Biomedical subjects
Russell N Van Gelder
Publications and source records attributed to Russell N Van Gelder.
Inner retinal photoreception independent of the visual retinoid cycle.
Mice lacking the visual cycle enzymes RPE65 or lecithin-retinol acyl transferase (Lrat) have pupillary light responses (PLR) that are less sensitive than those of mice with outer retinal degeneration (rd/rd or rdta). Inner retinal photoresponses are mediated by melanopsin-expressing, intrinsically photosensitive retinal ganglion cells (ipRGCs), suggesting that the melanopsin-dependent photocycle utilizes RPE65 and Lrat. To test this hypothesis, we generated rpe65(-/-); rdta and lrat(-/-); rd/rd mutant mice. Unexpectedly, both rpe65(-/-); rdta and lrat(-/-); rd/rd mice demonstrate paradoxically increased PLR photosensitivity compared with mice mutant in visual cycle enzymes alone. Acute pharmacologic inhibition of the visual cycle of melanopsin-deficient mice with all-trans-retinylamine results in a near-total loss of PLR sensitivity, whereas treatment of rd/rd mice has no effect, demonstrating that the inner retina does not require the visual cycle. Treatment of rpe65(-/-); rdta with 9-cis-retinal partially restores PLR sensitivity. Photic sensitivity in P8 rpe65(-/-) and lrat(-/-) ipRGCs is intact as measured by ex vivo multielectrode array recording. These results demonstrate that the melanopsin-dependent ipRGC photocycle is independent of the visual retinoid cycle.
Metaplastic squamous epithelial downgrowth after clear corneal cataract surgery.
PURPOSE: To report a case of metaplastic squamous epithelial downgrowth after cataract surgery. DESIGN: Interventional case report. METHODS: Clinical, laboratory, and histologic findings are presented. Our study is in compliance with institutional review board guidelines. RESULTS: A 76-year-old man developed anterior chamber inflammation five months after uncomplicated clear corneal cataract surgery. Despite antimicrobial and anti-inflammatory therapies, the inflammation persisted. An extensive examination failed to demonstrate an infectious etiology or lymphoma. Subsequently, the patient developed an incipient limbal lesion and iris mass. Immunostaining of a biopsy specimen from the iris mass indicated an epithelial-derived tumor. The prephthisical and painful eye was enucleated; histopathology of the globe revealed a contiguous lesion extending from the limbal mass to the iris tumor through the surgical incision site, a finding consistent with metaplastic squamous epithelial downgrowth. Systemic evaluation was negative. CONCLUSIONS: After intraocular surgery, metaplastic epithelial downgrowth may occur as a consequence of occult ocular surface squamous neoplasia and masquerade as chronic inflammation; clinicians should be aware of this rare complication.
Rubeosis and anterior segment ischemia associated with systemic cryoglobulinemia.
PURPOSE: To report two cases of iris neovascularization associated with systemic cryoglobulinemia. DESIGN: Retrospective case report. METHODS: Patient chart review and review of literature. RESULTS: Two patients with iris neovascularization in the absence of retinal ischemia were subsequently found to have systemic cryoglobulinemia. Successful treatment of one patient's underlying lymphoma led to stabilization and resolution of neovascularization. CONCLUSIONS: Systemic cryoglobulinemia may be associated with anterior segment ischemia and neovascularization, and should be considered in the differential diagnosis of iris neovascularization in the absence of apparent retinal ischemia.
Impact of being "on call".
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Abnormal anterior chamber associated immune deviation (ACAID) in 129-strain mice.
PURPOSE: To characterize anterior chamber immune deviation (ACAID) in 129-strain and mixed 129-strain mice. METHODS: ACAID was assayed using standard protocols with herpes simplex-1 (HSV-1) and trinitrophenol-hapten-spleen cells (TNP-spleen) in C57B1/6, 129P2, 129X1, and intercrossed strains. Systemic tolerance induction was assayed using an ultraviolet light skin tolerance protocol to 2,-4,6-trinitro-l-chlorobenzene (TNCB). RESULTS: 129X1 and C57Bl/6xl29Xl Fl mice did not show ACAID to HSV-1. C57Bl/6xl29P2 mice did not show ACAID to TNP-spleen. C57Bl/6xl29P2 mice did show normal peripheral immune deviation to TNCB. (C57Bl/6xl29Xl) x C57B1/6 N2 backcrossed mice showed a bimodal ACAID response to HSV-1 suggesting a single dominant allele in the 129X1 background responsible for suppressing ACAID. CONCLUSION: ACAID to multiple antigens is significantly reduced in 129-strain mice and their outcrossed progeny. Since 129-strain embryonic stem cells are widely used to generate knockout and transgenic mice, care must be taken to extensively backcross resultant strains in order to assess the effect of particular genes on ACAID.
Physiologic diversity and development of intrinsically photosensitive retinal ganglion cells.
Intrinsically photosensitive retinal ganglion cells (ipRGCs) mediate numerous nonvisual phenomena, including entrainment of the circadian clock to light-dark cycles, pupillary light responsiveness, and light-regulated hormone release. We have applied multielectrode array recording to characterize murine ipRGCs. We find that all ipRGC photosensitivity is melanopsin dependent. At least three populations of ipRGCs are present in the postnatal day 8 (P8) murine retina: slow onset, sensitive, fast off (type I); slow onset, insensitive, slow off (type II); and rapid onset, sensitive, very slow off (type III). Recordings from adult rd/rd retinas reveal cells comparable to postnatal types II and III. Recordings from early postnatal retinas demonstrate intrinsic light responses from P0. Early light responses are transient and insensitive but by P6 show increased photosensitivity and persistence. These results demonstrate that ipRGCs are the first light-sensitive cells in the retina and suggest previously unappreciated diversity in this cell population.
Pharmacological and rAAV gene therapy rescue of visual functions in a blind mouse model of Leber congenital amaurosis.
BACKGROUND: Leber congenital amaurosis (LCA), a heterogeneous early-onset retinal dystrophy, accounts for approximately 15% of inherited congenital blindness. One cause of LCA is loss of the enzyme lecithin:retinol acyl transferase (LRAT), which is required for regeneration of the visual photopigment in the retina. METHODS AND FINDINGS: An animal model of LCA, the Lrat-/- mouse, recapitulates clinical features of the human disease. Here, we report that two interventions--intraocular gene therapy and oral pharmacologic treatment with novel retinoid compounds--each restore retinal function to Lrat-/- mice. Gene therapy using intraocular injection of recombinant adeno-associated virus carrying the Lrat gene successfully restored electroretinographic responses to approximately 50% of wild-type levels (p < 0.05 versus wild-type and knockout controls), and pupillary light responses (PLRs) of Lrat-/- mice increased approximately 2.5 log units (p < 0.05). Pharmacological intervention with orally administered pro-drugs 9-cis-retinyl acetate and 9-cis-retinyl succinate (which chemically bypass the LRAT-catalyzed step in chromophore regeneration) also caused long-lasting restoration of retinal function in LRAT-deficient mice and increased ERG response from approximately 5% of wild-type levels in Lrat-/- mice to approximately 50% of wild-type levels in treated Lrat-/- mice (p < 0.05 versus wild-type and knockout controls). The interventions produced markedly increased levels of visual pigment from undetectable levels to 600 pmoles per eye in retinoid treated mice, and approximately 1,000-fold improvements in PLR and electroretinogram sensitivity. The techniques were complementary when combined. CONCLUSION: Intraocular gene therapy and pharmacologic bypass provide highly effective and complementary means for restoring retinal function in this animal model of human hereditary blindness. These complementary methods offer hope of developing treatment to restore vision in humans with certain forms of hereditary congenital blindness.
Nonvisual ocular photoreception in the mammal.
Rodents blind from outer retinal (rod and cone) degeneration still retain several light-dependent phenomena, including entrainment of the circadian clock and pupillary light responsiveness. This paradox is explained by the presence of intrinsically photosensitive retinal ganglion cells in the inner retina. These cells have unique properties, including a novel action spectrum, resistance to bleaching and adaptation under continuous light, and resistance to vitamin A depletion. Two candidate classes of photopigment have been proposed: melanopsin and cryptochromes. Physiologic analysis of circadian entrainment and pupillary light responsiveness in mice lacking these proteins leads to three conclusions: (1) outer and inner retinal photoreceptors provide partially redundant information to the inner retina, (2) melanopsin is required for inner retinal phototransduction in the absence of rod and cone signaling, and (3) cryptochromes contribute to the amplitude of inner retinal phototransduction but are not strictly required.
Presumed ocular histoplasmosis syndrome.
PURPOSE OF REVIEW: Presumed ocular histoplasmosis syndrome remains a significant cause of visual morbidity. We review recent literature on the pathogenesis and particularly on the treatment of complications of presumed ocular histoplasmosis syndrome. RECENT FINDINGS: The pathogenesis of presumed ocular histoplasmosis syndrome remains mysterious; although some recent molecular evidence suggests a direct link between Histoplasma capsulatum and presumed ocular histoplasmosis syndrome, other reports document nearly identical disease occurring in the absence of H. capsulatum seropositivity. Treatment options have advanced rapidly in the past few years. Small case series and clinical trials suggest excellent efficacy for photodynamic therapy in the treatment of subretinal neovascularization associated with presumed ocular histoplasmosis syndrome. Preliminary studies also suggest efficacy of intravitreal corticosteroids. A large randomized controlled clinical trial failed to show efficacy for subretinal surgery in the management of presumed ocular histoplasmosis syndrome, however. SUMMARY: Despite continued debate on the etiology of presumed ocular histoplasmosis syndrome, there have been significant advances in treatment of the blinding complications of presumed ocular histoplasmosis syndrome.
Nonvisual photoreception in the chick iris.
The embryonic chicken iris constricts to light ex vivo, but with characteristics atypical of visual phototransduction. The chick iris was most sensitive to short-wavelength light, demonstrating an action spectrum consistent with cryptochrome rather than with opsin pigments. Pupillary responses did not attenuate after saturating light exposure, but showed paradoxical potentiation. Iris photosensitivity was not affected by retinoid depletion or inhibitors of visual phototransduction. Knockdown of cryptochrome expression, but not of melanopsin expression, decreased iris photosensitivity. These data characterize a non-opsin photoreception mechanism in a vertebrate eye and suggest a conserved photoreceptive role for cryptochromes in vertebrates.
Resetting the clock: Dexras1 defines a path.
The signaling pathways by which light and activity shift the circadian clock are not well understood. In this issue of Neuron, Cheng et al. analyze mice lacking Dexras1 (a Ras family GTPase protein) and demonstrate an important role for G(i/o) signaling mediating both photic and nonphotic phase shifts of the circadian clock.
Recent insights into mammalian circadian rhythms.
This short review highlights recent progress in understanding the mammalian circadian clock. Advances in the understanding of the neuroanatomy of circadian rhythms, the molecular biology of the core clock mechanism, mechanisms of light entrainment of the circadian clock, clock synchronization among multiple tissues, and recent work on the relationship of the mouse circadian clock and cancer are discussed. This review is intended as an overview of recent research activity for the interested sleep disorders clinician or researcher.
Diagnosis of microsporidia keratitis by polymerase chain reaction.
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Sleep disturbances in young subjects with visual dysfunction.
PURPOSE: To determine whether the type of ophthalmic disease is predictive of sleep and wakefulness disturbances in young subjects with visual dysfunction. DESIGN: Prospective cohort study. PARTICIPANTS AND CONTROLS: Twenty-five subjects (ages 12-20) were recruited from the Missouri School for the Blind. Twelve controls with normal sight were recruited from a residential school. METHODS: Daily activity was monitored for 14 days using wrist actigraphy. Sleep and wakefulness measures were derived from actigraphy records by automated analysis. Visually impaired subjects were prospectively stratified by presence or absence of optic nerve disease. MAIN OUTCOME MEASURES: Daytime napping and regularity of awakening time (wake-up time instability). RESULTS: Subjects with optic nerve disease napped in the daytime significantly more than other visually impaired children or normal sighted controls: 28.1+/-4.0 minutes per day (mean +/- standard error) versus 11.9+/-2.4 minutes per day in equally visually impaired subjects with intact optic nerve function versus 6.2+/-2.2 minutes per day in subjects with normal sight (P<0.0001). These subjects also showed significantly more variable awakening times than the other groups. Logistic regression revealed that subjects with optic nerve disease are 9.1 times more likely to demonstrate daily napping of more than 20 minutes per day than equally blind subjects without optic nerve disease (95% confidence interval [CI] = 1.4-58.7, P = 0.02). Blind subjects with optic nerve disease are 21.3 times more likely than children with normal sight to nap more than 20 minutes on average per day (95% CI = 1.2-378, P = 0.04). CONCLUSIONS: Optic nerve disease is predictive of increased daytime napping in young visually impaired subjects, suggesting that the nature and presence of ophthalmic disease affect the probability of concomitant sleep timing disorders.
Clean thoughts about dirty genes.
The mouse has joined the fruit fly, bread mold, and cyanobacteria as a tractable genetic system for studying mechanisms of circadian rhythms. The circadian rhythms of "knock-out" mice for specific clock genes, however, have demonstrated significant variability between laboratories. In this brief review, the authors discuss possible sources of this variability, focusing particularly on questions of modifier loci of circadian rhythms that vary between inbred mouse strains. They conclude with a short list of recommendations for researchers working on circadian rhythms in mixed-strain mice.
Effect of vitamin A depletion on nonvisual phototransduction pathways in cryptochromeless mice.
Mice exhibit multiple nonvisual responses to light, including 1) photoentrainment of circadian rhythm; 2) "masking," which refers to the acute effect of light on behavior, either negative (activity suppressing) or positive (activity inducing); and 3) pupillary constriction. In mammals, the eye is the sole photosensory organ for these responses, and it contains only 2 known classes of pigments: opsins and cryptochromes. No individual opsin or cryptochrome gene is essential for circadian photoreception, gene photoinduction, or masking. Previously, the authors found that mice lacking retinol-binding protein, in which dietary depletion of ocular retinaldehyde can be achieved, had normal light signaling to the SCN, as determined by per gene photoinduction. In the present study, the authors analyzed phototransduction to the SCN in vitamin A-replete and vitamin A-depleted rbp-/- and rbp-/-cry1-/-cry2-/- mice using molecular and behavioral end points. They found that vitamin A-depleted rbp-/- mice exhibit either normal photoentrainment or become diurnal. In contrast, while vitamin A-replete rbp-/-cry1-/-cry2-/- mice are light responsive (with reduced sensitivity), vitamin A-depleted rbp-/-cry1-/-cry2-/- mice, which presumably lack functional opsins and cryptochromes, lose most behavioral and molecular responses to light. These data demonstrate that both cryptochromes and opsins regulate nonvisual photoresponses.