The effect of L-thyroxine supplementation in a neonatal rat model of ROP.

PURPOSE: The role of L-thyroxine in retinopathy of prematurity (ROP) is controversial. Recent animal studies suggest both high and low levels of serum thyroxine (exogenous supplementation and pharmacologic inhibition) are associated with preretinal neovascularization (NV) or retinal vascular retardation, a precursor of NV. To address this controversy, we studied L-thyroxine supplementation in an animal model of ROP. METHODS: Five hundred newborn Sprague-Dawley rats were raised in 20 expanded litters of 25, under conditions of fluctuating high and low oxygen and high carbon dioxide, to induce preretinal neovascularization. Rats received either 3 days of intraperitoneal T4, 7 days of T4 or saline control. Doses of T4 ranged from 0.005 microg/g to 0.5 microg/g. Retinae from left eyes were dissected, flat-mounted, and ADPase-stained. The presence and severity of NV, retinal vascular area, and retinal vascular density were scored in a masked manner. RESULTS: The incidence of NV was similar in rats receiving either 3 days of T4 or 7 days of T4 and saline controls (55% and 43% NV in 3-day experiments [0.05 microg g-1 day-1 and 0.5 microg g-1 day-1] compared with 51% in saline controls, p = 0.49; 52% and 38% in 7-day experiments [0.005 microg g-1 day-1 and 0.05 microg g-1 day-1], p = 0.22). Retinal vascular area and vessel density were also similar to saline controls. CONCLUSIONS: Systemic T4 supplementation does not increase, or decrease, the incidence or severity of preretinal neovascularization in an animal model of ROP, despite its positive effect on overall animal growth. Further work is needed to elucidate the potential role of premature infant hypothyroidism in the pathogenesis of ROP.

Differences between rat strains in models of retinopathy of prematurity.

PURPOSE: Genetic factors appear to modulate the incidence and severity of retinopathy of prematurity (ROP). Different rat strains may be analogous to genetic differences across human ethnic groups. We investigated the incidence and severity of neovascularization (NV) in Brown Norway (BN) and Sprague Dawley (SD) rats in oxygen-induced retinopathy (OIR) and acidosis-induced retinopathy (AIR) models for ROP. We also studied whether there was a difference in retinal vascular endothelial growth factor (VEGF) mRNA levels in OIR animals. METHODS: Newborn SD and BN rats (110 in both groups) were raised in standardized litters of ten (four OIR, twelve AIR, six non-gavaged room air controls). Beginning on day 1 of life, OIR litters were exposed to seven cycles of hyperoxia (80% O2, 20.5 h) and hypoxia (10% O2, 0.5 h) with a gradual return to 80% O2 over 3 h. This was followed by room air recovery for five days. OIR and OIR control rats were sacrificed on day 13 of life. AIR rats were gavaged twice daily with NH4Cl (10 mmol/kg) from day 2 to day 7 of life, or 15 mmol/kg twice daily on day 2 and then 10 mmol/kg twice daily from day 3 to day 7. AIR and AIR control rats were sacrificed on day 10 or day 13. Retinas from left eyes were dissected, ADPase stained and flatmounted. Presence and severity of NV (clock hours, 0 to 12) was scored by a masked observer. Right retinas from OIR and room air controls were processed for VEGF mRNA analysis. RESULTS: In OIR rats, the incidence of NV was higher in BN than SD rats (100% compared to 5%, p<0.0001). NV was more severe in BN rats (1 to 10 clock hours, median 7 clock hours compared to 0 to 1 clock hours, p=0.0001). In contrast, the incidence of NV in AIR rats was similar in BN and SD rats (4% compared to 0%, p=1.0) in the 10 mmol/kg study, and 18% compared to 0%, (p= 0.15) in the 15 mmol/kg study. Increased levels of retinal VEGF mRNA were found in BN OIR animals when compared to BN room air controls (1.4 fold increase) whereas retinal VEGF mRNA levels were similar between SD OIR and SD room air control animals. CONCLUSIONS: BN rats differ from SD rats in incidence and severity of NV in OIR. The findings in AIR were limited by the low incidence of NV and intolerance to higher multiple doses of NH4Cl. In OIR, the higher severity of NV was associated with higher retinal VEGF mRNA in BN OIR rats. Studies are warranted to investigate the genetic differences between Brown Norway and Sprague Dawley rats in models of ROP. These genetic studies may yield further clues into the pathogenesis of clinical ROP.

Factors that influence the development of posterior capsule opacification with a polyacrylic intraocular lens.

PURPOSE: To identify factors that contribute to posterior capsule opacification (PCO) after implantation of a 5.5 mm polyacrylic (IOL). DESIGN: A retrospective analysis of a cohort of sequential images taken from the PCO database at St. Thomas' Hospital, London, to include all patients with an AcrySof MA30 lens and a 1-year retroillumination image. METHODS: Records of age, gender, axial length, and PCO measurements using the POCO software system were available. Images were divided into those with greater or less than 10% PCO. The degree of rhexis-IOL contact was recorded in clock hours. RESULTS: Images of 60 eyes were analyzed. Twenty-one eyes had more than 10% PCO. No correlation was found between PCO and age, gender, or axial length. Forty-eight eyes (80%) had some loss of rhexis-IOL contact. These eyes had increased PCO (P < .001) compared with eyes with complete IOL-rhexis contact. More PCO developed when the rhexis was partly on and partly off the IOL. CONCLUSIONS: PCO is reduced when the rhexis is in complete contact with the anterior IOL surface. The failure to achieve this accounts for the majority of increased PCO seen in patients implanted with this IOL model. PCO formation is related to surgical technique as well as IOL design, and comparisons cannot be made between IOLs without taking this into consideration. These results support the trend to the use of larger optic IOLs to prevent PCO and also support the "capsule compression" theory of PCO prevention.

The effect of L-thyroxine supplementation on retinal vascular development in neonatal rats.

PURPOSE: Thyroxine (T4) plays a role in neuroretinal maturation, but little is known regarding its role in retinal vascularization. The neonatal rat retina is incompletely vascularized at birth, providing a model for the human premature infant retina and for retinopathy of prematurity (ROP). We hypothesized that T4 supplementation would accelerate vascular development of normal neonatal rat retina. METHODS: Two hundred twenty Sprague-Dawley rats were raised in litters of 10 in room air and received either 0.05 microg/g, 0.5 microg/g, or 1.0 microg/g of intraperitoneal T4 or saline control beginning on day 1 of life for 3 days, 7 days, or 3 days followed by 4 days recovery. Rats were sacrificed on either day 4 or day 8 of life. Left eyes were fixed, retinae dissected and ADPase-stained. Flat mounted retinae were digitized and total retinal areas and retinal vascular density were evaluated in a masked manner. Serum T4, thyroid stimulating hormone (TSH), and insulin-like growth factor-1 (IGF-1) were measured at each time point. RESULTS: Retinal vascular density was reduced in animals receiving daily 1 microg/g T4 compared with saline controls after 3 days of T4 (16.8 +/- 1.4 vessels/mm vs. 18.3 +/- 1.3 vessels/mm, p = 0.04) and 7 days of T4 (14.4 +/- 1.3 vessels/mm vs. 16.8 +/- 1.1 vessels/mm, p < 0.0006). However, retinal vascular density returned to normal after 3 days of treatment and 4 days of recovery. Vascularized retinal area was reduced in animals receiving 1 microg/g T4 for 3 days followed by 4 days recovery compared with saline controls (85 +/- 6% vs. 92 +/- 3%, p = 0.002). At lower doses of T4 (0.05 microg/g and 0.5 microg/g for 3 or 7 days) and at 1 microg/g T4 for 7 days, there was no effect on vascularized retinal area. Serum T4 levels were increased, with corresponding TSH suppression, after T4 treatment for 3 or 7 days. Serum IGF-1 levels were unaffected by T4 supplementation. CONCLUSIONS: Systemic T4 supplementation at 1 microg/g per day was detrimental to retinal vascular development in neonatal animals. If these effects are paralleled in human neonates, T4 supplementation might increase, rather than decrease, the risk of developing ROP. Further work on the role of T4 in the pathogenesis of ROP is warranted.