stores that appears independent of IP(3) and ryanodine receptor activation.