An increase in the expression of the glial fibrillary acidic protein (GFAP) gene by astrocytes appears to constitute a crucial component of the brain's response to injury because it is seen in many different species and features prominently in diverse neurological diseases. Previously, we have used a modified GFAP gene (C-339) to target the expression of beta-galactosidase (beta-gal) to astrocytes in transgenic mice (Mucke et al.; New Biol 3:465-474 1991). To determine to what extent the in vivo expression of GFAP-driven fusion genes is influenced by intragenic GFAP sequences, the E. coli lacZ reporter gene was either placed downstream of approximately 2 kb of murine GFAP 5' flanking region (C-259) or ligated into exon 1 of the entire murine GFAP gene (C-445). Transgenic mice expressing C-259 versus C-445 showed similar levels and distributions of beta-gal activity in their brains. Exclusion of intragenic GFAP sequences from the GFAP-lacZ fusion gene did not diminish injury-induced upmodulation of astroglial beta-gal expression or increase beta-gal expression in non-astrocytic brain cells. These results demonstrate that 2 kb of murine GFAP 5' flanking region is sufficient to restrict transgene expression primarily to astrocytes and to mediate injury-responsiveness in vivo. This sequence therefore constitutes a critical target for mediators of reactive astrocytosis. While acute penetrating brain injuries induced focal increases in beta-gal expression around the lesion sites in C-259, C-445, and C-339 transgenic mice, infection of C-339 transgenic mice with scrapie led to a widespread upmodulation of astroglial beta-gal expression. Hence, GFAP-lacZ transgenic mice can be used to monitor differential patterns of astroglial activation in vivo. These and related models should facilitate the assessment of strategies aimed at the in vivo manipulation of GFAP expression and astroglial activation.

Objective To assess the efficacy and short-term safety of levodopa as adjunctive treatment to patching for amblyopia. Design Randomized, placebo-controlled trial. Participants One hundred thirty-nine children 7 to 12 years of age with residual amblyopia resulting from strabismus, anisometropia or both combined (20/50 to 20/400) following patching. Methods Sixteen weeks of oral levodopa or placebo administered 3 times a day while patching the fellow eye 2 hours per day. Main Outcome Measures Mean change in best-corrected amblyopic-eye visual acuity at 18 weeks. Results At 18 weeks, amblyopic-eye visual acuity improved from randomization by an average of 5.2 letters in the levodopa group and 3.8 letters in the placebo group (difference adjusted for baseline visual acuity = +1.4 letters, 1-sided P=0.06; 2-sided 95% confidence interval = −0.4 to +3.3 letters). No serious adverse effects from levodopa were reported during treatment. Conclusions For children 7 to 12 years of age with residual amblyopia following patching therapy, oral levodopa while continuing to patch 2 hours per day does not produce a clinically or statistically meaningful improvement in visual acuity compared with placebo and patching.

IMPORTANCECataract is an important cause of visual impairment in children. Data from a large pediatric cataract surgery registry can provide real-world estimates of visual outcomes and the 5-year cumulative incidence of adverse events. OBJECTIVE To assess visual acuity (VA), incidence of complications and additional eye operations, and refractive error outcomes 5 years after pediatric lensectomy among children younger than 13 years. DESIGN, SETTING, AND PARTICIPANTSThis prospective cohort study used data from the Pediatric Eye Disease Investigator Group clinical research registry. From June 2012 to July 2015, 61 eye care practices in the US, Canada, and the UK enrolled children from birth to less than 13 years of age who had undergone lensectomy for any reason during the preceding 45 days. Data were collected from medical record reviews annually thereafter for 5 years until September 28, 2020. EXPOSURES Lensectomy with or without implantation of an intraocular lens (IOL).MAIN OUTCOMES AND MEASURES Best-corrected VA and refractive error were measured from 4 to 6 years after the initial lensectomy. Cox proportional hazards regression was used to assess the 5-year incidence of glaucoma or glaucoma suspect and additional eye operations. Factors were evaluated separately for unilateral and bilateral aphakia and pseudophakia.RESULTS A total of 994 children (1268 eyes) undergoing bilateral or unilateral lensectomy were included (504 [51%] male; median age, 3.6 years; range, 2 weeks to 12.9 years). Five years after the initial lensectomy, the median VA among 701 eyes with available VA data (55%) was 20/63 (range, 20/40 to 20/100) in 182 of 316 bilateral aphakic eyes (58%), 20/32 (range, 20/25 to 20/50) in 209 of 386 bilateral pseudophakic eyes (54%), 20/200 (range, 20/50 to 20/618) in 124 of 202 unilateral aphakic eyes (61%), and 20/65 (range, 20/32 to 20/230) in 186 of 364 unilateral pseudophakic eyes (51%). The 5-year cumulative incidence of glaucoma or glaucoma suspect was 46% (95% CI, 28%-59%) in participants with bilateral aphakia, 7% (95% CI, 1%-12%) in those with bilateral pseudophakia, 25% (95% CI, 15%-34%) in those with unilateral aphakia, and 17% (95% CI, 5%-28%) in those with unilateral pseudophakia. The most common additional eye surgery was clearing the visual axis, with a 5-year cumulative incidence of 13% (95% CI, 8%-17%) in participants with bilateral aphakia, 33% (95% CI, 26%-39%) in those with bilateral pseudophakia, 11% (95% CI, 6%-15%) in those with unilateral aphakia, and 34% (95% CI, 28%-39%) in those with unilateral pseudophakia. The median 5-year change in spherical equivalent refractive error was −8.38 D (IQR, −11.38 D to −2.75 D) among 89 bilateral aphakic eyes, −1.63 D (IQR, −3.13 D to −0.25 D) among 130 bilateral pseudophakic eyes, −10.75 D (IQR, −20.50 D to −4.50 D) among 43 unilateral aphakic eyes, and −1.94 D (IQR, −3.25 D to −0.69 D) among 112 unilateral pseudophakic eyes. CONCLUSIONS AND RELEVANCEIn this cohort study, development of glaucoma or glaucoma suspect was common in children 5 ye...

IMPORTANCEIntravitreal bevacizumab effectively treats severe retinopathy of prematurity (ROP), but it enters the bloodstream and may reduce serum vascular endothelial growth factor (VEGF), potentially causing detrimental effects on developing organs in the premature infant.OBJECTIVE To evaluate the association of intravitreal bevacizumab with plasma bevacizumab and VEGF concentrations at 2 and 4 weeks after predefined, de-escalating doses of intravitreal bevacizumab were administered to infants with severe ROP. DESIGN, SETTING, AND PARTICIPANTSThis phase 1 dose de-escalation case series study was conducted at 10 US hospitals of ophthalmology institutions from May 21, 2015, to May 7, 2019. Blood samples were collected 2 and 4 weeks after intravitreal bevacizumab injection. Participants included 83 premature infants with type 1 ROP in 1 or both eyes and no previous ROP treatment. Data were analyzed from April 2017 to August 2021.INTERVENTIONS Study eyes received a single bevacizumab injection of 0.250 mg, 0.125 mg, 0.063 mg, 0.031 mg, 0.016 mg, 0.008 mg, 0.004 mg, or 0.002 mg. When the fellow eye required treatment, one dose higher was administered. Total dose administered at baseline was defined as the sum of doses given to each eye within 3 days of initial study-eye injection. MAIN OUTCOMES AND MEASURESPlasma bevacizumab concentration at 2 and 4 weeks after injection and the percentage change in plasma VEGF concentrations from pretreatment levels. RESULTS A total of 83 infants (mean [SD] age, 25 [2] weeks; 48 boys [58%]) were included in this study. Higher doses of bevacizumab administered at baseline were associated with higher plasma bevacizumab concentrations at 2 weeks (ρ, 0.53; 95% CI, 0.31-0.70) and 4 weeks (ρ, 0.44; 95% CI, 0.18-0.64). Plasma VEGF concentrations decreased by 50% or more from pretreatment levels in 40 of 66 infants (61%) at 2 weeks and 31 of 61 infants (51%) at 4 weeks, but no association was observed between the total dose of bevacizumab administered at baseline and percentage change in plasma VEGF concentrations 2 weeks (ρ, −0.04; 95% CI, −0.28 to 0.20) or 4 weeks (ρ, −0.17; 95% CI, −0.41 to 0.08) after injection.CONCLUSIONS AND RELEVANCE Results of this phase 1 dose de-escalation case series study revealed that bevacizumab doses as low as 0.002 mg were associated with reduced plasma VEGF levels for most infants at 2 and 4 weeks after intravitreal administration; however, no association was observed between total bevacizumab dose administered and reductions in plasma VEGF levels from preinjection to 2 weeks or 4 weeks. Additional studies are needed to evaluate the long-term effects of low-dose bevacizumab on neurodevelopment and retinal structure.

No abstract