Albino Eyes Research Articles

Human equivalent doses of l-DOPA rescues retinal morphology and visual function in a murine model of albinism

l-DOPA is deficient in the developing albino eye, resulting in abnormalities of retinal development and visual impairment. Ongoing retinal development after birth has also been demonstrated in the developing albino eye offering a potential therapeutic window in humans. To study whether human equivalent doses of l-DOPA/Carbidopa administered during the crucial postnatal period of neuroplasticity can rescue visual function, OCA C57BL/6 J-c2J OCA1 mice were treated with a 28-day course of oral l-DOPA/Carbidopa at 3 different doses from 15 to 43 days postnatal age (PNA) and for 3 different lengths of treatment, to identify optimum dosage and treatment length. Visual electrophysiology, acuity, and retinal morphology were measured at 4, 5, 6, 12 and 16 weeks PNA and compared to untreated C57BL/6 J (WT) and OCA1 mice. Quantification of PEDF, βIII-tubulin and syntaxin-3 expression was also performed. Our data showed impaired retinal morphology, decreased retinal function and lower visual acuity in untreated OCA1 mice compared to WT mice. These changes were diminished or eliminated when treated with higher doses of l-DOPA/Carbidopa. Our results demonstrate that oral l-DOPA/Carbidopa supplementation at human equivalent doses during the postnatal critical period of retinal neuroplasticity can rescue visual retinal morphology and retinal function, via PEDF upregulation and modulation of retinal synaptogenesis, providing a further step towards developing an effective treatment for albinism patients.

Analysis of the Refractive Profile of Children with Oculocutaneous Albinism versus an Age-Matched Non-Albino Group.

PurposeTo find out and analyze the points of difference in the refractive profile between children with complete oculocutaneous albinism (OCA) and an age-matched, non-albino group seeking paediatric ophthalmic examination.MethodsA cross-sectional study was conducted on 164 infants and young children in Paediatric Ophthalmology Center, Sohag City, Egypt. Informed consent was obtained from the participants’ guardians. The study divided the population into 2 equal groups: albino group = 82 eyes, non-albino group = 82 eyes. Cycloplegic refraction and average keratometric measurements using the hand-held autokeratometer were taken for the study groups.ResultsIn the albino group, astigmatism and hypermetropia were the most common refractive errors, 100% and 62% respectively, with significant difference between both groups. Mean total (TA), corneal (CA) and lenticular astigmatism (LA) were significantly higher in albino group (P<0.05). All albino eyes were high astigmats (≥1.25 D).ConclusionThis study is novel in being comparative and includes the largest sample size ever reported for albino eyes of infants and children. High WTR astigmatism is the most prevalent refractive error in albinos with an overall bias toward hyperopia, but extreme errors (>−11.00D myopia or >+10.00D hyperopia) are not common. Albino eyes have a significantly higher degree of LA which compensates for the high CA to decrease the amount of TA. The study emphasizes the importance of refraction examination and visual rehabilitation for OCA children as early as possible to reduce eye morbidity-associated low vision.

Fundus Camera Guided Photoacoustic Ophthalmoscopy

Purpose: To demonstrate the feasibility of fundus camera guided photoacoustic ophthalmoscopy (PAOM) system and its multimodal imaging capabilities.Methods: We integrated PAOM and a fundus camera consisting of a white-light illuminator and a high-sensitivity, high-speed CCD. The fundus camera captures both retinal anatomy and PAOM illumination at the same time to provide a real-time feedback when we position the PAOM illuminating light. We applied the integrated system to image rat eyes in vivo and used full-spectrum, visible (VIS), and near infrared (NIR) illuminations in fundus photography.Results: Both albino and pigmented rat eyes were imaged in vivo. During alignment, different trajectories of PAOM laser scanning were successfully visualized by the fundus camera, which reduced the PAOM alignment time from several minutes to 30 s. In albino eyes, in addition to retinal vessels, main choroidal vessels were observed using VIS-illumination, which is similar to PAOM images. In pigmented eyes, the radial striations of retinal nerve fiber layer were visualized by fundus photography using full-spectrum illumination; meanwhile, PAOM imaged both retinal vessels and the retinal pigmented epithelium melanin distribution.Conclusions: The results demonstrated that PAOM can be well-integrated with fundus camera without affecting its functionality. The fundus camera guidance is faster and easier comparing with our previous work. The integrated system also set the stage for the next-step verification between oximetry methods based on PAOM and fundus photography.

Comparative analysis of transcriptional profiles between two apoptotic pathways of light-induced retinal degeneration

Light exposure can exacerbate the condition of a variety of human retinal diseases by increasing the rate of photoreceptor cell death. How light negatively affects photoreceptor cell survival is not yet fully understood. Previous studies involving light damage models have revealed two independent apoptotic pathways: low levels of light induce retinal degeneration in the arrestin −/− mouse via constitutive activation of the phototransduction cascade, whereas strong light exposure to the retina, such as in an albino eye, elicits photoreceptor cell death via activator protein (AP-1) induction. In order to better understand the initial gene expression changes underlying light damage, dark-reared arrestin −/− and albino BALB/c mice were exposed to constant white light (2000 lux), and their retinal morphology was assessed as a function of time. The expression profiles of retinal transcripts were then compared between dark-adapted and light-exposed arrestin −/−, pigmented wild-type and BALB/c mice at a time point when morphological changes were minimal. As expected, the dark-adapted samples showed little difference in expression pattern between the three genotypes. Among the genes differentially regulated by light in BALB/c, but not arrestin −/− retinas, were c-fos and other stress-induced early response genes. In both mouse models, a marked increase in expression of the bZIP family of transcription factors was observed. Our results show a select group of unique and overlapping sets of genes induced by light in the two mouse models. These expression changes may constitute the underlying initiating events leading to the two distinct mechanisms of light damage.

Retinal mitosis is regulated by dopa, a melanin precursor that may influence the time at which cells exit the cell cycle: analysis of patterns of cell production in pigmented and albino retinae.

A melanin-associated agent seems to play a role in regulating retinal development. When absent, diverse deficits occur. There is evidence that this agent regulates patterns of mitosis. This study examines retinal development in pigmented and albino rats to identify the regulating agent and its mode of action. Throughout neurogenesis, many more mitotic profiles are found in albinos than pigmented animals. At the peak of retinal neurogenesis, approximately 50% more mitotic profiles are found in albinos than in matched pigmented animals, resulting in abnormal retinal thickening. Concurrently, increasing numbers of pyknotic nuclei are identified, such that later in development retinal thickness normalises. However, the crude centre-to-periphery pattern of cell production is preserved. Abnormal cell proliferation is found in a range of albino rat strains, but it is not present in their brains, confirming that the abnormality is ocular and melanin related. Dopa is a critical element in initial stages of melanin synthesis and is present in abnormally low levels in developing albino retinae. Furthermore, it is an antimitotic agent. Addition of dopa to albino eyes in vitro normalises patterns of cell production. These results are consistent with the hypothesis that dopa is a major regulator of retinal cell production and that it influences the capacity of cells to exit the cell cycle.

Development of receptoral responses in pigmented and albino guinea-pigs (Cavia porcellus).

We describe the postnatal development of the electroretinogram (ERG) receptoral response in the guinea pig. In addition, the time course and nature of maturation was compared between albino and pigmented strains to consider the role that melanogenesis might have in this process. Electroretinograms were collected on groups of albino and pigmented animals from postnatal day (PD) PD1 to PD60. A-wave amplitudes and implicit times were extracted from filtered data (0-75 Hz). Receptoral components were modelled using the delayed gaussian model of Hood and Birch [1] fitted as an ensemble to the raw data. Guinea pigs show saturated amplitudes (RmP3) that are 50% of adult values at birth, these mature by PD12. Receptoral delay (t(d)) also undergoes some postnatal maturation, while phototransduction gain (log S) is adult-like at birth. Albino animals had significantly (p<0.05) larger RmP3 and log S across all ages. Guinea pigs have significant postnatal development in their receptoral response. Maturation of RmP3 implies a postnatal increase in rod outer segment length. Whereas the adult values of log S implies a mature phototransduction process at birth. We argue that the likely cause for the larger log S of albino eyes is compatible with theories of increased levels of internal light. Whereas the larger RmP3, even after allowing for increased light effectiveness, may reflect a lower ocular resistance in albino eyes due to their lower levels of melanin. Furthermore, decreased RmP3 and log S with age is observed in the pigmented group only and is consistent with increased ocular resistance due to melanin development in this strain.

Ocular effects of the venom from the spitting cobra (Naja nigricollis).

N. nigricollis venom caused transient corneal oedema, extensive chemosis and pupillary dilation when applied topically to the corneas of albino and pigmented rabbits. After 1 month, permanent corneal scarring, neovascularization and deepithelialization was noted in albino eyes, whereas minimal scarring or deepithelialization occurred in pigmented eyes. In contrast, mydriasis and cycloplegia occurred initially in the pigmented eye, with the pupil remaining fixed and dilated for more than 7 days. The albino pupil, however, returned to normal within 2-3 days. Preliminary penetration studies using labelled venom revealed that N. nigricollis venom was mainly bound in the corneal stroma of the albino eye and showed poor penetration, whereas minimal corneal binding and poor penetration was noted in the pigmented eye. It appears that the high initial corneal edema may result from the intrinsic release of histamine and acetylcholine. The progression of corneal edema to liquefaction and opacification is probably due to the release of an endogenous corneal damaging factor by the venom presumably a collagenase or proteinase. Treatment with corticosteroids significantly increased the severity of the keratoconjunctivitis and deepithelialization, whereas treatment with heparin significantly reduced the keratoconjunctivitis and prevented further opacification. It is postulated that heparin might act through its chelating effect on ions necessary for the action of the proteolytic enzymes.

Anti-T4-Tyrosinase Monoclonal Antibodies—Specific Markers for Pigmented Melanocytes

Tyrosinase (EC 1.14.18.1) is the enzyme essential to pigment formation in mammals; this enzyme is specifically localized in melanocytes, which occur primarily in the skin, hair bulbs, and eyes. Three hybridomas, TMH-1, TMH-2, and TMH-3, which produce monoclonal antibodies directed against tyrosinase, were obtained by fusion of SP2/0 myeloma cells and lymphocytes of rats hyperimmunized with purified melanosomal tyrosinase. These three monoclonal antibodies bound specifically to the mature, T4 form of tyrosinase, and did not bind to either of the precursor forms (T1 or T2) of the enzyme, which demonstrates that further posttranslational modifications of this enzyme occur which had not previously been detected. Epitope mapping studies have shown that at least two different immunologic determinants on tyrosinase are recognized by these antibodies. All three antibodies showed positive immunofluorescence staining of pigmented murine melanocytes from various sources, including B16 melanoma growing in vivo and in vitro, epidermal melanocytes, and retinal melanocytes. The antibodies did not cross-react with unpigmented cells, including K1735 amelanotic melanoma cells, albino murine skin or eye tissue, fibrosarcoma cells, rat fibroblasts, or epidermal keratinocytes. These monoclonal antibodies are sensitive, highly specific probes for pigmented mammalian melanocytes.

Calcium binding in pigmented and albino eyes.

The localization of calcium binding sites in eyes was determined autoradiographically after extracting endogenous Ca from tissue sections and replacing it with 45Ca. The strongest labeling was associated with pigmented tissues due to the high concentration of melanin, which was shown to bind Ca effectively and in a pH-dependent fashion. The second strongest binding was over the tapetum lucidum of the cat eye, and moderate labeling was associated with eye muscles and epithelium and endothelium of the cornea. The neural retina was generally more lightly labeled than the surrounding tissue of the eye; here the plexiform layers stood out in comparison to the nuclear layers, as did a band located internal to the photoreceptor outer segments. The possibility that the Ca buffering capacity of melanin may represent the common denominator for the various neurological defects found in hypopigmentation mutants is discussed.

Effect of ocular pigmentation on pilocarpine pharmacology in the rabbit eye. II. Drug response

The time course of the miotic response of pilocarpine in albino and pigmented rabbit eyes was studied after ocular application of 0.11. 0.43, 0.85 and 2.30 mg doses in eye drops and 0.85 and 2.30 mg doses in polymer matrices. When administered in eye drops ocular pigmentation delayed the onset of the peak effect of the 3 smallest pilocarpine doses. The magnitude of the peak effect was lower in pigmented than in albino eyes after 0.11 and 0.43 mg doses, but equal after larger doses. Ocular pigmentation increased the relative biophasic availability of 0.85 and 2.30 mg doses of pilocarpine. This was due to the slower elimination rate of pilocarpine from pigmented tissues. The relative biophasic availability of 0.11 and 0.43 mg doses of pilocarpine was not affected by the ocular pigmentation, because of the opposite effects of lower peak effect and slower elimination rate on biophasic availability in pigmented eyes. The administration of pilocarpine in polymer matrices increased the relative biophasic availability of the drug. When administered in polymer matrices, pilocarpine showed a typical time course of prolonged pulse-entry of the drug into the eye.

Retinofugal pathways from albino eyes embryonically transplanted to normal and albino axolotls.

Albino axolotl eyes were transplanted embryonically to normal and albino axolotl hosts. The animals were allowed to mature for several months and then their transplanted eyes were injected with tritiated proline. The projections from these albino eyes were compared with those obtained from similar transplants of normally pigmented eyes. Special attention was paid to the crossed and uncrossed components of the projections. No differences were found between normal and albino transplants. These results indicate that abnormal retinofugal crossing, which results from a lack of pigmentation in the mammalian eye, does not occur in the axolotl even when the fraction of retinal cells projecting ipsilaterally is experimentally increased by transplanting supernumerary eyes into embryos.

Disposition of topically applied vitamin A in the albino rabbit eye

Using radiotracer techniques, the disposition of vitamin A in the albino eye was studied following instillation of its solution in arachis oil in tear chamber, Early peak times were observed in the conjunctiva and the cornea suggesting rapid uptake of the drug by these tissues. Perhaps because of their proximity to the fear pool, these two tissues possessed the highest concentration of vitamin A. Sustained drug concentration was evident in all the ocuiar tissues studied—conjunctiva, cornea, aqueous humor and iris-ciliary body—beginning at 30 min post-instillation. This presumably was due to a reservoir for vitamin A in the precorneal area and perhaps the corneal epithelium; the nature of this reservoir has yet to be resolved. The significance was that vitamin A was available to the conjunctiva and the cornea from topical dosing, the two tissues known to undergo changes in vitamin A deficiency and dry-eye states. Unfortunately, these data as yet do not permit the formulation of a dosage regimen for topically applied vitamin A in the treatment of xerophthalmia.

Ultrastructural, histochemical and biochemical studies of the melanin metabolism in pallid mouse eye

In an attempt to determine the factors involved in ocular pigment variation, the eyes of pallid mice (c57BL/6J-Pa/Pa), and those of littermate black mice (C57BL/6J-+/Pa) were examined ultrastructurally, histochemically, and biochemically. As controls, the eyes of black and congenic albino mice (C57BL/6J +/C2J and -C2J/C2J) were also examined. In the developing pallid mouse eye the retinal pigment epithelium (RPE) and choroid contained immature melanosomes with incomplete melanization. In the adult pallid RPE, numerous lysosomal structures containing melanin components were present, while in choroid, melanosome numbers not only increased but many were aggregated in large membrane-bound granules. These RPE and choroidal structures may be melanolysosomes because of their histochemical acid phosphatase positive reactions. Biochemically, the activity of acid phosphatase in ocular homogenates of pallid eyes was significantly higher than in either the black eyes of +/Pa or in the albino and black eyes of the C2J genotypes. Dopa reactions at the light and electron microscopic levels indicated that Dopa oxidase activity was present in the cells of the RPE and choroid of both pallid and black mice. Histochemically the Dopa reaction of pallid pigment cells seemed to be equal to that of black ones, suggesting that tyrosinase production might be normal in pallid pigment cells. Biochemically, however, tyrosinase activity in the pallid eye was significantly lower than in the black control. It is concluded that the active digestion of melanosomes, as well as the low ocular tyrosinase activity and the immaturity of pallid melanosomes, may contribute to the pigment dilution observed in the pallid mouse eye.

Methadone accumulation in ocular tissue

For up to 6 days after administration of tritiated methadone the eyes of albino (Sprague Dawley) and pigmented (Long Evans) rats and frogs (Rana pipens) were assayed for methadone and metabolites in various eye substructures. The pigmented structures of the eye were found to contain the highest concentration of radioactivity at all time periods tested. At 6 days after administration of a single dose the pigmented epithelium of the rat retina showed a 100 times greater concentration of radioactivity than the blood. At 6 hours after dosage the pigmented eyes showed a 40 times greater concentration than the albino eyes suggesting that methadone does have a strong affinity for the pigmented structures of the eye.

Corneal Sensitivity in Albinos

The study reports measurements of corneal sensitivity in albino eyes obtained with a Cochet-Bonnet aesthesiometer. It was found to be much less sensitive (150% on average) than in a group of normal eyes. This result may have some bearing on the correction of albinos by contact lenses.

Tyrosinase positive oculocutaneous albinism in the goldfish, Carassius auratus L., an ultrastructural and biochemical study of the eye

Ultrastructural studies, and cytochemical and biochemical determinations of tyrosinase activity were conducted on the pigment epithelium of albino and xanthic goldfish eyes. In eyes of xanthic goldfish, two types of melanosomes are present, spherical and elongated. Melanized melanosomes are absent in the eyes of the albino goldfish, but elongated lamellar premelanosomes are observed. Internal vesicles are present in both melanosome types in the pigment epithelium of the xanthic goldfish but are absent in premelanosomes of the albino. There are also differences in the distribution of lipid droplets, smooth endoplasmic reticulum and Golgi complexes with the latter two being more abundant in the albino. Tyrosinase was not identified cytochemically; however, the enzyme was demonstrated biochemically in the pigment epithelia of both albino and xanthic goldfish. The enzyme is associated with the particulate and soluble fractions fo both types of eyes. Particulate albino tyrosinase may be solubilized by triton X-100 treatment. Tyrosinase inhibitors are present in the particulate fractions of both albino and xanthic goldfish eyes. Thus, in the goldfish, ocular albinism appears to be a multiple defect at the molecular and ultrastructural levels.

Aqueous chamber drug distribution volume measurement in rabbits.

A method was developed for aqueous chamber drug distribution volume measurement in the albino rabbit, and the apparent volume of distribution was determined for inulin, pilocarpine alkaloid, and 1-hexanoic acid. The method consists of injecting a suitable concentration of drug, in an appropriate volume of fluid, into the anterior chamber of the eye and monitoring the decline in drug concentration as a function of time by periodic sampling of the aqueous humor. Graphical analysis of the resulting data yields both the apparent volume of distribution and the turnover rate constant of the aqueous humor. The technique does traumatize the eye, causing formation of plasmoid aqueous, which does not interfere with the apparent drug distribution volume measurement or the determination of aqueous humor turnover. Inulin was used to determine the physiological aqueous volume, 287 mul, in good agreement with literature values. The turnover rate constant was 0.016 min-1, also in good agreement with literature values. The apparent volume of distribution for pilocarpine alkaloid was 575 mul in albino eyes and 760 mul in pigmented irides; for 1-hexanoic acid in albino eyes, it was 760 mul. For pilocarpine alkaloid, literature citations on the fraction of dose absorbed have been based on an assumed apparent volume of distribution of 250-300 mul. Therefore, a factor of two error has been introduced when using albino eyes and a factor of almost three has been introduced when using pigmented eyes. The implication of the apparent volume of distribution for pilocarpine in its ocular disposition is discussed, as is the unexpected observation that pilocarpine alkaloid apparently inhibits formation of plasmoid aqueous and follows one-compartment kinetics during these studies. Is is shown that the one-compartment kinetics for pilocarpine are due to its biological activity in the aqueous chamber.

Tissue distribution of 14-C-rifampicin II. Accumulation in melanin-containing structures.

Abstract: The tissue distribution of 14C‐rifampicin was investigated by whole body autoradiography in brown mice surviving up to 30 days after a single intravenous injection. In contrast to the findings in albino mice a long‐term retention was observed in the uveal tract, the inner ear and the skin. Similar results were obtained in pigmented rats. Sections of organs from a human foetus incubated in 14C‐rifampicin showed selective accumulation in the pigment epithelium of the eye. Quantitative determinations of radioactivity were performed of the blood, liver, lung, kidney and eye of mice up to 4 days after a single intravenous injection of 14C‐rifampicin. A 15‐fold difference was found between the pigmented and the albino eye after 4 days. The findings were interpreted as evidence for a melanin affinity of rifampicin and discussed in relation to its possible ocular and otological side effects, which seem to be mostly unverified and very infrequent even during long‐term therapy. However, the accumulation of transplacentally transferred drug in the eye and the inner ear provides a further reason for restricting its use during pregnancy.

Homoimmune Uveitis in the Guinea Pig

Introduction As noted in Sections II 1 and III, 2 of this series, experimental homoimmune uveitis primarily affected part or all of the uveal tract. Secondary involvement occurred in the vitreous, retina, and limbus. The possibility of spontaneous uveitis as well as adjuvantinduced uveitis had to be considered. It also was necessary to identify injuries and intercurrent ocular disease in the guinea pig and evaluate their relationship with clinical and histologic homoimmune uveitis. Materials Donor Eyes. —Some of the pigmented and albino eyes which were used for the preparation of pigmented and albino uveal antigens, comprising approximately 5,000 eyes, were studied grossly for eye disease. Normal Eyes (Nonexperimental). —Selected animals were chosen from the donor guinea pig group as well as from nonexperimental adult and newborn animals. This group composed approximately 60 eyes. Adjuvant Control Eyes. —The 250 eyes of control animals in Experiments I, II, III, IV made up

The Fatty Infiltration of the Liver of Mice resulting from the Ingestion of Medical Liquid Paraffin, etc

The fatty infiltration of the liver which follows the ingestion of medicinal liquid paraffin and many other varieties of mineral oils is more prevalent among females than among males, and is more prevalent among pigmented eye animals than among albino eye animals. When access to the oil lasts for about 30 weeks some 40 per cent, of pigmented eye females and 20 per cent. of the albino eye males may show the condition.It is the intermediate products, lubricating oils, obtained by distillation of a crude mineral oil which contain the bulk of the constituents which lead to fatty infiltration of the liver, while it is the so-called “spirits” and the residues left in the still which tend to lead to excessive hyaline degeneration of the organs in general. There is evidence to show that fatty infiltration of the liver and hyaline degeneration of the organs are mutually antagonistic, but there is little evidence to show that either condition is directly related to the cancerous process.