Maintaining retinal astrocytes normalizes revascularization and prevents vascular pathology associated with oxygen-induced retinopathy.

Astrocytes are well known modulators of normal developmental retinal vascularization. However, relatively little is known about the role of glial cells during pathological retinal neovascularization (NV), a leading contributor to vision loss in industrialized nations. We demonstrate that the loss of astrocytes and microglia directly correlates with the development of pathological NV in a mouse model of oxygen-induced retinopathy (OIR). These two distinct glial cell populations were found to have cooperative survival effects in vitro and in vivo. The intravitreal injection of myeloid progenitor cells, astrocytes, or astrocyte-conditioned media rescued endogenous astrocytes from degeneration that normally occurs within the hypoxic, vaso-obliterated retina following return to normoxia. Protection of the retinal astrocytes and microglia was directly correlated with accelerated revascularization of the normal retinal plexuses and reduction of pathological intravitreal NV normally associated with OIR. Using astrocyte-conditioned media, several factors were identified that may contribute to the observed astrocytic protection and subsequent normalization of the retinal vasculature, including vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF). Injection of VEGF or bFGF at specific doses rescued the retinas from developing OIR-associated pathology, an effect that was also preceded by protection of endogenous glia from hypoxia-induced degeneration. Together, these data suggest that vascular-associated glia are also required for normalized revascularization of the hypoxic retina. Methods developed to target and protect glial cells may provide a novel strategy by which normalized revascularization can be promoted and the consequences of abnormal NV in retinal vascular diseases can be prevented.

Treatment of persistent shoulder pain with sodium hyaluronate: a randomized, controlled trial. A multicenter study.

BACKGROUND: Presently, there are no approved nonoperative therapies for the ongoing treatment of persistent shoulder pain. Preliminary data suggest that intra-articular sodium hyaluronate injections may be beneficial for the treatment of persistent shoulder pain resulting from various etiologies. The present study evaluated the efficacy and safety of sodium hyaluronate (Hyalgan; molecular weight, 500 to 730 kDa) for these patients. METHODS: Six hundred and sixty patients with persistent shoulder pain and limitation resulting from glenohumeral joint osteoarthritis, rotator cuff tear, and/or adhesive capsulitis who had had a failure of conventional therapy were enrolled in this double-blind, randomized, phosphate-buffered saline solution-controlled study, and 456 patients completed twenty-six weeks of follow-up. Patients were randomized to receive either five weekly intra-articular injections of sodium hyaluronate, three weekly intra-articular injections of sodium hyaluronate followed by two weekly intra-articular injections of saline solution, or five weekly intra-articular injections of saline solution. The main outcomes were improvement in terms of shoulder pain on movement at thirteen weeks after the initiation of treatment (as assessed with use of a 100-mm visual analog scale) and the treatment effect throughout twenty-six weeks. RESULTS: For the overall intent-to-treat population, patients who were managed with sodium hyaluronate had greater pain relief than controls did; significant differences were noted at Week 7 (for the five-injection hyaluronate group), Week 17 (for the three and five-injection hyaluronate groups), and Week 26 (for the three-injection hyaluronate group). Analysis of the stratified populations clearly established that this effect was due to benefits experienced by the patients with osteoarthritis. The treatment effect through twenty-six weeks was significant in patients with osteoarthritis in the three-injection (p = 0.003) and five-injection (p = 0.002) groups, with no significant difference for either regimen in patients without osteoarthritis. The safety profile was very favorable, with no product-related serious adverse effects and no between-group differences for any reported adverse event. CONCLUSIONS: Although the primary end point of this study (that is, improvement in terms of shoulder pain at thirteen weeks) was not achieved, the overall findings, including secondary end points, indicate that sodium hyaluronate (500 to 730 kDa) is effective and well tolerated for the treatment of osteoarthritis and persistent shoulder pain that is refractory to other standard nonoperative interventions.

T2-TrpRS inhibits preretinal neovascularization and enhances physiological vascular regrowth in OIR as assessed by a new method of quantification.

PURPOSE: A carboxyl-terminal fragment of tryptophan tRNA synthetase (T2-TrpRS) has demonstrated potent angiostatic activity during retinal developmental neovascularization in vivo. The effects of T2-TrpRS on pathologic neovascularization were tested and compared with a potent VEGF antagonist using the mouse model of oxygen-induced retinopathy (OIR). METHODS: C57BL/6J mice were transiently exposed to hyperoxic conditions (75% O2) between postnatal day 7 (P7) and P12 and then returned to room air. Retinas were isolated, blood vessels stained with isolectin Griffonia simplicifolia, images of retinal whole-mounts acquired, and the area of vascular obliteration and extent of preretinal neovascularization quantified. This method was compared to the commonly used method of OIR quantification in which the number of pre-inner limiting membrane (ILM) nuclei is counted in serial sections of whole eyes. To assess the angiostatic activity of T2-TrpRS, mice were injected intravitreally at P12 with either T2-TrpRS, a VEGF aptamer, or vehicle (PBS) alone, and the effects on area of obliteration and on preretinal neovascular tuft formation were assessed. RESULTS: Using a modified method of quantification in the mouse OIR model based on images of isolectin-stained retinal wholemounts, we were able to assess reliably and consistently both vascular obliteration and preretinal neovascular tuft formation in the same specimen. T2-TrpRS demonstrated potent angiostatic activity, reducing the appearance of pathologic neovascular tufts by up to 90%. Surprisingly, T2-TrpRS also enhanced physiological revascularization of the obliterated retinal vasculature, reducing these areas by up to 60% compared with PBS-injected eyes. In contrast, the VEGF antagonist, while similarly reducing preretinal neovascular tuft formation, did not enhance revascularization of the obliterated areas. CONCLUSIONS: Use of a rapid, quantifiable method to assess the effect of T2-TrpRS on retinal angiogenesis in the OIR model demonstrates the importance of a quantification system that permits simultaneous analysis of a drug's effect on vascular obliteration as well as on preretinal neovascularization. The results obtained using this method suggest enhanced clinical value for compounds such as T2-TrpRS that not only inhibit pathologic neovascularization, but also facilitate physiological revascularization of ischemic tissue.