Effect of prior glaucoma surgery on intraocular pressure immediately after anti-vascular endothelial growth factor injection.

BACKGROUND: To characterize how prior incisional glaucoma surgery affects the intraocular pressure (IOP) elevation immediately following intravitreal anti-VEGF injections (IVI). METHODS: Single institution, experimental study. Patients with a history of incisional glaucoma surgery who were receiving anti-VEGF injections were recruited as well as control eyes. Pre- and post-injection IOP measurements were compared as well as time to recovery to within 5 and 10 mmHg of baseline IOP. RESULTS: Ten eyes with a history of glaucoma surgery and 29 control eyes receiving anti-VEGF injections were included. The most common indication for intravitreal anti-VEGF injection was proliferative diabetic retinopathy in both surgical and control eyes (50% vs 45%, p = 1.00). Post-injection IOP was significantly decreased compared to baseline IOP after anti-VEGF injection in surgical versus control eyes (26.5 ± 8.9 mmHg vs 44.2 ± 8.5 mmHg, respectively, p < 0.001). The mean change in IOP following intravitreal anti-VEGF injection was lower in surgical eyes (10.7 ± 6.6 mmHg vs 28.6 ± 8.3 mmHg, p < 0.001). The mean time for the IOP to return to within 10 mmHg of pre-injection IOP was less in surgical eyes (5.2 ± 4.1 min vs 13.3 ± 7.6 min, p = 0.002). CONCLUSIONS: Eyes with prior incisional glaucoma surgery demonstrated a significantly lower post-injection IOP elevation and a faster recovery to within 10 mmHg of their pre-injection IOP. Incisional glaucoma surgery may be considered for patients where the attenuation of post-injection IOP elevation is needed and other less invasive measures have failed.

Thomas A. Swift's Electric Rifle Injuries to the Eye and Ocular Adnexa: The Management of Complex Trauma.

PURPOSE: To report the ocular and adnexal injuries sustained by patients with Thomas A. Swift's electric rifles (TASER; TASER International, Scottsdale, AZ), review the literature, and discuss the management of this complex trauma. DESIGN: Multicenter, retrospective case series and literature review. PARTICIPANTS: Seventeen eyes of 16 patients (5 eyes of 5 patients treated at 3 institutions, and 12 eyes of 11 previously reported cases). METHODS: The clinical data of 17 eyes were pooled. Spearman's correlation coefficient was used to assess the association between the extent of TASER injury and patient outcomes. MAIN OUTCOME MEASURES: Extent of TASER injury (zone of injury, penetrating vs. perforating) and association with patient outcomes (visual acuity [VA] and retinal detachment [RD]). RESULTS: In our cohort, 4 patients were transported by law enforcement and 1 was transferred from a community hospital. Four patients were taken to the operating room for TASER removal and globe repair; 1 patient underwent removal in the emergency room. Of 17 pooled cases, 12 (71%) involved open-globe injury. Of these, there was a high rate of zone 3 injuries (100%; n = 12) and a high incidence of RD (73%; 8 of 11, eviscerated eye excluded). Among patients with closed-globe injury (n = 5), 1 patient demonstrated exudative RD and 1 patient demonstrated retinal dialysis with RD. Of 10 patients with RD, 1 (10%) achieved resolution with monitoring (exudative RD); 1 (10%) underwent cryopexy and pneumatic retinopexy; 3 (30%) underwent vitrectomy, and 5 (50%) with poor prognosis did not undergo vitreoretinal surgery. In the 3 patients who underwent vitrectomy, all 3 (100%) demonstrated redetachment resulting from proliferative vitreoretinopathy and required additional surgery. Visual acuity on presentation was significantly correlated with final VA (ρ = 0.783; P = 0.02). Men (94%) were more likely than women (6%) to sustain TASER trauma. Median age was 26 years. There was a 50% rate of loss to follow-up. CONCLUSIONS: Thomas A. Swift's electric rifle injuries to the eyes or ocular adnexa represent complex trauma. Zone 3 injuries are common. The visual prognosis is guarded, and eyes may require multiple surgeries to preserve vision. Patients are at high risk for loss to follow-up by way of incarceration.

Optic Nerve Head Perfusion Before and After Intravitreal Antivascular Growth Factor Injections Using Optical Coherence Tomography-based Microangiography.

PURPOSE: To use optical coherence tomography angiography (OCTA) to evaluate the changes in optic nerve head perfusion following intravitreal antivascular endothelial growth factor injections. METHODS: Preinjection and postinjection intraocular pressure (IOP) and OCTA images were taken of both the injected and uninjected fellow eyes. RESULTS: Mean preinjection IOP was 16.6±4.7 mm Hg, which increased to a mean of 40.3±13.0 mm Hg (P<0.0001) during the first postinjection image and remained elevated at 36.1±11.5 mm Hg (P<0.0001) during the second postinjection image. Although no significant change was observed in flux, vessel area density, or normalized flux when comparing the OCTA preinjection and first postinjection images, a significant decrease at the second postinjection image was observed (P=0.03, 0.02, and 0.03, respectively). No significant change was observed in the uninjected fellow eye during the same time period (P=0.47, 0.37, and 0.38, respectively). CONCLUSIONS: Following an antivascular endothelial growth factor injection, mean IOP increased significantly and OCTA imaging of the optic nerve demonstrated a mild but significant decrease in optic nerve head perfusion parameters. Clinicians performing these injections should be aware of these findings and monitor the status of the optic nerve in patients undergoing injections.

Transplantation of Human Embryonic Stem Cell-Derived Retinal Cells into the Subretinal Space of a Non-Human Primate.

PURPOSE: Previous studies have demonstrated the ability of retinal cells derived from human embryonic stem cells (hESCs) to survive, integrate into the host retina, and mediate light responses in murine mouse models. Our aim is to determine whether these cells can also survive and integrate into the retina of a nonhuman primate, Saimiri sciureus, following transplantation into the subretinal space. METHODS: hESCs were differentiated toward retinal neuronal fates using our previously published technique and cultured for 60 to 70 days. Differentiated cells were further treated with 20 µM N-[N-(3,5-Difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT) for a period of 5 days immediately prior to subretinal transplantation. Differentiated cells were labeled with a lentivirus expressing GFP. One million cells (10,000 cells/µL) were injected into the submacular space into a squirrel monkey eye, using an ab externo technique. RESULTS: RetCam imaging demonstrated the presence and survival of human donor cells 3 months after transplantation in the S. sciureus eye. Injected cells consolidated in the temporal macula. GFP+ axonal projections were observed to emanate from the central consolidation of cells at 1 month, with some projecting into the optic nerve by 3 months after transplantation. CONCLUSIONS: Human ES cell-derived retinal neurons injected into the submacular space of a squirrel monkey survive at least 3 months postinjection without immunosuppression. Some donor cells appeared to integrate into the host inner retina, and numerous donor axonal projections were noted throughout, with some projecting into the optic nerve. TRANSLATIONAL RELEVANCE: These data illustrate the feasibility of hESC-derived retinal cell replacement in the nonhuman primate eye.

Reductive carboxylation is a major metabolic pathway in the retinal pigment epithelium.

The retinal pigment epithelium (RPE) is a monolayer of pigmented cells that requires an active metabolism to maintain outer retinal homeostasis and compensate for oxidative stress. Using 13C metabolic flux analysis in human RPE cells, we found that RPE has an exceptionally high capacity for reductive carboxylation, a metabolic pathway that has recently garnered significant interest because of its role in cancer cell survival. The capacity for reductive carboxylation in RPE exceeds that of all other cells tested, including retina, neural tissue, glial cells, and a cancer cell line. Loss of reductive carboxylation disrupts redox balance and increases RPE sensitivity to oxidative damage, suggesting that deficiencies of reductive carboxylation may contribute to RPE cell death. Supporting reductive carboxylation by supplementation with an NAD+ precursor or its substrate α-ketoglutarate or treatment with a poly(ADP ribose) polymerase inhibitor protects reductive carboxylation and RPE viability from excessive oxidative stress. The ability of these treatments to rescue RPE could be the basis for an effective strategy to treat blinding diseases caused by RPE dysfunction.

It's never too late to save a photoreceptor.

Recent gene therapy progress has raised the possibility that vision loss caused by inherited retinal degeneration can be slowed or prevented. Unfortunately, patients are not usually diagnosed until enough degeneration has occurred that the deterioration in vision is noticeable. Therefore, effective gene therapy must halt degeneration to stabilize and preserve any remaining vision. Gene therapy methods currently in human clinical trials rely on subretinal or intravitreal injections of adeno-associated virus to deliver the therapeutic gene. To date, long-term results in patients treated with subretinal injections for Leber congenital amaurosis have been mixed. Proposed limitations include variability in the gene delivery method and a possible point of no return, at which treatment would be ineffective. In this issue of the JCI, Koch et al. describe a well-controlled and precise mouse model for testing the ability of gene therapy to halt the progress of degeneration. Instead of viral-mediated therapeutic gene delivery, the authors induced expression of an integrated transgene at specific times during the course of photoreceptor degeneration. In Pde6b-deficient retina, this strategy halted degeneration, even when more than 70% of photoreceptors had already degenerated. The results of this study demonstrate that retinal degeneration can be stopped, even at late stages of disease.

Seed in soil, with an epigenetic view.

It is becoming increasingly evident that discrete genetic alterations in neoplastic cells alone cannot explain multistep carcinogenesis whereby tumor cells are able to express diverse phenotypes during the complex phases of tumor development and progression. The epigenetic model posits that the host microenvironment exerts an initial, inhibitory constraint on tumor growth that is followed by acceleration of tumor progression through complex cell-matrix interactions. This review emphasizes the epigenetic aspects of breast cancer development in light of such interactions between epithelial cells ("seed") and the tumor microenvironment ("soil"). Our recent research findings suggest that epigenetic perturbations induced by the tumor microenvironment may play a causal role in promoting breast cancer development. It is believed that abrogation of these initiators could offer a promising therapeutic strategy.

Retinopathy in persons without diabetes: the Los Angeles Latino Eye Study.

PURPOSE: To assess the prevalence of retinopathy and its relationship to sociodemographic and clinical characteristics in a population-based cohort of adult Latinos without diabetes mellitus. METHODS: This was a population-based, cross-sectional study comprising 6357 Latinos, 40 years of age and older, from six census tracts in La Puente, Los Angeles, California. An interviewer-administered questionnaire assessed sociodemographic factors and medical history. Color fundus photographs were taken and graded in a masked manner according to a modified Airlie House Classification Grading System. Participants underwent a physical examination that included height, weight, blood pressure, random serum glucose, and glycosylated hemoglobin measurements. Univariate and multivariate logistic regression analyses were used to assess associations between sociodemographic and clinical characteristics and retinopathy in persons without diabetes. RESULTS: The prevalence of retinopathy among individuals without diabetes in the Los Angeles Latino Eye Study (LALES) population was 6.6% (95% confidence interval 5.9%-7.4%). Stepwise logistic regression indicated that stage II hypertension (World Health Organization 2003 Guidelines), male gender, current smoking status, and obesity (body mass index >or= 30 kg/m(2)) were associated with retinopathy (odds ratio = 4.3, 1.6, 1.4, and 1.3, respectively). No statistically significant associations with retinopathy were present for Native American ancestry; country of origin; health insurance status; history of cardiovascular disease; or history of aspirin, oral contraceptive, or hormone replacement therapy. CONCLUSIONS: The data suggest that the prevalence of retinopathy in nondiabetic individuals among Latinos of primarily Mexican ancestry is significant. Independent risk indicators for retinopathy in the study population are hypertension, male gender, current smoking status, and obesity.

Characterization of the mouse adenylyl cyclase type VIII gene promoter: regulation by cAMP and CREB.

Adenylyl cyclase (AC) type VIII has been implicated in several forms of neural plasticity, including drug addiction and learning and memory. In the present study, we directly examined the role for the transcription factor CREB (cAMP response element binding protein) in regulating ACVIII expression by cloning a 5.2 kilobase region upstream of the translation start site of the mouse ACVIII gene. Analysis of this fragment revealed consensus elements for several transcription factors, including a canonical cAMP response element (CRE) in close proximity to the transcription initiation region. Next, ACVIII promoter activity was studied in two neural-derived cell lines and in primary cultures of rat striatal neurons. Activation of the cAMP pathway by forskolin treatment increased promoter activity, and a series of deletion and point mutants demonstrated that this activation is mediated specifically via the canonical CRE site. Gel shift assays confirmed that this site can bind CREB and several CREB family proteins. Further, activation of the ACVIII promoter by forskolin was potentiated by expression of a constitutively active form of CREB, CREB-VP16, whereas it was inhibited by expression of a dominant-negative form of CREB, A-CREB. Finally, over-expression of CREB in vivo, by viral-mediated gene transfer, induced ACVIII promoter activity in the brains of ACVIII-LacZ transgenic mice. These results suggest that the ACVIII gene is regulated by CREB in vitro and in vivo and that this regulation may contribute to CREB-dependent neural plasticity.