Visual regulation of refractive development: insights from animal studies.

Investigations employing animal models have demonstrated that ocular growth and refractive development are regulated by visual feedback. In particular, lens compensation experiments in which treatment lenses are used to manipulate the eye's effective refractive state have shown that emmetropization is actively regulated by signals produced by optical defocus. These observations in animals are significant because they indicate that it should be possible to use optical treatment strategies to influence refractive development in children, specifically to slow the rate of myopia progression. This review highlights some of the optical performance properties of the vision-dependent mechanisms that regulate refractive error development, especially those that are likely to influence the efficacy of optical treatment strategies for myopia. In this respect, the results from animal studies have been very consistent across species; however, to facilitate extrapolation to clinical settings, results are presented primarily for nonhuman primates. In agreement with preliminary clinical trials, the experimental data show that imposed myopic defocus can slow ocular growth and that treatment strategies that influence visual signals over a large area of the retina are likely to be most effective.

COX-2 and iNOS are critical in advanced glycation end product-activated chondrocytes in vitro.

BACKGROUND: The advanced glycation end products (AGEs) accumulate in joints of osteoarthritis patients. This study aimed to investigate the roles of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) pathways in AGE-mediated cartilage damage. MATERIALS AND METHODS: Methylglyoxal-modified albumin was used as the source of AGE. Porcine and human chondrocytes were prepared from the joint cartilage of pigs and osteoarthritis patients. The activation of COX-2, iNOS, nuclear factor-kappaB (NF-kappaB), activator protein-1 (AP-1) and protein kinases was determined by Western blotting, kinase assay, electrophoretic mobility shift assay (EMSA) or transfection assay. Prostaglandin E(2) (PGE(2)) and NO concentrations were determined by enzyme-linked immunosorbent assay (ELISA) and Griess reaction respectively. The enzymatic activity of COX was determined by measuring the conversion of arachidonic acid to PGE(2). The release of sulphated glycosaminoglycan and the intensity of Safranin O staining were used to measure cartilage degradation. RESULTS: AGE potently induced COX-2-PGE(2) and iNOS-NO activation in porcine and human chondrocytes. Meanwhile, the upstream molecules regulating COX-2/iNOS activation, such as AP-1, NF-kappaB, extracellular signal regulated protein kinase (ERK) and c-jun N-terminal kinase (JNK), were activated by AGE. Although AGE could not activate p38 directly, by measuring COX enzyme activity, the inhibition of p38 resulted in suppressing AGE-induced conversion of arachidonic acid to PGE(2). Furthermore, successful blockage of either COX-2 or NOS activity significantly reduced AGE-mediated proteoglycan release and cartilage degradation. CONCLUSIONS: This study highlights the significance of COX-2 and iNOS pathways in AGE-mediated OA pathogenesis and their potential as therapeutic targets that are beyond pain killing for OA treatment.

Continuous ambient lighting and eye growth in primates.

PURPOSE: To determine the effect of continuous light exposure on ocular growth and emmetropization in infant monkeys. METHODS: Nine infant rhesus monkeys were reared with the normal vivarium lights on continuously. The 24-hour light cycle was initiated between 1 and 4 weeks of age and maintained for 6 months. The ocular effects of continuous light were assessed by cycloplegic retinoscopy, keratometry, and A-scan ultrasonography. Longitudinal control data were obtained from 23 normal infants that were reared with an illumination cycle that included defined light and dark phases (either 12-hour light:12-hour dark or 8.5-hour light:15.5 hour dark). RESULTS: In contrast to previous studies involving light-reared chickens, no monkeys exhibited exaggerated ocular growth. There were no significant differences between treated and control monkeys in corneal radius, overall eye size, or the axial dimensions of individual ocular components. At the end of the treatment period, eight of the nine experimental monkeys also exhibited the moderate hyperopic errors (range, +1.5 to +3.4 D) that are typically found in normal animals. Aspects of emmetropization were, however, unusual for three monkeys. One monkey manifested a -0.50 D myopic error that was associated with an abnormally steep cornea but had normal axial lengths. Two additional monkeys developed persistent axial anisometropias. CONCLUSIONS: In infant primates constant light exposure does not promote the constellation of ocular changes (in particular corneal flattening, a decrease in anterior chamber depth, and an increase in vitreous chamber depth) that has been observed in light-reared chickens. The slight variations from the expected developmental sequence observed in three infants may reflect individual differences. However, it is also possible that aspects of the emmetropization process may not operate as effectively under constant light as they do under an ordinary light/dark cycle.

The degree of image degradation and the depth of amblyopia.

PURPOSE: To determine whether the depth of monocular form-deprivation amblyopia is dependent on the degree of retinal image degradation. METHODS: Chronic monocular form deprivation was produced in nine infant rhesus monkeys by securing one of three different strengths of diffuser spectacle lenses in front of the treated eye and a clear zero-powered lens in front of the fellow eye. Three infant monkeys reared with plano lenses in front of both eyes provided control data. The treatment lenses were worn continuously from approximately 3 weeks of age for periods ranging between 11 and 19 weeks. When the monkeys were approximately 18 months of age, psychophysical procedures were used to measure the effects of the rearing procedures on the spatial contrast sensitivity function for each eye. RESULTS: The treated eyes of all nine diffuser-reared monkeys showed contrast sensitivity deficits that were indicative of amblyopia. On average, the interocular grating acuity difference increased systematically from 0.6 octaves for the weakest diffuser lens to 2.3 +/- 0.7 and 3.5 +/- 0.8 octaves for the intermediate and strongest diffuser lenses, respectively. There was a close correspondence between the magnitude of the amblyopic deficits and the reduction in retinal image contrast produced by the diffuser lenses. CONCLUSIONS: The results demonstrate that the depth of monocular, nonstrabismic amblyopia is strongly influenced by the degree of retinal image degradation experienced early in life.

Vision-dependent changes in the choroidal thickness of macaque monkeys.

PURPOSE: To determine whether changes in the eye's effective refractive state produce changes in the thickness of the choroid in infant monkeys. METHODS: Normal developmental changes in choroidal thickness were studied in 10 normal rhesus monkeys. Hyperopia or myopia was induced by rearing 26 infant monkeys with either spectacle or diffuser lenses secured in front of one or both eyes. The treatment lenses were worn continuously beginning at approximately 3 weeks of age for an average of 120 days. Refractive status and ocular axial dimensions, including choroidal thickness, were measured by retinoscopy and high-frequency A-scan ultrasonography, respectively. RESULTS: Three lines of evidence indicate that the normal increase in choroidal thickness that occurs during early maturation can be altered by the eye's refractive state. First, in monkeys experiencing form deprivation or those in the process of compensating for imposed optical errors, choroidal thickness and refractive error were significantly correlated with eyes developing myopia having thinner choroids than those developing hyperopia. Second, the choroids in eyes recovering from binocularly induced myopia increased in thickness at a faster rate than the choroids in recovering hyperopic eyes. Third, monkeys recovering from induced anisometropias showed interocular alterations in choroidal thickness that were always in the appropriate direction to compensate for the anisometropia. These changes in choroidal thickness, which were on the order of 50 microm, occurred quickly and preceded significant changes in overall eye size. CONCLUSIONS: Changes in the eye's effective refractive state produce rapid compensating changes in choroidal thickness. Although these choroidal changes are small relative to the eye's refractive error, they may play an important role in the visual regulation of axial growth associated with emmetropization.

Form-deprivation myopia in monkeys is a graded phenomenon.

To shed light on the potential role of the phenomenon of form-deprivation myopia in normal refractive development, we investigated the degree of image degradation required to produce axial myopia in rhesus monkeys. Starting at about 3 weeks of age, diffuser spectacle lenses were employed to degrade the retinal image in one eye of 13 infant monkeys. The diffusers were worn continuously for periods ranging between 11 and 19 weeks. The effects of three different strengths of optical diffusers, which produced reductions in image contrast that ranged from about 0.5 to nearly 3 log units, were assessed by retinoscopy and A-scan ultrasonography. Control data were obtained from ten normal infants and three infants reared with clear, zero-powered lenses over both eyes. Eleven of the 13 treated infants developed form-deprivation myopia. Qualitatively similar results were obtained for the three diffuser groups, however, the degree of axial myopia varied directly with the degree of image degradation. Thus, form-deprivation myopia in monkeys is a graded phenomenon and can be triggered by a modest degree of chronic image degradation.

The role of optical defocus in regulating refractive development in infant monkeys.

Early in life, the two eyes of infant primates normally grow in a coordinated manner toward the ideal refractive state. We investigated the extent to which lens-induced changes in the effective focus of the eye affected refractive development in infant rhesus monkeys. The main finding was that spectacle lenses could predictably alter the growth of one or both eyes resulting in appropriate compensating refractive changes in both the hyperopic and myopic directions. Although the effective operating range of the emmetropization process in young monkeys is somewhat limited, the results demonstrate that emmetropization in this higher primate, as in a number of other species, is an active process that is regulated by optical defocus associated with the eye's effective refractive state.

Developmental visual system anomalies and the limits of emmetropization.

Optical defocus can within certain limits predictably alter ocular growth and refractive development in infant monkeys. However defocus, particularly unilateral defocus associated with anisometropia, can also promote abnormal sensory and motor development. We investigated the relationship between the effective operating range for emmetropization in infant monkeys and the refractive errors that produced amblyopia. Specifically, we examined the refractive-error histories of monkeys that did not demonstrate compensating ocular growth for imposed refractive errors and used operant psychophysical methods to measure contrast sensitivity functions for 17 infant monkeys that were reared with varying degrees of optically imposed anisometropia. Imposed anisometropias that were within the operating range of the monkey's emmetropization process were eliminated by differential interocular growth and did not produce amblyopia. On the other hand imposed anisometropias that failed to initiate compensating growth consistently produced amblyopia; the depth of the amblyopia varied directly with the magnitude of the imposed anisometropia. These results indicate that amblyopia and anisometropia are frequently associated because persistent anisometropia causes amblyopia. However, the failure of emmetropization in infants with refractive conditions that are known to promote sensory and motor anomalies indicates that factors other than optical defocus, presumably factors associated with the development of amblyopia and/or strabismus, can also influence early refractive development and in some cases cause anisometropia.

Extended-wear, soft, contact lenses produce hyperopia in young monkeys.

To investigate the effects of experimentally induced defocus on eye growth and refractive development, one eye of four infant rhesus monkeys was fit with either a +3.0 D (N = 2) or -3.0 D (N = 2) extended-wear, soft, contact lens, and the other eye was fit with a zero-powered, control lens. The lens rearing regimen was started between 12 and 22 days of age and continued for 24 to 64 days. Hyperopic shifts in refractive error were found in all eyes, including the eyes treated with plano lenses. In addition to these absolute hyperopic shifts, 1.5 to 3.25 D of axial anisometropia were produced in all four monkeys, with the eyes wearing the powered lenses becoming relatively more hyperopic than the control eyes wearing the plano lenses. The induced hyperopia and anisometropia decreased rapidly after lens removal. The reapplication of the lenses at later ages in two animals produced smaller, but similar, changes. It appears that in very young primates extended-wear, soft, contact lenses can alter eye growth and refractive development through both visual and nonvisual mechanisms.

Spectacle lenses alter eye growth and the refractive status of young monkeys.

The influence of visual experience on ocular development in higher primates is not well understood. To investigate the possible role of defocus in regulating ocular growth, spectacle lenses were used to optically simulate refractive anomalies in young monkeys (for example, myopia or nearsightedness). Both positive and negative lenses produced compensating ocular growth that reduced the lens-induced refractive errors and, at least for low lens powers, minimized any refractive-error differences between the two eyes. These results indicate that the developing primate visual system can detect the presence of refractive anomalies and alter each eye's growth to eliminate these refractive errors. Moreover, these results support the hypothesis that spectacle lenses can alter eye development in young children.

Effects of optically induced blur on the refractive status of young monkeys.

In each of eight rhesus monkeys, one eye was defocused with a -9 D contact lens beginning before 1 month of age for periods of 2-3 months. At the end of the rearing period, interocular comparisons showed that one subject had developed a relative axial myopia (3.0 D), however, five monkeys had developed a relative axial hyperopia (2.0-3.5 D). After discontinuing the contact-lens rearing procedure, the induced refractive errors diminished over time in all subjects. These results indicate that the defocus threshold for form-deprivation myopia is relatively high and that substantial levels of optical defocus which do not exceed this threshold typically produce axial hyperopia. The recovery data suggests that monkeys have an emmetropization mechanism which is sensitive to optical defocus, but the failure of this mechanism to compensate for the refractive errors simulated during the lens-rearing procedures suggests that this mechanism has a limited operating range.

Effects of purine nucleoside analogues with a cyclobutane ring and erythromycin A oxime derivatives on duck hepatitis B virus replication in vivo and in cell culture and HIV-1 in cell culture.

The effects on duck hepatitis B virus (DHBV) replication of specific analogues of two classes of chemical compounds not previously tested against hepadnaviruses are described. One is erythromycin A-9-methyloxime (EMO) and other oxime derivatives of erythromycin A, and the other is purine nucleoside analogues (cyclobut A and cyclobut G) with cyclobutane rings. Viral replication was assessed by measuring serum levels of DHBV DNA in infected ducklings and DHBV DNA in infected primary duck hepatocyte cultures. Administration of EMO 15 mg/kg of body weight IM to infected ducklings resulted in a rapid fall in DHBV DNA levels during therapy and a return to pretreatment levels after EMO administration was stopped. There was local toxicity at injection sites with muscle necrosis in some animals. When 100 mg/kg EMO was administered by gastric tube no such viral response was observed. The difference in virus response to EMO 15mg/kg IM and 100 mg/kg by gastric tube was not due to failure to achieve comparable blood and tissue levels of EMO administered by the different routes. The results suggest an indirect effect dependent on IM injection of EMO rather than a direct antiviral effect of the compound. Administration of cyclobut G or cyclobut A at 70 mg/kg IM led to a rapid reduction of DHBV DNA to undetectable levels in serum, and in only 1 of 4 animals did DHBV DNA became detectable again within 10 days after stopping the drug.(ABSTRACT TRUNCATED AT 250 WORDS)

Correlation of optical components with ocular refraction among teen-agers in Taipei.

From 2 senior-high and 2 vocational schools in Taipei, 3251 children with age 16-19 were randomly selected to study the relationship between ocular refraction and its main optical components, corneal curvature and axial length. While the corneal curvature was found to play only a minor role in the determination of ocular refraction, the measurements of axial length parallelled the degree of myopia (r = 0.74). A two-years' longitudinal study of additional 411 children from one junior-high school (age 13 through 15) further pointed to the importance of axial length in the production and progression of myopia.