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Biomedical subjects

Young H Kwon

Publications and source records attributed to Young H Kwon.

At least 19 recordsLinked to original sources
PubMed2006

Gene expression profile of the adult human retinal ganglion cell layer.

PURPOSE: Pathophysiological events in the retinal ganglion cell layer (GCL) are a prominent feature of several optic neuropathies including glaucoma. The purpose of this study was to identify and catalog genes whose expression in the human retina is restricted to the GCL. METHODS: Laser capture microdissection (LCM) technology was used to isolate tissue from the perimacular retina of three human donors without retinal or optic nerve disease. RNA was isolated from the (1) retinal GCL and (2) the inner and outer nuclear layers of the same retina, and the gene expression profiles of both fractions were determined using Affymetrix Hu133Plus 2.0 GeneChips. Data were analyzed to identify those genes whose expression is substantially more prevalent in the GCL when compared to the outer retinal layers. Differential expression of selected genes was confirmed by real-time PCR and immunohistochemistry. RESULTS: The results show that mRNA levels of previously described ganglion cell markers, e.g. the neurofilament genes (NEFH, NEF3, or NEFL) and the Brn3a transcription factor (POU4F1), were highly enriched in the isolated GCL fraction. In contrast, transcripts for genes associated with phototransduction (RHO), photoreceptor development (NR2E3), or interphotoreceptor matrix constituents (IMPG1) were nearly absent from the GCL fraction. Using bioinformatics approaches over 80 genes were identified whose expression in the human retina appears to be limited to the GCL. CONCLUSIONS: We have successfully used LCM technology to generate gene expression profiles of highly enriched GCL fractions of the normal human retina. These data not only provide clues to the normal function of retinal ganglion cells but also serve as a resource in the development of ganglion cell specific markers or transfection vectors, and the identification of candidate genes for hereditary forms of glaucoma.

Aged↗
PubMed2006

Retinal synthesis and deposition of complement components induced by ocular hypertension.

Inappropriate activity of the complement cascade contributes to the pathophysiology of several neurodegenerative conditions. This study sought to determine if components of the complement cascade are synthesized in the retina following the development of ocular hypertension (OHT) and if complement accumulates in association with retinal ganglion cells. Toward this goal the gene expression levels of complement components 1qb (C1qb) and 3 (C3) were determined in the retina by quantitative polymerase chain reaction in human eyes with elevated intraocular pressure (IOP) and healthy retinal tissue as well as in a rat model of OHT induced by laser cauterization of the trabecular meshwork and episcleral veins. Immunohistochemical methods were employed to determine the sites of complement deposition in the retina and optic nerve head. Our data demonstrate that transcript levels for C1q and C3 are significantly elevated in retinae subjected to OHT, both in the animal model as well as in human eyes. Immunohistochemical analyses indicate that C1q and C3 accumulate specifically in the retinal ganglion cell layer and the nerve fiber layer. In addition, we demonstrate that the terminal complement complex, or membrane attack complex, is formed both in the human and rat model as a consequence of OHT. Complement activation, particularly formation of membrane attack complexes, has the potential to exacerbate ganglion cell death through bystander lysis or glial cell activation. The results show that complement activation occurs in the retina that has been subjected to elevated IOP, and may have implications in pathophysiology of glaucoma.

Animals↗
PubMed2006

Visual stimulus-induced changes in human near-infrared fundus reflectance.

PURPOSE: Imaging studies from anesthetized feline, primate, and human retinas have revealed near-infrared fundus reflectance changes induced by visible light stimulation. In the present study, the spatial and temporal properties of similar changes were characterized in normal, awake humans. METHODS: Five normal human subjects were studied. A modified fundus camera was used to image changes in retinal reflectance of 780-nm near-infrared light imaged onto a 12-bit charge-coupled device (CCD) camera in response to a green (540 nm) visual stimulus. During 60 seconds of recording (frame rate, 3 Hz) 10 cycles were recorded, during each of which 3 seconds of blank and then 3 seconds of either vertical bar or blank stimulus was projected. The change in the average near-infrared reflectance of the stimulated retinal region relative to an equal-sized nonstimulated region (r is the ratio of reflectance between the two retinal areas) was analyzed with a mixed model for repeated measures. RESULTS: The mixed model showed a significant average decrease in r of 0.14% (95% CI, -0.25 to -0.03) over all subjects induced by bar stimulus cycles, with a gradual return to baseline after stimulus offset, compared with only a 0.04% (95% CI, -0.11-+0.20) decrease in r induced by blank, nonstimulated cycles. The mixed model for individuals showed a decreasing linear trend in r over time during bar stimulation, but no decrease for blank cycles in three of five subjects. CONCLUSIONS: There was a localized decrease in reflectance in response to 780-nm near-infrared light in the retinal region exposed to a visual stimulus, which was significant in three of five subjects. It is presumed that the reflectance change represents the functional activity of the retina in response to a visual stimulus.

Adult↗
PubMed2006

Neuroglobin and cytoglobin: oxygen-binding proteins in retinal neurons.

PURPOSE: The goal of this study was to describe the detailed localization of the novel oxygen-binding molecules, neuroglobin (Ngb) and cytoglobin (Cygb), in mammalian retinas and to determine whether Ngb and Cygb are neuronal or glial proteins in the retina. METHODS: Antibodies directed against Ngb and Cygb were used to examine their patterns of distribution in normal canine retinas. Immunoblot analysis was performed to verify antibody specificity and the presence of Ngb and Cygb in canine tissues. Double-labeling immunohistochemistry was performed with the Ngb and Cygb antibodies along with antibodies against neuronal (MAP-2, class III beta-tubulin (TUJ1), PKCalpha, and calretinin) and glial antigens (vimentin and CRALBP). Tissue sections were analyzed with light and confocal microscopy. RESULTS: Ngb and Cygb proteins were observed in different retinal cells. Cygb (but not Ngb) was also present in canine kidney, liver, lung, and heart tissue. Immunohistochemical analysis of canine retinas demonstrated Ngb immunoreactivity (IR) in the ganglion cell layer (GCL), inner (INL) and outer (ONL) nuclear layers, inner (IPL) and outer plexiform (OPL) layers, photoreceptor inner segments (IS), and retinal pigment epithelium (RPE). Ngb IR was localized within retinal neurons, but not in glia. Cygb IR was found in neurons and their processes in the GCL, IPL, INL, and OPL and within the RPE, but not in glia. CONCLUSIONS: Ngb and Cygb are widely distributed in retinal neurons and RPE, but not in glial cells of the canine retina. Their structure and distribution is suggestive of a possible role in oxygen transport in the mammalian retina.

Animals↗
PubMed2005

Morphological integration and functional assessment of transplanted neural progenitor cells in healthy and acute ischemic rat eyes.

We have functionally and morphologically characterized the retina and optic nerve after neural progenitor cell transplants to healthy rat eyes and eyes damaged by acute elevation of intraocular pressure (IOP). Green fluorescent protein-expressing adult rat hippocampal progenitor cells (AHPCs) were transplanted by intravitreal injection into healthy eyes and eyes damaged with acute ocular hypertension. Pupil light reflexes (PLR) and electroretinograms (ERGs) were recorded preoperatively and postoperatively. Eyes were subsequently prepared for immunohistochemical analysis and confocal imaging. Transplanted AHPCs were found in 8 of 15 (53%) acute ischemic eyes 62 days after surgery and 5 of 10 (50%) healthy eyes 32 days after grafting. Analysis of PLR and ERG function in acute ischemic eyes revealed no statistically significant difference compared to controls after transplantation for all observed functional parameters. Transplant into healthy rat eyes revealed no PLR or ERG amplitude deficits between transplanted and non-transplanted (control) eyes. Morphological and immunohistochemical analysis revealed that transplanted AHPCs survived and differentiated in both normal and injured retinal environments. Morphological integration occurred primarily within the inner retinal layers of the acute ischemic eyes. AHPCs were found to express neuronal and glial markers following transplantation. Transplanted AHPCs have the ability to integrate and differentiate in ischemia damaged retinas. PLR and ERG analysis revealed no significant difference in functional outcome in transplant recipient eyes.

Acute Disease↗
PubMed2005

Retinal ganglion cell death in glaucoma: mechanisms and neuroprotective strategies.

Various cellular and molecular mechanisms that may lead to apoptotic cell death of retinal ganglion cells in glaucoma are discussed. These cellular mechanisms include neurotrophic factor deprivation, ischemia, glial cell activation, glutamate excitotoxicity, and abnormal immune response. Based on experimental and clinical evidence, the rationale for various neuroprotective strategies is described.

Apoptosis↗
PubMed2004

A novel p21WAF1/CIP1 transcript is highly dependent on p53 for its basal expression in mouse tissues.

p21WAF1/CIP1 is an important transcriptional target of p53 and it plays a critical role in growth arrest after DNA damage. Here, we report the identification of a novel alternate mouse p21 transcript that is conserved in evolution. It differs from the classical p21WAF1/CIP1 transcript in the first exon, which is located at approximately 2.8 kb upstream of transcriptional start site of p21WAF1/CIP1 and is sandwiched between two p53 binding sites. This novel p21 transcript is present in most mouse tissues with highest levels of expression in the spleen. In contrast to the classical p21WAF1/CIP1 transcript, this new transcript is highly dependent on p53 for its basal expression, as evidenced by its absence in nearly all of p53-/- mouse tissues. This transcript is also absent at nonpermissive temperature in a 10-1 mouse cell line lacking endogenous p53 and harboring temperature-sensitive p53 mutant. However, this novel transcript is induced to appreciable levels in the presence of high p53 activity at the permissive temperature. Our data suggest that p53-dependent induction of p21 may be an additive effect conferred by individual increases in the alternate and classical p21 transcripts.

Animals↗
PubMed2004

Atypical pigment dispersion syndrome in a child.

PURPOSE: To describe the features of atypical pigment dispersion in a child. DESIGN: Observational case report. METHODS: Retrospective chart review. RESULTS: An 8-year-old boy presented with midperipheral iris transillumination defects, iris backbowing, heavy pigmentation of the trabecular meshwork, and elevated intraocular pressure. He also had several atypical features including emmetropia, mild posterior subcapsular cataract, small pupils, and peripheral anterior synechiae. CONCLUSION: Pigment dispersion in childhood is unusual and may have different features from those classically described in adults.

Cataract↗
PubMed2004

Functional evaluation of retina and optic nerve in the rat model of chronic ocular hypertension.

PURPOSE: To functionally characterize the rat retina and optic nerve after chronic elevation of the intraocular pressure (IOP) using electroretinography (ERG) and computerized pupillometry. METHODS: Chronic elevation of the IOP was induced in Brown Norway rats by combined injection of indocyanine green dye (ICG) into the anterior chamber and diode laser treatment, followed by ERG and pupil light reflex (PLR) monitoring. RESULTS: Laser treatment induced significant elevation of the IOP in operated eyes for 6 weeks, with maximal values observed 14 days postoperatively (ctrl=18.4+/-2.4 and operated=35+/-8.4 mmHg; mean+/-sd). Preoperative values for the PLR(ratio) were 68.5+/-4% (mean+/-sem; %). Three days postoperatively the PLR(ratio) decreased to 60.3+/-10.3%, but was not significantly different compared to preoperative values (p > 0.05 Kruskal-Wallis non-parametric test with Dunn's post-test). However, 7, 14 and 21 days postoperatively the PLR function dramatically decreased to 14.6+8.6, 11.5+/-6.7 and 12.6+/-4%, respectively, and was significantly smaller compared to preoperative values (p < 0.01). At day 28 the PLR significantly recovered and was not significantly different compared to preoperative values (PLR(ratio)=38.5+/-8.6, p > 0.05). However, 35 days after surgery the PLR started to decrease once again in the operated eyes (PLR(ratio)=17.2+/-7.4%) and was significantly smaller again compared to preoperative values (p < 0.05) The PLR values continued to decrease until the end of experiment (60 days postoperatively). ERG analysis of operated eyes revealed significantly decreased amplitudes of a- and b-waves 10d postoperatively, while oscillatory potentials (OPs) and flicker ERG (flERG) amplitudes were not detectable. However, 28 days postoperatively OPs significantly, but temporarily recovered, while a-wave, b-wave and flERG amplitudes did not significantly change compared to values observed 10d postoperatively. The ERG analysis of the operated eyes revealed significantly reduced amplitudes 60 days postoperatively. Histological analysis revealed degeneration of all retina layers and optic nerve axons. CONCLUSIONS: Chronic ocular hypertension in rats produces dramatic damage to all retinal layers and optic nerves observed by morphological and functional methods which significantly correlate with the IOP elevation. Outer retina of glaucomatous rats seems to be more susceptible to the damage due to chronic elevation of the IOP. Chronic hypertensive rat eyes have capacity to temporarily recover function of the inner retina and optic nerve.

Animals↗
PubMed2003

Vitreous amino acid concentrations in patients with glaucoma undergoing vitrectomy.

OBJECTIVE: To measure vitreous concentrations of glutamate and other amino acids in patients with glaucoma undergoing vitrectomy. METHODS: Undiluted vitreous samples were collected from patients undergoing vitrectomy at the University of Iowa (Iowa City) between 1997 and 1998 (n = 69). Vitreous concentrations of 16 amino acids, including glutamate, were determined using high-pressure liquid chromatography. Patients with a history of diabetes mellitus were excluded from the analysis. The study group consisted of those with a history of glaucoma (n = 8), and the control group included those with an epiretinal membrane and/or macular hole with no history of glaucoma (n = 17). Comparison of amino acid concentrations between the 2 groups was performed using a multifactor main effects model that adjusted for the effect of 10 selected covariates. Power analysis was done to determine the level of significant difference in amino acid concentrations. RESULTS: The glaucoma group comprised vitreal specimens from patients with primary open-angle (n = 3) and angle-closure glaucomas that included aqueous misdirection (n = 2), uveitis with secondary angle-closure (n = 2), and Axenfeld Rieger syndrome (n = 1). Indications for vitrectomy in this group included epiretinal membrane, retinal detachment, aqueous misdirection, and uveitis. The control group included specimens from patients with a macular hole (n = 11) and epiretinal membrane (n = 7), with 1 eye having both. Surgical indications in controls were macular hole, retinal detachment, and epiretinal membrane. The mean +/- SD levels of vitreous glutamate, glycine, gamma-aminobutyric acid, and alanine were 6.1 +/- 2.4, 16.3 +/- 7.5, 0.8 +/- 0.3, and 260.5 +/- 101.9 microM, respectively, in glaucoma and 5.2 +/- 2.3, 8.5 +/- 2.5, 0.6 +/- 0.2, and 159.5 +/- 54.9 microM in controls (P >.05 for all). None of the 16 amino acid concentrations measured showed a statistically significant difference between glaucoma and controls (P values between.06 and >.99). A power analysis indicated that a 1.8-fold elevation in the glutamate level was needed to reach significance. MAIN OUTCOME MEASURES: Vitreous amino acid concentrations. CONCLUSIONS: None of the 16 amino acids measured, including glutamate, were significantly elevated in the vitreous of glaucomatous eyes compared with controls. Our results are not consistent with the simple hypothesis of glutamate excitotoxicity in glaucoma. Instead, our findings indicate the dynamic nature of extracellular glutamate, whose concentration is dependent on complex mechanisms not yet fully understood. Further studies are needed to fully elucidate the role of glutamate in the pathogenesis of glaucoma.

Aged↗
PubMed2003

A family with Axenfeld-Rieger syndrome and Peters Anomaly caused by a point mutation (Phe112Ser) in the FOXC1 gene.

PURPOSE: Mutations of the forkhead transcription factor gene FOXC1 result in anterior segment anomalies. No description of the spectrum of defects resulting from a single point mutation of this gene exists in the ophthalmology literature. We have screened all available patients with Axenfeld-Rieger genes (PITX2 and FOXC1). In this report, we clinically characterize the spectrum of ocular and systemic manifestations in one family resulting from a previously reported point mutation (Phe112Ser) in FOXC1. DESIGN: Observational case series. METHODS: Ten members of a multigenerational family were examined for signs of glaucoma, anterior segment abnormalities, and systemic features of Axenfeld-Rieger syndrome. The examinations were performed in an ophthalmology examination room or in the patients' homes. Blood was obtained from 10 members and screened for mutations in FOXC1 using direct DNA sequencing. RESULTS: A single mutation causing a T to C change in codon 112 (Phe112Ser) of FOXC1 was present in six members of the family. Five of these six patients were examined and all demonstrated anterior segment anomalies. One patient had Axenfeld anomaly, one had Rieger syndrome, and one had both Axenfeld anomaly and Peters anomaly. Additionally, some members demonstrated cardiac abnormalities, which may be secondary to their FOXC1 mutation. CONCLUSIONS: A wide spectrum of clinical phenotypes can result from a single point mutation of FOXC1. This report confirms that Rieger syndrome (with dental and facial abnormalities) can be caused by a mutation in FOXC1. It is also the first report of Peters anomaly being caused by a FOXC1 mutation.

Abnormalities, Multiple↗
PubMed2003

Evaluation of optineurin sequence variations in 1,048 patients with open-angle glaucoma.

PURPOSE: To investigate the association of sequence variations in the optineurin (OPTN) gene in patients with open-angle glaucoma. DESIGN: Prospective case control study. METHODS: The OPTN gene was screened for sequence variations using a combination of single-strand conformational polymorphism analysis and automated DNA sequencing. A total of 1,299 subjects (1048 glaucoma patients and 251 controls) were screened for variations in the four portions of the gene that had been previously associated with glaucoma. A subset of these subjects (376 patients and 176 controls) was screened for variations in the entire coding sequence. Twenty-four percent of the patients and 35% of the controls were Japanese, whereas the remainder were predominantly Caucasian. Allele frequencies were compared with the Fisher exact test. RESULTS: The OPTN sequence variations were not significantly associated with any form of high-tension open-angle glaucoma. One proband with familial normal-tension glaucoma was found to harbor the previously reported Glu50Lys variation. Another previously reported change, Met98Lys, was associated with normal-tension glaucoma in Japanese but not in Caucasian patients. CONCLUSIONS: This study provides some additional evidence for the association of the Glu50Lys OPTN sequence variation with familial normal tension glaucoma. However, because familial normal-tension glaucoma is so rare, this change seems to be responsible for less than 0.1% of all open-angle glaucoma. The Arg545Gln variation is likely to be a nondisease-causing polymorphism. The Met98Lys change may be associated with a fraction of normal-tension glaucoma in patients of Japanese ethnicity.

Base Sequence↗
PubMed2003

Temporary elevation of the intraocular pressure by cauterization of vortex and episcleral veins in rats causes functional deficits in the retina and optic nerve.

PURPOSE: To evaluate visual function in rats with chronic elevation of intraocular pressure (IOP). METHODS: Chronic ocular hypertension was induced in the left eye of 14 adult Brown Norway rats by cauterizing 3 vortex veins and 2 major episcleral veins; the right eye served as a non-operated control. A control group (n=5) was sham operated on the left eye. Prior to surgery, the IOP was measured with a Tonopen, the pupil light reflex (PLR) evaluated with a custom-made computerized pupillometer and electroretinograms (ERGs) were recorded simultaneously from both eyes post surgically: IOP was measured on weeks 1, 3, 5 and 8 post-operatively, pupil light reflexes on weeks 1, 4 and 8 post-operatively, and ERGs on weeks 4 and 8 post-operatively. Sixty five days postoperatively, rats were euthanized and optic nerves and eye globes were prepared for histological analysis. RESULTS: Seven days after surgery 5/14 rats developed significant elevation of the IOP in operated eyes (control eyes: 25.1+/-0.5mmHg; operated eyes: 34.1+/-0.6mmHg; mean+/-SEM; p=0.0004; Paired t-test). Elevation of the IOP was sustained at 3 (p=0.002) and 5 (p=0.007) weeks postoperatively. However, IOP values did not significantly differ between control and operated eyes 8 weeks postoperatively (p=0.192, Paired t-test). Sham operated animals showed no elevation of the IOP 7 days postoperatively. When the ratio between consensual and direct PLR (PLR(ratio)=consensual/direct PLR; pupil of unoperated eye recorded) was examined in rats which developed elevation of the IOP, preoperative values were 92.2+/-4% (mean+/-SEM), 1 week postoperatively 65+/-4% (significantly different from preoperative values, p<0.05 Repeated Measures ANOVA with Dunnett's Multiple Comparison test, n=5), 4 weeks postoperatively 60.6+/-3.2% (p<0.01, n=5). By 8 weeks postoperatively, pupil responses had essentially recovered 75.4+/-6.9% (p>0.05, n=5). Rats whose IOP values did not rise after surgery and sham operated rats did not develop pupil deficits 4 weeks postoperatively. Rats with elevated IOP displayed a significant decrease in ERG amplitudes in operated eyes at 4 weeks (a-wave(operated)/a-wave(control) (a-wave ratio)=42+/-14% (mean+/-SEM); b-wave(operated)/b-wave(control) (b-wave ratio)=43+/-16%) but not at 8 weeks postoperatively (a-wave ratio=88+/-8.4%; b-wave ratio=82.9+/-9%). Sham operated and rats whose IOP values remained non-elevated after surgery did not develop ERG deficits 4 weeks after surgery. Histological analysis did not reveal any damage in the eyes of animals with elevated intraocular ocular pressure with the exception of one rat, which still had ERG and pupil deficits at the end of experiment. CONCLUSIONS: Development of ERG and PLR deficits are proportional to the elevation of the IOP in the rat model of chronic ocular hypertension. Functional monitoring of the ERG and PLR are useful objective techniques for the detection of retina and optic nerve deficits.

Animals↗
PubMed2003

Characterization of the pupil light reflex, electroretinogram and tonometric parameters in healthy mouse eyes.

PURPOSE: To characterize the pupil light reflex (PLR), electroretinographic (ERG) and tonometric parameters which might be of importance for the in vivo characterization of mouse models of chronic ocular hypertension. METHODS: C57/BL6 mice were used for experiments. The PLR was evaluated with a computerized pupillometer (n = 14), ERGs were recorded simultaneously from both eyes (n = 23) and IOP was measured with a modified Goldmann tonometer (n = 23). RESULTS: The analysis of the PLR parameters confirmed the consensual PLR did not have significantly different amplitude (p > 0.1) and latency time (p > 0.1) compared to the direct PLR. However, PLR velocity (p = 0.004) was significantly smaller in the consensual PLR. Electroretinography revealed a-wave amplitude of 168.3 +/- 9.6 microV with latency of 27.5 +/- 0.6 ms and b-wave 403 +/- 28.8 microV with latency of 22.7 +/- 0.6 ms. The flicker ERG recording revealed amplitudes of 20.6 +/- 2.4 microV. Tonometry experiments revealed that modified Goldmann tonometer measurements correlated well with invasive manometry (r(2) = 0.89). The mean IOP of the mouse was 15.3 +/- 0.6 mmHg. CONCLUSIONS: Consensual PLR in mice is relatively slower than the direct PLR, but retains the same degree of constriction comparing to the direct PLR. A modified Goldmann tonometer seems to be a reliable non-invasive tool for IOP measurements in mice.

Animals↗