We have expanded our efforts to generate high spatial resolution images showing the distibution of carotenoid macular pigments in the human retina using Raman spectroscopy. A low level of macular pigments is associated with an increased risk of developing age-related macular degeneration, a leading cause of irreversible blindness. Using excised human eyecups and resonant excitation of the pigment molecules with narrow bandwidth blue light from a filtered arc lamp, we record Raman images originating from the carbon-carbon double bond stretch vibrations of lutein and zeaxanthin, the carotenoids comprising human macular pigments. Our Raman images reveal significnt differences among subjects, both in regard to absolute levels ss well as spatial distribution within the macula. Since the light levels used to obtain these images are well below established ssafety limits, this technique holds promise for developing a rapid screening diagnostic in large populations at risk for vision loss from age-realted macular degeneration.
Gellermann, Werner; Ermakov, Igor V.; McClane, Robert W.
Interest in macular pigment has been growing since it was first identified 200 years ago. Because of its antioxidant properties and putative protection against age-related macular degeneration (AMD), clinical, experimental, and epidemiologic studies have attempted to show a positive correlation between the high density of macular pigment and low risk for macular degeneration. Since the two main components of macular pigment, lutein and zeaxanthin, cannot be endogenously synthesized, oral supplementation may be an efficient means to increase macular pigment density. However, the ideal dosage for such supplementation remains to be determined, since absorption varies greatly from one subject to another. Hence, reliable quantitative measurement of macular pigment density is necessary before any beneficial effects of oral supplementation on AMD occurrence can be demonstrated; then at-risk subjects who would require such supplementation can be targeted. Several techniques can be used to measure macular pigment density noninvasively in vivo. Psychophysical methods are the most commonly used. They include heterochromatic flicker photometry and Raman spectroscopy. Heterochromatic flicker is the most widely used method and seems to be the easiest and least costly. However, because it requires very good cooperation from patients and a good grasp of the instructions, it is probably the least reliable and reproducible method. Raman spectroscopy, on the other hand, requires less cooperation on the part of the patient. Subjects are asked to overlap a blue disc and a red polka-dot pattern to ensure proper alignment of the eye. Since these instructions are simpler than those for heterochromatic flicker photometry, this technique is more reliable. Overall, the data obtained are more objective because they are based on the analysis of a signal emitted after an argon laser excitation of the macular pigment. Nevertheless, data are closely related to pupil diameter. Finally Raman spectroscopy requires expensive equipment. Physical methods are based on retinal excitation by an incident light and the analysis of the reflected signal obtained. These methods are mainly represented by autofluorescence measurement and fundus reflectance. These two techniques differ in the wavelength used in the incident light, because the reflected signal is itself related to the amount of incident light absorbed by retinal structures. Both techniques allow rapid and objective measurement of spatial distribution of macular pigment. The software of the modified Scanning Laser Ophthalmoscope (Heidelberg, Germany) further creates a density map image after digital subtraction of the log reflectance data obtained at two different wavelengths. Physical methods require little cooperation from patients and could be considered the most objective and high-performance technique available today. However, the instruments are still expensive and therefore cannot be widely used in clinical practice. PMID:18563047
Rougier, M B; Delyfer, M N; Korobelnik, J F
We have imaged the spatial distribution of macular carotenoid pigments (MPs) in the human retina, employing Raman spectroscopy. Using excised human eyecups as initial test samples and resonant excitation of the pigment molecules with narrow-bandwidth blue light from a mercury arc lamp, we record Raman images originating from the carbon-carbon double-bond stretch vibrations of the molecules. Preliminary Raman images reveal significant differences in the MPs of different samples in regard to absolute levels as well as spatial variation. This technique holds promise as a method of rapid screening of MPs in large populations at risk for vision loss from age-related macular degeneration, a leading cause of blindness.
Gellermann, Werner; Ermakov, Igor V.; McClane, Robert W.; Bernstein, Paul S.
Clinical studies of carotenoid macular pigments (MP) have been limited by the lack of noninvasive, objective instruments. We introduce a novel noninvasive optical instrument, an MP Raman detector, for assessment of the carotenoid status of the human retina in vivo. The instrument uses resonant excitation of carotenoid molecules in the visible wavelength range, and quantitatively measures the highly specific Raman signals that originate from the single- and double-bond stretch vibrations of the pi-conjugated carotenoid molecule's carbon backbone. The instrument is a robust, compact device and suitable for routine measurements of MP concentrations in a clinical setting. We characterized and tested the instrument in clinical studies of human subjects to validate its function and to begin to establish its role as a possible screening test for macular pathologies. We also show that the MP Raman spectroscopy technology has potential as a novel, highly specific method for rapid screening of carotenoid antioxidant levels in large populations at risk for vision loss from age-related macular degeneration, the leading cause of blindness of the elderly in the developed world. PMID:14715066
Ermakov, Igor; Ermakova, Maia; Gellermann, Werner; Bernstein, Paul S
Three dietary carotenoids, lutein (L), zeaxanthin (Z) and meso-zeaxanthin (MZ) accumulate at the central retina (macula), where they are collectively referred to as macular pigment (MP). MP’s pre-receptoral absorption of blue light and consequential attenuation of the effects of chromatic aberration and light scatter are important for optimal visual function. Furthermore, antioxidant activity of MP’s constituent carotenoids and the same blue light-filtering properties underlie the rationale for its putative protective role for age-related macular degeneration (AMD). Supplementation with L, Z and MZ augments MP and enhances visual performance in diseased and non-diseased eyes, and may reduce risk of AMD development and/or progression.
Loskutova, Ekaterina; Nolan, John; Howard, Alan; Beatty, Stephen
Three dietary carotenoids, lutein (L), zeaxanthin (Z) and meso-zeaxanthin (MZ) accumulate at the central retina (macula), where they are collectively referred to as macular pigment (MP). MP's pre-receptoral absorption of blue light and consequential attenuation of the effects of chromatic aberration and light scatter are important for optimal visual function. Furthermore, antioxidant activity of MP's constituent carotenoids and the same blue light-filtering properties underlie the rationale for its putative protective role for age-related macular degeneration (AMD). Supplementation with L, Z and MZ augments MP and enhances visual performance in diseased and non-diseased eyes, and may reduce risk of AMD development and/or progression. PMID:23760061
Loskutova, Ekaterina; Nolan, John; Howard, Alan; Beatty, Stephen
Abstract Background. Because patients with cystic fibrosis (CF) are living longer, chronic malabsorption of carotenoids associated with CF resulting in decreased macular pigment (MP) may affect macular long-term health in later-life pathology. This study compared the macular pigment optical density (MPOD) and corresponding central macular volume (MV) of adult CF subjects and age-matched normal controls subjects to determine whether chronic malabsorption associated with CF could adversely affect macular photoreceptor anatomy. Objective. Our aim was to compare MPOD with measurements of central MV in CF patients with age-matched controls. Design. In nine adult CF patients (ages: 29-46) without a history of carotenoid supplementation or known retinal or optic nerve disease MPOD and MV were measured by heterochromatic flicker photometry (HFP) and optical coherence tomography (OCT), respectively, and compared to results obtained from 14 age-matched controls. Results. MPOD was significantly reduced at 15' and 30' eccentricities in CF subjects compared to normal subjects (mean difference -0.21 at 15', -0.25 at 30', p < 0.005). No significant difference, in MV noted at any of the eccentricities tested between CF and normal subjects (CF: normal MV ratios ranged from 0.94 to 1.1 for all eccentricities with p > 0.1 at all eccentricities). Best corrected vision acuity and fundus examination were normal in all subjects. Conclusions. Unsupplemented CF patients have markedly lower levels of macular carotenoids (e.g., lutein and zeaxanthin), but well-maintained visual function and no significant reductions in central MV primarily composed of macular photoreceptors. Future studies are needed to determine whether the lifelong decrease in protective central retinal carotenoids predisposes CF patients to later-life retinal pathology. PMID:24628396
Shi, A J; Morrissey, B M; Durbin-Johnson, B; Pilli, S; Zawadzki, R J; Cross, C E; Park, S S
Clinical studies of carotenoid macular pigments (MP) and chronic retina disease have been limited by the lack of non-invasive, objective techniques. In this paper we describe anovel, noninvasive optical techniques based on the resonant Raman spectroscopy for the assessment of the carotenoid status of human retina in vivo. Using resonant excitation in the visible, we measure the Raman signals that originate from the single- and double-bond stretch vibrations of the ?-conjugated carotenoid molecule's carbon backbone. MP Raman detector, robust device useful for routine measurements of MP concentration in a clinical setting, has been developed and tested in clinical studies in humans to validate its function and to begin to establish its role as a possible screening test for macular pathologies. We report our first results on using carotenoid Raman detection in imaging mode. The results on retinal Raman imaging reveal highly specific and quantitative information regarding the spatial distribution of macular pigments. We also compare Raman technology with others availabe today subjective and objective MP detection methods and show that Raman spectroscopic technology has tremendous potential as a breakthrough method for rapid screening of carotenoid antioxidant levels in large populations that are at risk for vision loss from age-related macular degeneration, the leading cause of blindness of the elderly in the developed world.
Ermakov, Igor V.; Ermakova, Maia R.; Gellermann, Werner; Bernstein, Paul S.
We present a case of an otherwise healthy 10-year-old girl who presented with asymptomatic brown macules over the trunk and proximal extremities, of three months' duration. The cutaneous examination revealed multiple, dark brown, discrete, round to oval macules and a few mildly elevated lesions over the trunk and proximal limbs. The individual lesion was 1-3 cm in diameter and a few showed velvety appearance over the surface. Darier's sign was negative. The histopathological study from the velvety lesion showed acanthosis, papillomatosis and increased melanin in the basal layer. The upper dermis showed sparse perivascular infiltrate of lymphocytes without any dermal melanophages. It fulfilled the criteria for idiopathic eruptive macular pigmentation with additional histological finding of papillomatosis. PMID:23130237
Verma, Shikha; Thakur, Binod Kumar
We have developed a reflection-based capability of the RetCam(®) platform, an FDA-cleared pediatric retinal-imaging instrument, for the purpose of measuring macular pigment levels as well as their spatial distributions in infants and children. Our modifications include narrow-band blue-wavelength excitation of the macular pigment absorption in combination with spectrally selective blue-wavelength readout of the reflection signals received by the instrument's CCD detector array. Furthermore, an algorithm is developed that allows the computation of optical density maps for the macular pigment relative to peripheral retinal areas. This made it possible for the first time to directly measure macular pigment levels and their spatial features in the developing human retina. In contrast to adults, infants with measurable pigment levels had almost exclusively a narrow, circularly symmetric, pigment distribution. The described methodology holds promise for future investigations into the role of macular pigment in the developing human retina and the effect of dietary interventions in diseases resulting from a lack of normal carotenoid levels. PMID:24196405
Sharifzadeh, Mohsen; Bernstein, Paul S; Gellermann, Werner
THERE is little doubt that the macular and foveal region of the human retina is lacking in blood vessels detectable by histological means1. By subjective observation of the red corpuscles in blue light, Weale2 has recently confirmed Gescher's estimate of 1° 30'' for the visual angle within which the vessels of the central artery of the retina are absent. We
H. J. A. Dartnall; L. C. Thomson
We present a technique for estimating the density of the human macular pigment noninvasively that takes advantage of the autofluorescence of lipofuscin, which is normally present in the human retinal pigment epi- thelium. By measuring the intensity of fluorescence at 710 nm, where macular pigment has essentially zero absorption, and stimulating the fluorescence with two wavelengths, one well absorbed by
François C. Delori; Douglas G. Goger; Billy R. Hammond; D. Max Snodderly; Stephen A. Burns
There is currently strong interest in developing noninvasive technologies for the detection of macular carotenoid pigments in the human eye. These pigments, consisting of lutein and zeaxanthin, are taken up from the diet and are thought to play an important role in the prevention of age-related macular degeneration, the leading cause of blindness in the elderly in the Western world. It may be possible to prevent or delay the onset of this debilitating disease with suitable dietary intervention strategies. We review the most commonly used detection techniques based on heterochromatic flicker photometry, fundus reflectometry, and autofluorescense techniques and put them in perspective with recently developed more molecule-specific Raman detection methods. PMID:14715058
Gellermann, Werner; Bernstein, Paul S
There is increasing recognition that the optical and antioxidant properties of the xanthophyll carotenoids lutein and zeaxanthin play an important role in maintaining the health and function of the human macula. In this review article, we assess the value of non-invasive quantification of macular pigment levels and distributions to identify individuals potentially at risk for visual disability or catastrophic vision loss from age-related macular degeneration, and we consider the strengths and weaknesses of the diverse measurement methods currently available.
Bernstein, Paul S.; Delori, Francois C.; Richer, Stuart; van Kuijk, Frederik J. M.; Wenzel, Adam J.
Purpose. While the role of the macular pigment carotenoids in the prevention of age-related macular degeneration has been extensively studied in adults, comparatively little is known about the physiology and function of lutein and zeaxanthin in the developing eye. We therefore developed a protocol using a digital video fundus camera (RetCam) to measure macular pigment optical density (MPOD) and distributions in premature infants and in children. Methods. We used blue light reflectance to image the macular pigment in premature babies at the time of retinopathy of prematurity (ROP) screening and in children aged under 7 years who were undergoing examinations under anesthesia for other reasons. We correlated the MPOD with skin carotenoid levels measured by resonance Raman spectroscopy, serum carotenoids measured by HPLC, and dietary carotenoid intake. Results. We enrolled 51 infants and children ranging from preterm to age 7 years. MPOD correlated significantly with age (r = 0.36; P = 0.0142), with serum lutein + zeaxanthin (r = 0.44; P = 0.0049) and with skin carotenoid levels (r = 0.42; P = 0.0106), but not with dietary lutein + zeaxanthin intake (r = 0.13; P = 0.50). All premature infants had undetectable macular pigment, and most had unusually low serum and skin carotenoid concentrations. Conclusions. Our most remarkable finding is the undetectable MPOD in premature infants. This may be due in part to foveal immaturity, but the very low levels of serum and skin carotenoids suggest that these infants are carotenoid insufficient as a consequence of low dietary intake and/or severe oxidative stress. The potential value of carotenoid supplementation in the prevention of ROP and other disorders of prematurity should be a fruitful direction for further investigation.
Bernstein, Paul S.; Sharifzadeh, Mohsen; Liu, Aihua; Ermakov, Igor; Nelson, Kelly; Sheng, Xiaoming; Panish, Cynthia; Carlstrom, Bonnie; Hoffman, Robert O.; Gellermann, Werner
PURPOSE. Age and advanced disease in the fellow eye are the two most important risk factors for age-related macular degen- eration (AMD). In this study, the authors investigated the rela- tionship between these variables and the optical density of macular pigment (MP) in a group of subjects from a northern European population. METHODS. The optical density of MP was measured
Stephen Beatty; Ian J. Murray; David B. Henson; Dave Carden; Hui-Hiang Koh; Michael E. Boulton
A low density of macular pigment may represent a risk factor for age-related macular degeneration (AMD) by permitting greater blue light damage. This study was carried out to determine the effects on macular pigment optical density of dietary supplementation with lutein, one of the pigment constituents. Two subjects consumed lutein esters, equivalent to 30 mg of free lutein per day,
JOHN T LANDRUM; RICHARD A BONE; HILDA JOA; MARK D KILBURN; LINDA L MOORE; KATHLEEN E SPRAGUE
Purpose To evaluate the application of 488 and 514?nm fundus autofluorescence (FAF) and macular pigment optical density (MPOD) imaging in diabetic macular oedema (DMO) and to demonstrate the typical imaging features. Patients and Methods A hundred and twenty-five eyes of 71 consecutive patients with diabetic retinopathy who underwent examination at a specialist university clinic employing a modified Heidelberg Retina Angiograph, using two different light sources of 488 and 514?nm wavelength, were retrospectively reviewed. MPOD images were calculated using modified Heidelberg Eye Explorer software. All images were evaluated by two independent masked graders. Features from FAF and MPOD images were correlated with optical coherence tomography (OCT) imaging findings and inter-grader variability, sensitivity and specificity were calculated using OCT as reference. Results Sixty-seven eyes had DMO on OCT. The inter-grader variability was 0.84 for 488?nm FAF, 0.63 for 514?nm FAF and 0.79 for MPOD imaging. Sensitivity and specificity for detection of DMO were 80.6 and 89.7% for 488?nm FAF; 55.2 and 94.8% for 514?nm FAF; and 80.6 and 91.4% for MPOD imaging. In 488?nm FAF and MPOD imaging, DMO was better visualised in comparison with 514?nm FAF imaging, P<0.01. MPOD revealed displacement of macular pigment by intraretinal cysts. Conclusion MPOD imaging, and particularly its combination with 488?nm and 514?nm FAF, provides a valuable addition to OCT in the evaluation of DMO and is clinically useful in rapid en-face assessment of the central macula.
Waldstein, S M; Hickey, D; Mahmud, I; Kiire, C A; Charbel Issa, P; Chong, N V
Raman spectroscopy holds promise as a novel noninvasive technology for the quantification of the macular pigments (MP) lutein and zeaxanthin. These compounds, which are members of the carotenoid family, are thought to prevent or delay the onset of age-related macular degeneration, the leading cause of irreversible blindness in the elderly. It is highly likely that they achieve this protection through their function as optical filters and/or antioxidants. Using resonant excitation in the visible region, we measure and quantify the Raman signals that originate from the carbon double bond (C=C) stretch vibrations of the ?-conjugated molecule backbone. In this manuscript we describe the construction and performance of a novel compact MP Raman instrument utilizing dielectric angle-tuned band-pass filters for wavelength selection and a single-channel photo-multiplier for the detection of MP Raman responses. MP concentration measurements are fast and accurate, as seen in our experiments with model eyes and living human eyes. The ease and rapidity of Raman MP measurements, the simplicity of the instrumentation, the high accuracy of the measurements, and the lack of significant systematic errors should make this technology attractive for widespread clinical research.
ERMAKOV, IGOR V.; ERMAKOVA, MAIA R.; GELLERMANN, WERNER
Raman spectroscopy holds promise as a novel noninvasive technology for the quantification of the macular pigments (MP) lutein and zeaxanthin. These compounds, which are members of the carotenoid family, are thought to prevent or delay the onset of age-related macular degeneration, the leading cause of irreversible blindness in the elderly. It is highly likely that they achieve this protection through their function as optical filters and/or antioxidants. Using resonant excitation in the visible region, we measure and quantify the Raman signals that originate from the carbon double bond (C=C) stretch vibrations of the pi-conjugated molecule backbone. In this manuscript we describe the construction and performance of a novel compact MP Raman instrument utilizing dielectric angle-tuned band-pass filters for wavelength selection and a single-channel photo-multiplier for the detection of MP Raman responses. MP concentration measurements are fast and accurate, as seen in our experiments with model eyes and living human eyes. The ease and rapidity of Raman MP measurements, the simplicity of the instrumentation, the high accuracy of the measurements, and the lack of significant systematic errors should make this technology attractive for widespread clinical research. PMID:16053555
Ermakov, Igor V; Ermakova, Maia R; Gellermann, Werner
We have used resonant Raman scattering spectroscopy as a novel, noninvasive, in vivo optical technique to measure the concentration of the macular carotenoid pigments lutein and zeaxanthin in the living human retina of young and elderly adults. Using a backscattering geometry and resonant molecular excitation in the visible wavelength range, we measure the Raman signals originating from the single- and double-bond stretch vibrations of the ?-conjugated molecule's carbon backbone. The Raman signals scale linearly with carotenoid content, and the required laser excitation is well below safety limits for macular exposure. Furthermore, the signals decline significantly with increasing age in normal eyes. The Raman technique is objective and quantitative and may lead to a new method for rapid screening of carotenoid pigment levels in large populations at risk for vision loss from age-related macular degeneration, the leading cause of blindness in the elderly in the United States.
Gellermann, Werner; Ermakov, Igor V.; Ermakova, Maia R.; McClane, Robert W.; Zhao, Da-You; Bernstein, Paul S.
Purpose: The 3 carotenoids lutein, zeaxanthin, and meso-zeaxanthin, which account for the ‘yellow spot’ at the macula and which are referred to as macular pigment (MP), are believed to play a role in visual function and protect against age-related macular degeneration (AMD) via their optical and antioxidant properties. This study was undertaken to compare MP optical density (MPOD) in a
John M. Nolan; Roseanne Kenny; Claire O’Regan; Hilary Cronin; James Loughman; Eithne E. Connolly; Patricia Kearney; Edward Loane; Stephen Beatty
Background Macular pigment has been the focus of much attention in recent years, as a potential modifiable risk factor for age-related\\u000a macular degeneration. This interest has been heightened by the ability to measure macular pigment optical density (MPOD) in\\u000a vivo.\\u000a \\u000a \\u000a \\u000a \\u000a Method A systematic literature search was undertaken to identify all available papers that have used in vivo MPOD techniques. The\\u000a papers were
Olivia Howells; Frank Eperjesi; Hannah Bartlett
BACKGROUNDSubthreshold (retinal pigment epithelium) photocoagulation is a new photocoagulation method, which treats the retinal pigment epithelium (RPE) and avoids damage to the neural retina. The initial results in this prospective pilot study on various macular diseases are presented.METHODS12 patients with diabetic maculopathy (group I), 10 with soft drusen (group II), and four with central serous retinopathy (CSR) (group III) were
Johann Roider; Ralf Brinkmann; Christopher Wirbelauer; Horst Laqua; Reginald Birngruber
It is thought that direct quenching of singlet oxygen and scavenging free radicals by macular pigment carotenoids is a major mechanism for their beneficial effects against light-induced oxidative stress. Corresponding data from human tissue remains unavailable, however. In the studies reported here, electron paramagnetic resonance (EPR) spectroscopy was used to measure light-induced singlet oxygen generation in postmortem human macula and retinal pigment epithelium/choroid (RPE/choroid). Under white-light illumination, production of singlet oxygen was detected in RPE/choroid but not in macular tissue, and we show that exogenously added macular carotenoids can quench RPE/choroid singlet oxygen. When the singlet oxygen quenching ability of the macular carotenoids was investigated in solution, it was shown that a mixture of meso-zeaxanthin, zeaxanthin, and lutein in a ratio of 1:1:1 can quench more singlet oxygen than the individual carotenoids at the same total concentration.
Li, Binxing; Ahmed, Faisal; Bernstein, Paul S.
BackgroundTo determine long-term functional and morphological changes after full macular translocation (FMT) with 360° retinotomy in patients with retinal pigment epithelium (RPE) tears, in light of the increasing number of reports of this complication following vascular endothelial growth factor (VEGF)-modulating therapy.MethodsWe retrospectively reviewed a consecutive series of six patients with RPE tears secondary to neovascular age-related macular degeneration who underwent
A. Polito; M. Cereda; F. Romanelli; G. Pertile
We have developed a CCD-camera-based nonmydriatic instrument that detects fluorescence from retinal lipofuscin chromophores ("autofluorescence") as a means to indirectly quantify and spatially image the distribution of macular pigment (MP). The lipofuscin fluorescence intensity is reduced at all retinal locations containing MP, since MP has a competing absorption in the blue-green wavelength region. Projecting a large diameter, 488 nm excitation spot onto the retina, centered on the fovea, but extending into the macular periphery, and comparing lipofuscin fluorescence intensities outside and inside the foveal area, it is possible to spatially map out the distribution of MP. Spectrally selective detection of the lipofuscin fluorescence reveals an important wavelength dependence of the obtainable image contrast and deduced MP optical density levels, showing that it is important to block out interfering fluorescence contributions in the detection setup originating from ocular media such as the lens. Measuring 70 healthy human volunteer subjects with no ocular pathologies, we find widely varying spatial extent of MP, distinctly differing distribution patterns of MP, and strongly differing absolute MP levels among individuals. Our population study suggests that MP imaging based on lipofuscin fluorescence is useful as a relatively simple, objective, and quantitative noninvasive optical technique suitable to rapidly screen MP levels and distributions in healthy humans with undilated pupils. PMID:16985523
Sharifzadeh, Mohsen; Bernstein, Paul S; Gellermann, Werner
We have developed a CCD-camera-based nonmydriatic instrument that detects fluorescence from retinal lipofuscin chromophores (“autofluorescence”) as a means to indirectly quantify and spatially image the distribution of macular pigment (MP). The lipofuscin fluorescence intensity is reduced at all retinal locations containing MP, since MP has a competing absorption in the blue–green wavelength region. Projecting a large diameter, 488 nm excitation spot onto the retina, centered on the fovea, but extending into the macular periphery, and comparing lipofuscin fluorescence intensities outside and inside the foveal area, it is possible to spatially map out the distribution of MP. Spectrally selective detection of the lipofuscin fluorescence reveals an important wavelength dependence of the obtainable image contrast and deduced MP optical density levels, showing that it is important to block out interfering fluorescence contributions in the detection setup originating from ocular media such as the lens. Measuring 70 healthy human volunteer subjects with no ocular pathologies, we find widely varying spatial extent of MP, distinctly differing distribution patterns of MP, and strongly differing absolute MP levels among individuals. Our population study suggests that MP imaging based on lipofuscin fluorescence is useful as a relatively simple, objective, and quantitative noninvasive optical technique suitable to rapidly screen MP levels and distributions in healthy humans with undilated pupils.
Sharifzadeh, Mohsen; Bernstein, Paul S.; Gellermann, Werner
We have developed a CCD-camera-based nonmydriatic instrument that detects fluorescence from retinal lipofuscin chromophores ("autofluorescence") as a means to indirectly quantify and spatially image the distribution of macular pigment (MP). The lipofuscin fluorescence intensity is reduced at all retinal locations containing MP, since MP has a competing absorption in the blue-green wavelength region. Projecting a large diameter, 488 nm excitation spot onto the retina, centered on the fovea, but extending into the macular periphery, and comparing lipofuscin fluorescence intensities outside and inside the foveal area, it is possible to spatially map out the distribution of MP. Spectrally selective detection of the lipofuscin fluorescence reveals an important wavelength dependence of the obtainable image contrast and deduced MP optical density levels, showing that it is important to block out interfering fluorescence contributions in the detection setup originating from ocular media such as the lens. Measuring 70 healthy human volunteer subjects with no ocular pathologies, we find widely varying spatial extent of MP, distinctly differing distribution patterns of MP, and strongly differing absolute MP levels among individuals. Our population study suggests that MP imaging based on lipofuscin fluorescence is useful as a relatively simple, objective, and quantitative noninvasive optical technique suitable to rapidly screen MP levels and distributions in healthy humans with undilated pupils.
Sharifzadeh, Mohsen; Bernstein, Paul S.; Gellermann, Werner
PurposeAccurate assessment of the amount of macular pigment (MPOD) is necessary to investigate the role of carotenoids and their assumed protective functions. High repeatability and reliability are important to monitor patients in studies investigating the influence of diet and supplements on MPOD. We evaluated the Macuscope (Macuvision Europe Ltd., Lapworth, Solihull, UK), a recently introduced device for measuring MPOD using
R de Kinkelder; R L P van der Veen; F D Verbaak; D J Faber; T G van Leeuwen; T T J M Berendschot; TTJM Berendschot
Age-related macular degeneration (AMD) is the leading cause of severe visual impairment in the elderly in developed countries. AMD patients have ele- vated levels of iron within the retinal pigment epithelia (RPE), which may lead to oxidative damage to mitochon- dria, disruption of retinal metabolism, and vision impair- ment or loss. As a possible model for iron-induced AMD, we investigated
Ludmila A. Voloboueva; David W. Killilea; Hani Atamna; Bruce N. Ames
Purpose. Age-Related Eye Disease Study 2 (AREDS2) is a randomized, placebo-controlled study designed to determine whether supplementation with 10 mg of lutein and 2 mg of zeaxanthin per day can slow the rate of progression of age-related macular degeneration (AMD). Although some biomarkers of response to carotenoid supplementation such as serum concentrations are part of the AREDS2 protocol, measurement of carotenoid concentrations in the eye and other tissues is not. In this approved ancillary study, macular pigment optical density (MPOD), macular pigment distributions, and skin carotenoid levels at enrollment and at each annual visit were measured to assess baseline carotenoid status and to monitor response to assigned interventions. Methods. All subjects enrolled at the Moran Eye Center had MPOD and macular pigment spatial distributions measured by dual-wavelength autofluorescence imaging and total skin carotenoids measured by resonance Raman spectroscopy. Results. Baseline MPOD in enrolled subjects was unusually high relative to an age-matched control group that did not consume carotenoid supplements regularly, consistent with the high rate of habitual lutein and zeaxanthin consumption in Utah AREDS2 subjects prior to enrollment. MPOD did not correlate with serum or skin carotenoid measurements. Conclusions. Useful information is provided through this ancillary study on the ocular carotenoid status of AREDS2 participants in the target tissue of lutein and zeaxanthin supplementation: The macula. When treatment assignments are unmasked at the conclusion of the study, unique tissue-based insights will be provided on the progression of AMD in response to long-term, high-dose carotenoid supplementation versus diet alone. (ClinicalTrials.gov number, NCT00345176.)
Bernstein, Paul S.; Ahmed, Faisal; Liu, Aihua; Allman, Susan; Sheng, Xiaoming; Sharifzadeh, Mohsen; Ermakov, Igor; Gellermann, Werner
Background Pancreatic insufficiency in cystic fibrosis (CF), even with replacement pancreatic enzyme therapy, is often associated with decreased carotenoid absorption. Because the macular pigment of the retina is largely derived from 2 carotenoids, lutein and zeaxanthin, the decreased serum concentrations seen in CF may have consequences for ocular and retinal health Objectives Our aims were to determine plasma carotenoid concentrations, determine absorption and distribution of macular pigment, and assess retinal health and visual function in CF patients. Design In 10 adult CF patients (ages 21–47 y) and 10 age- and sex-matched healthy control subjects, we measured macular pigment density in vivo, measured serum lutein and zeaxanthin concentrations, and comprehensively assessed visual performance (including contrast sensitivity, color discrimination, and retinal function) under conditions of daylight illumination. Results Serum lutein and zeaxanthin were significantly reduced (P< 0.005) in CF patients (x?± SD:87 ± 36.1 and 27 ± 15.8 nmol/L, respectively) compared with control subjects (190 ± 72.1 and 75 ± 23.6 nmol/L, respectively). Although macular pigment optical density was significantly lower (P < 0.0001) in the CF group (0.24 ± 0.11) than in the control group (0.53 ± 0.12), no significant differences in visual function were observed. Conclusions Adults with CF have dramatically low serum and macular concentrations of carotenoids (lutein and zeaxanthin), but their ocular status and visual function are surprisingly good. The clinical implications of low plasma concentrations of carotenoids in CF are yet to be clarified.
Schupp, Christine; Olano-Martin, Estibaliz; Gerth, Christina; Morrissey, Brian M; Cross, Carroll E; Werner, John S
Background: Age-related macular degeneration (ARMD) is caused by abnormal retinal pigment epithelium (RPE) and may be complicated by choroidal neovascularization. The object of treatment would be to replace the diseased RPE with normal human RPE. • Method: Five patients with ARMD (preoperative visual acuity 0.08–0.2) underwent removal of subretinal fibrovascular membranes using pars plana vitrectomy techniques. Human fetal RPE (15–17
Peep V. Algvere; Lennart Berglin; Peter Gouras; Yaohua Sheng
Light exposure has been implicated in age-related macular degeneration (AMD). This study was designed to measure cumulative light distribution on the retina to determine whether it peaked in the macula. An eye-tracker recorded the subject's field of view and pupil size, and superimposed the gaze position. Fifteen naďve subjects formed a test group; 5 formed a control group. In phase 1, all subjects viewed a sequence of photographic images. In phase 2, the naďve subjects observed a video; in phase 3, they performed computer tasks; in phase 4, the subjects walked around freely. In phase 1, control subjects were instructed to gaze at bright features in the field of view and, in a second test, at dark features. Test group subjects were allowed to gaze freely for all phases. Using the subject's gaze coordinates, we calculated the cumulative light distribution on the retina. As expected for control subjects, cumulative retinal light distributions peaked and dipped in the fovea when they gazed at bright or dark features respectively in the field of view. The light distribution maps obtained from the test group showed a consistent tendency to peak in the macula in phase 3, a variable tendency in phase 4, but little tendency in phases 1 and 2. We conclude that a tendency for light to peak in the macula is a characteristic of some individuals and of certain tasks. In these situations, risk of AMD could be increased but, at the same time, mitigated by the presence of macular carotenoids.
Bone, Richard A.; Gibert, Jorge C.; Mukherjee, Anirbaan
Increasing evidence suggests a beneficial effect of lutein and zeaxanthin on the progression of age-related macular degeneration. The aim of this study was to investigate the effect of lutein or zeaxanthin enriched eggs or a lutein enriched egg-yolk based buttermilk beverage on serum lutein and zeaxanthin concentrations and macular pigment levels. Naturally enriched eggs were made by increasing the levels of the xanthophylls lutein and zeaxanthin in the feed given to laying hens. One hundred healthy volunteers were recruited and randomized into 5 groups for 90 days. Group one added one normal egg to their daily diet and group two received a lutein enriched egg-yolk based beverage. Group three added one lutein enriched egg and group four one zeaxanthin enriched egg to their diet. Group five was the control group and individuals in this group did not modify their daily diet. Serum lutein and zeaxanthin concentrations and macular pigment densities were obtained at baseline, day 45 and day 90. Macular pigment density was measured by heterochromatic flicker photometry. Serum lutein concentration in the lutein enriched egg and egg yolk-based beverage groups increased significantly (p<0.001, 76% and 77%). A strong increase in the serum zeaxanthin concentration was observed in individuals receiving zeaxanthin enriched eggs (P< 0.001, 430%). No changes were observed in macular pigment density in the various groups tested. The results indicate that daily consumption of lutein or zeaxanthin enriched egg yolks as well as an egg yolk-based beverage show increases in serum lutein and zeaxanthin levels that are comparable with a daily use of 5 mg supplements. Trial Registration ClinicalTrials.gov NCT00527553
Kelly, Elton R.; Plat, Jogchum; Haenen, Guido R. M. M.; Kijlstra, Aize; Berendschot, Tos T. J. M.
There is now a consensus, based on histological, biochemical and spectral absorption data, that the yellow colour observed at the macula lutea is a consequence of the selective accumulation of dietary xanthophylls in the central retina of the living eye. Scientific research continues to explore the function(s) of MP in the human retina, with two main hypotheses premised on its putative capacity to (1) protect the retina from (photo)-oxidative damage by means of its optical filtration and/or antioxidant properties, the so-called protective hypothesis and (2) influence the quality of visual performance by means of selective short wavelength light absorption prior to photoreceptor light capture, thereby attenuating the effects of chromatic aberration and light scatter, the so-called acuity and visibility hypotheses. The current epidemic of age-related macular degeneration has directed researchers to investigate the protective hypothesis of MP, while there has been a conspicuous lack of work designed to investigate the role of MP in visual performance. The aim of this review is to present and critically appraise the current literature germane to the contribution of MP, if any, to visual performance and experience.
Loughman, James; Davison, Peter A.; Nolan, John M.; Akkali, Mukunda C.; Beatty, Stephen
We describe resonance Raman imaging (RRI) of macular pigment (MP) distributions in the living human eye. MP consists of the antioxidant carotenoid compounds lutein and zeaxanthin, is typically present in high concentrations in the healthy human macula relative to the peripheral retina, and is thought to protect this important central region from age-related macular degeneration. We demonstrate that RRI is capable of quantifying and imaging the spatially strongly varying MP distribution in the human retina. Using laser excitation of the MP molecules at 488nm, and sequential camera detection of light emitted back from the retina at the MP's strongest Raman peak position and at an off-peak position, RRI maps of MP are obtained at a resolution below 50microm within a fraction of a second per exposure. RRI imaging can be carried out with undilated pupils and provides a highly molecule-specific diagnostic imaging approach for MP distributions in human subjects. PMID:18382494
Sharifzadeh, Mohsen; Zhao, Da-You; Bernstein, Paul S; Gellermann, Werner
We describe resonance Raman imaging (RRI) of macular pigment (MP) distributions in the living human eye. MP consists of the antioxidant carotenoid compounds lutein and zeaxanthin, is typically present in high concentrations in the healthy human macula relative to the peripheral retina, and is thought to protect this important central region from age-related macular degeneration. We demonstrate that RRI is capable of quantifying and imaging the spatially strongly varying MP distribution in the human retina. Using laser excitation of the MP molecules at 488 nm, and sequential camera detection of light emitted back from the retina at the MP’s strongest Raman peak position and at an off-peak position, RRI maps of MP are obtained at a resolution below 50 ?m within a fraction of a second per exposure. RRI imaging can be carried out with undilated pupils and provides a highly molecule-specific diagnostic imaging approach for MP distributions in human subjects.
Sharifzadeh, Mohsen; Zhao, Da-You; Bernstein, Paul S.; Gellermann, Werner
Age-related macular degeneration (AMD) is a sight threating retinal eye disease that affects millions of aging individuals world-wide. Choroid-retinal pigment epithelium (RPE)-neuroretina axis in the posterior compartment of the eye is the primary site of AMD pathology. There are compelling evidence to indicate association of vascular endothelial growth factors (VEGF) to AMD. Here, we report the inhibitory actions of resveratrol (RSV) on inflammatory cytokine, TGF-? and hypoxia induced VEGF secretion by human retinal pigment epithelial cells (HRPE). HRPE cultures prepared from aged human donor eyes were used for the studies in this report. HRPE secreted both VEGF-A and VEGF-C in small quantities constitutively. Stimulation with a mixture of inflammatory cytokines (IFN-?, TNF-?, IL-1?), significantly increased the secretion of both VEGF-A and VEGF-C. RSV, in a dose dependent (10-50 uM) manner, suppressed VEGF-A and VEGF-C secretion induced by inflammatory cytokines significantly. RT-PCR analysis indicated that effects of RSV on VEGF secretion were possibly due to decreased mRNA levels. TGF-? and cobalt chloride (hypoxia mimic) also upregulated HRPE cell production of VEGF-A, and this was inhibited by RSV. In contrast, RSV had no effect on anti-angiogenic molecules, endostatin and pigment epithelial derived factor secretion. Studies using an in vitro scratch assay revealed that wound closure was also inhibited by RSV. These results demonstrate that RSV can suppress VEGF secretion induced by inflammatory cytokines, TGF-? and hypoxia. Under pathological conditions, over expression of VEGF is known to worsen AMD. Therefore, RSV may be useful as nutraceutical in controlling pathological choroidal neovascularization processes in AMD. PMID:24729934
Nagineni, Chandrasekharam N; Raju, Raghavan; Nagineni, Krishnasai K; Kommineni, Vijay K; Cherukuri, Aswini; Kutty, R Krishnan; Hooks, John J; Detrick, Barbara
BackgroundRetinal pigment epithelial (RPE) transplantation presents a potential treatment for age-related macular degeneration (AMD). A suitable transplant membrane that can support an intact functioning RPE monolayer is required. Expanded polytetrafluoroethylene (ePTFE) possesses the physical properties required for a transplanting device; however, cells do not attach and spread on ePTFE. This study investigated the ability of surface-modified ePTFE to optimise the
Y Krishna; C Sheridan; D Kent; V Kearns; I Grierson; R Williams
PURPOSE To determine macular pigment (MP) optical density (OD) in patients with ABCA4-associated retinal degenerations (ABCA4-RD) and the response of MP and vision to supplementation with lutein. METHODS Stargardt disease or cone-rod dystrophy patients with foveal fixation and with known or suspected disease-causing mutations in the ABCA4 gene were included. MPOD profiles were measured with heterochromatic flicker photometry. Serum carotenoids, visual acuity, foveal sensitivity and retinal thickness were quantified. Changes in MPOD and central vision were determined in a subset of patients receiving oral supplementation with lutein for 6 months. RESULTS MPOD in patients ranged from normal to markedly abnormal. As a group, ABCA4-RD patients had reduced foveal MPOD and there was strong correlation with retinal thickness. Average foveal tissue concentration of MP, estimated by dividing MPOD by retinal thickness, was normal in patients whereas serum concentration of lutein and zeaxanthin was significantly lower than normal. After oral lutein supplementation for 6 months, 91% of the patients showed significant increases in serum lutein and 63% of the patient eyes showed a significant augmentation in MPOD. The retinal responders tended to be female, and have lower serum lutein and zeaxanthin, lower MPOD and greater retinal thickness at baseline. Responding eyes had significantly lower baseline MP concentration compared to non-responding eyes. Central vision was unchanged after the period of supplementation. CONCLUSIONS MP is strongly affected by the stage of ABCA4 disease leading to abnormal foveal architecture. MP could be augmented by supplemental lutein in some patients. There was no change in central vision after 6 months of lutein supplementation. Long-term influences on the natural history of this supplement on macular degenerations require further study.
Aleman, Tomas S.; Cideciyan, Artur V.; Windsor, Elizabeth A. M.; Schwartz, Sharon B.; Swider, Malgorzata; Chico, John D.; Sumaroka, Alexander; Pantelyat, Alexander Y.; Duncan, Keith G.; Gardner, Leigh M.; Emmons, Jessica M.; Steinberg, Janet D.; Stone, Edwin M.; Jacobson, Samuel G.
Age-related macular degeneration (ARMD) is the leading cause for visual impairment and blindness in the elder population. Laser photocoagulation, photodynamic therapy and excision of neovascular membranes have met with limited success. Submacular transplantation of autologous iris pigment epithelial (IPE) cells has been proposed to replace the damaged retinal pigment epithelium following surgical removal of the membranes. We tested our hypothesis
Irina Semkova; Florian Kreppel; Gerhard Welsandt; Thomas Luther; Jolanta Kozlowski; Hanna Janicki; Stefan Kochanek; Ulrich Schraermeyer
Background & aims Lutein and zeaxanthin accumulate in retina (macular pigment). Their nutritional status can be assessed using dietary or biochemical markers and both have been associated with macular pigment optical density. We proposed to assess dietary and status markers of lutein and zeaxanthin in a group of healthy Spanish volunteers, considering the potential influence of age, gender and serum lipids to investigate the predictors of the macular pigment optical density. Methods Serum lutein and zeaxanthin concentrations, dietary intake and macular pigment optical density were determined in 108 healthy men and women (20–35 and 45–65 years), using high-performance liquid chromatography, 3-day food records and heterochromic flicker photometry, respectively. Mann–Whitney U-test, Spearman correlation coefficient and multivariate regression analysis were used for the statistical study. Results Serum concentrations and dietary intake of lutein plus zeaxanthin (p?0.0001 and p?=?0.001, respectively) were higher in older vs younger subjects, whereas macular pigment optical density was lower (p?=?0.038). The highest correlation coefficients between intake and serum were for fruit and serum lutein (??=?0.452, p?0.0001) and for fruit and lutein?+?zeaxanthin (??=?0.431, p?0.0001) in the younger group. Macular pigment optical density correlated with serum xanthophylls (??=?0.223, p?=?0.02) and fruit and vegetable intake (??=?0.350, p?=?0.0002), showing highest correlations when lutein and zeaxanthin were expressed in relation to serum lipids in older subjects (??=?0.262, p?=?0.006). Multivariate regression analysis identified age and serum lutein as major predictors of macular pigment optical density (total sample), and a coefficient of determination of 29.7% for the model including lutein?+?zeaxathin/cholesterol?+?triglycerides, sex and fruit?+?vegetables in the older group. Conclusions The establishment of normal/reference ranges for serum lutein and zeaxanthin should consider age ranges and be expressed in relation to lipid concentrations, at least in subjects over 45 years, as this could influence macular pigment optical density. The macular pigment optical density showed age-specific correlations with lutein plus zeaxanthin expressed in relation to serum lipid concentrations as well as with the fruit and vegetable intake.
Lutein and zeaxanthin, two oxygenated carotenoids, exclusively accumulate in the macula, protecting the underlying photoreceptors and retinal pigment epithelial cells from damaging blue radiation of sunlight. As macular pigment, lutein and zeaxanthin are also potent antioxidants protecting the vulnerable regions of retina from free radical injury. Oxidative stress and cumulative light damage play an important role in pathogenesis of age-related macular degeneration (AMD), the leading cause of vision loss in the elderly population. Antioxidant and lutein supplementation has been shown to decrease the risk and prevent the progression of AMD. The egg yolk is a highly bioavailable source of lutein and zeaxanthin and thus a possible contender for AMD prevention and treatment. Consumption of 2 egg yolks/d for 5 weeks was shown herein to significantly increase serum lutein and zeaxanthin concentration and clinically improve macular pigment concentrations at 0.5° retinal eccentricity in an older adult population taking cholesterol-lowering statins. Four egg yolks/d not only raised serum lutein and zeaxanthin significantly but also macular pigment densities at 0.25°, 0.5° and 1° retinal eccentricity. A positive outcome of the 2 egg yolk consumption was the significant increase in serum HDL-C with a tendency of serum LDL-C to decrease, although not significantly. Four egg yolks/d seemed to cross the threshold for dietary cholesterol tolerance as serum LDL-C tended to increase, although not significantly, despite the significant increase in serum HDL-C. There is a strong possibility that greater build up of lutein and zeaxanthin in the macula may have been observed with 2 egg yolks/d if the intervention period was longer than 5 weeks. Addition of up to 2 eggs a day to the diet is suggested to benefit an older adult population, especially those who are already taking cholesterol-lowering statins by (a) building their macular pigment and possibly protect against AMD and (b) raising serum HDL-C without an adverse affect on serum LDL-C and TC:HDL-C ratio. Increased cholesterol, lutein and zeaxanthin intake from the 2 and 4 egg yolk interventions did not decrease the absorption of other carotenoids, such as alpha-cryptoxanthin, beta-cryptoxanthin, lycopene, alpha-carotene and beta-carotene, tocopherols and retinol from the diet. An unexpected increase was observed in serum alpha-cryptoxanthin and gamma-tocopherol concentrations during the 4 egg yolk phase, these carotenoids are normally present in low concentrations in serum. Lipoprotein distribution of carotenoids and tocopherols was also not affected by the increased egg consumption. In the pursuit of designing a highly bioavailable matrix for lutein/zeaxanthin, similar to the egg yolk micellar matrix, nanoemulsion formulations of lutein were developed using the MicrofluidizerRTM Processor technology. Lutein nanoemulsions are O/W emulsions of lutein which have particle sizes in the nanometer range (? 200 nm). Lutein consumed orally as a nanoemulsion was shown to have significantly greater bioavailability than lutein supplement-pills in pilot-scale clinical studies described here. However, lutein nanoemulsions did not raise plasma lutein concentrations to the same extent as egg yolks in a study performed on BALB/c mice. Formation of mixed micelles in the intestinal lumen during digestion and uptake of these micelles by enterocytes are crucial steps that dictate bioavailability i.e. the proportion of ingested lutein/carotenoid that enters the blood circulation and accumulates in the peripheral tissues such as the macula. In-vitro stomach and intestinal digestion experiments showed lutein nanoemulsions have significantly greater micellarization efficiency compared to egg yolks. Nanoemulsions with a phospholipid (PL) emulsifier containing 80% phosphatidyl choline (PC) or Polysorbate 80 as the emulsifier had better ability to form micelles during the intestinal digestion phase compared to a PL emulsifier with only 45% PC content. The micellar matrix coupled with nanometer sized parti
Observational epidemiological studies have shown that low carotenoid intake and/or low carotenoid blood levels increase the risk of degenerative diseases like age-related macular degeneration. Functional foods enriched with plant sterol or stanol esters may lower serum concentrations of fat-soluble carotenoids. Theoretically, as a result the macular pigment optical density (MPOD), a marker for eye health, may change. We carried out a double-blind placebo-controlled human intervention trial with a duration of 18 months to evaluate the possible effects of plant stanol and sterol esters on serum lutein/zeaxanthin concentration in relation to the MPOD. Forty-seven subjects were randomly assigned to one of the three treatment groups: margarine without added plant sterols or stanols, plant sterol-enriched margarine, or plant stanol-enriched margarine. Serum cholesterol and lutein/zeaxanthine concentrations and the MPOD were evaluated at baseline and at study end. Changes in lipid-adjusted serum lutein/zeaxanthine concentrations between baseline and study end differed significantly between the three groups (P = 0.001). We found no differences in the MPOD between the three treatment groups, despite the differences in both absolute and cholesterol-standardized serum lutein/zeaxanthine concentrations. This shows that the observed reduction in serum carotenoid concentrations during 18 months consumption of these functional foods does not affect MPOD. PMID:18986598
Berendschot, Tos T J M; Plat, Jogchum; de Jong, Ariënne; Mensink, Ronald P
Age-related macular degeneration (AMD) is a complex, degenerative and progressive eye disease that usually does not lead to complete blindness, but can result in severe loss of central vision. Risk factors for AMD include age, genetics, diet, smoking, oxidative stress and many cardiovascular-associated risk factors. Autophagy is a cellular housekeeping process that removes damaged organelles and protein aggregates, whereas heterophagy, in the case of the retinal pigment epithelium (RPE), is the phagocytosis of exogenous photoreceptor outer segments. Numerous studies have demonstrated that both autophagy and heterophagy are highly active in the RPE. To date, there is increasing evidence that constant oxidative stress impairs autophagy and heterophagy, as well as increases protein aggregation and causes inflammasome activation leading to the pathological phenotype of AMD. This review ties together these crucial pathological topics and reflects upon autophagy as a potential therapeutic target in AMD. PMID:23590900
Kaarniranta, Kai; Sinha, Debasish; Blasiak, Janusz; Kauppinen, Anu; Veréb, Zoltán; Salminen, Antero; Boulton, Michael E; Petrovski, Goran
We have generated high spatial resolution images showing the distribution of carotenoid macular pigments in the human retina using Raman spectroscopy. A low level of macular pigments is associated with an increased risk of developing age-related macular degeneration, a leading cause of irreversible blindness. Using excised human eyecups and resonant excitation of the pigment molecules with narrow bandwidth blue light from a mercury arc lamp, we record Raman images originating from the carbon-carbon double bond stretch vibrations of lutein and zeaxanthin, the carotenoids comprising human macular pigments. Our Raman images reveal significant differences among subjects, both in regard to absolute levels as well as spatial distribution within the macula. Since the light levels used to obtain these images are well below established safety limits, this technique holds promise for developing a rapid screening diagnostic in large populations at risk for vision loss from age-related macular degeneration.
Gellermann, Werner; Emakov, Igor V.; McClane, Robert W.
Purpose: To determine in vivo lipofuscin (LF)-induced topographic variations of fundus autofluorescence in eyes with geographic\\u000a atrophy (GA) of the retinal pigment epithelium (RPE) associated with age-related macular degeneration (ARMD).? Methods: Fundus autofluorescence was examined with a confocal scanning laser ophthalmoscope (Heidelberg Retina Angiograph)\\u000a after excitation with an argon laser (488 nm) and detection of the emitted light above 500
Frank G. Holz; Caren Bellmann; Melenaos Margaritidis; Florian Schütt; Tilman P. Otto; Hans E. Völcker
The retinal pigment epithelium (RPE) plays a key role in supporting photoreceptor survival and function, and RPE loss and\\u000a dysfunction in age-related macular degeneration (AMD) leads to photoreceptor death. AMD is one of the leading causes of blindness,\\u000a yet there is neither a cure nor a way to prevent it. In this chapter, we discuss recent progress in the study
Dennis O. Clegg; David Buchholz; Sherry Hikita; Teisha Rowland; Qirui Hu; Lincoln V. Johnson
This study compares in vivo measurements of macular pigment (MP) obtained using customized heterochromatic flicker photometry (cHFP; Macular Metrics Densitometer(™)), dual-wavelength fundus autofluorescence (Heidelberg Spectralis(®) HRA + OCT MultiColor) and single-wavelength fundus reflectance (Zeiss Visucam(®) 200). MP was measured in one eye of 62 subjects on each device. Data from 49 subjects (79%) was suitable for analysis. Agreement between the Densitometer and Spectralis was investigated at various eccentricities using a variety of quantitative and graphical methods, including: Pearson correlation coefficient to measure degree of scatter (precision), accuracy coefficient, concordance correlation coefficient (ccc), paired t-test, scatter and Bland-Altman plots. The relationship between max MP from the Visucam and central MP from the Spectralis and Densitometer was investigated using regression methods. Agreement was strong between the Densitometer and Spectralis at all central eccentricities (e.g. at 0.25° eccentricity: accuracy = 0.97, precision = 0.90, ccc = 0.87). Regression analysis showed a very weak relationship between the Visucam and Densitometer (e.g. Visucam max on Densitometer central MP: R(2) = 0.008, p = 0.843). Regression analysis also demonstrated a weak relationship between MP measured by the Spectralis and Visucam (e.g. Visucam max on Spectralis central MP: R(2) = 0.047, p = 0.348). MP values obtained using the Heidelberg Spectralis are comparable to MP values obtained using the Densitometer. In contrast, MP values obtained using the Zeiss Visucam are not comparable with either the Densitometer or the Spectralis MP measuring devices. Taking cHFP as the current standard to which other MP measuring devices should be compared, the Spectralis is suitable for use in a clinical and research setting, whereas the Visucam is not. PMID:24007642
Dennison, Jessica L; Stack, Jim; Beatty, Stephen; Nolan, John M
Age-related macular degeneration (AMD) is the leading cause of severe visual impairment in the elderly in developed countries. AMD patients have elevated levels of iron within the retinal pigment epithelia (RPE), which may lead to oxidative damage to mitochondria, disruption of retinal metabolism, and vision impairment or loss. As a possible model for iron-induced AMD, we investigated the effects of excess iron in cultured human fetal RPE cells on oxidant levels and mitochondrial cytochrome c oxidase (complex IV) function and tested for protection by N-tert-butyl hydroxylamine (Nt-BHA), a known mitochondrial antioxidant. RPE exposure to ferric ammonium citrate resulted in a time- and dose-dependent increase in intracellular iron, which increased oxidant production and decreased glutathione (GSH) levels and mitochondrial complex IV activity. NtBHA addition to iron-overloaded RPE cells led to a reduction of intracellular iron content, oxidative stress, and partial restoration of complex IV activity and GSH content. NtBHA might be useful in AMD due to its potential to reduce oxidative stress, mitochondrial damage, and age-related iron accumulation, which may damage normal RPE function and lead to loss of vision.
Voloboueva, Ludmila A.; Killilea, David W.; Atamna, Hani; Ames, Bruce N.
A comparison of macular pigment optical density (MPOD) spatial profiles determined by an optical and a psychophysical technique is presented. We measured the right eyes of 19 healthy individuals, using fundus reflectometry at 0, 1, 2, 4, 6, and 8 deg eccentricity; and heterochromatic flicker photometry (HFP) at 0, 0.5, 1, 2, 3, 4, 5, 6, and 7 deg, and a reference point at 8 deg eccentricity. We found a strong correlation between the two techniques. However, the absolute estimates obtained by fundus reflectometry data were higher than by HFP. These differences could partly be explained by the fact that at 8 deg eccentricity the MPOD is not zero, as assumed in HFP. Furthermore, when performing HFP for eccentricities of <1 deg, we had to assume that subjects set flicker thresholds at 0.4 deg horizontal translation when using a 1-deg stimulus. MPOD profiles are very similar for both techniques if, on average, 0.05 DU is added to the HFP data at all eccentricities. An additional correction factor, dependent on the steepness of the MPOD spatial distribution, is required for 0 deg.
van der Veen, Rob L. P.; Berendschot, Tos T. J. M.; Makridaki, Maria; Hendrikse, Fred; Carden, David; Murray, Ian J.
Summary Background The aim of this paper is to report the incidence of retinal pigment epithelial (RPE) tears in patients treated with ranibizumab for subfoveal fibrovascular retinal pigment epithelial detachment (FVPED) due to occult age-related macular degeneration (AMD). Material/Methods Thirty patients were treated according to the following schedule: saturation phase, further treatment was based on activity of the degeneration process. Visual acuity (VA), optical coherence tomography (OCT) and fluorescein angiography (FA) parameters were evaluated and compared. Results Patients had a mean improvement of +4.7±8.1 letters at month 12. The mean number of needed injections was 6.8±1.8 (range, 3 to 9). RPE tears in fovea occurred in 8 cases (27% of all patients). Analysis of variance revealed significant upper mean values of ETDRS letters for the subgroup without RPE tears. Mean values of PED height were significant upper for RPE tears without baseline. Statistical analysis revealed that in the subgroup without RPE tears mean values of VA significantly differed in succeeding periods compare to baseline (P<0.001). Visual improvement or stabilization was observed in 90.9% of patients without RPE tears (significant improvement of 15 or more letters in 22.7%–5/22) and in 87.5% of patients with RPE tears (significant improvement was not observed). Baseline leakage parameters, lesion and leakage parameters at month 12 were significantly higher in patients with RPE tears. The chi-square test revealed statistically significant associations between RPE tears and subretinal fluid in OCT (P<0.05) at month 12. Conclusions In eyes with FVPED and RPE tears treated with ranibizumab, stabilization of visual acuity without significant improvement is predictable. One of the risk factors common to RPE tears may be baseline leakage parameters and pretreatment distorted RPE contour in OCT. During ranibizumab therapy in eyes with RPE tears, upper parameters of FVPED height may occur without significant differences in fovea and macula volume compare to eyes without RPE tears.
Morgan and colleagues demonstrated that the RPE cell mosaic can be resolved in the living human eye non-invasively by imaging the short-wavelength autofluorescence using an adaptive optics (AO) ophthalmoscope. This method, based on the assumption that all subjects have the same longitudinal chromatic aberration (LCA) correction, has proved difficult to use in diseased eyes, and in particular those affected by age-related macular degeneration (AMD). In this work, we improve Morgan’s method by accounting for chromatic aberration variations by optimizing the confocal aperture axial and transverse placement through an automated iterative maximization of image intensity. The increase in image intensity after algorithmic aperture placement varied depending upon patient and aperture position prior to optimization but increases as large as a factor of 10 were observed. When using a confocal aperture of 3.4 Airy disks in diameter, images were obtained using retinal radiant exposures of less than 2.44 J/cm2, which is ~22 times below the current ANSI maximum permissible exposure. RPE cell morphologies that were strikingly similar to those seen in postmortem histological studies were observed in AMD eyes, even in areas where the pattern of fluorescence appeared normal in commercial fundus autofluorescence (FAF) images. This new method can be used to study RPE morphology in AMD and other diseases, providing a powerful tool for understanding disease pathogenesis and progression, and offering a new means to assess the efficacy of treatments designed to restore RPE health.
Rossi, Ethan A.; Rangel-Fonseca, Piero; Parkins, Keith; Fischer, William; Latchney, Lisa R.; Folwell, Margaret A.; Williams, David R.; Dubra, Alfredo; Chung, Mina M.
Macular telangiectasia type 2 is a bilateral disease of unknown cause with characteristic alterations of the macular capillary network and neurosensory atrophy. Its prevalence may be underestimated and has recently been shown to be as high as 0.1% in persons 40 years and older. Biomicroscopy may show reduced retinal transparency, crystalline deposits, mildly ectatic capillaries, blunted venules, retinal pigment plaques, foveal atrophy, and neovascular complexes. Fluorescein angiography shows telangiectatic capillaries predominantly temporal to the foveola in the early phase and a diffuse hyperfluorescence in the late phase. High-resolution optical coherence tomography (OCT) may reveal disruption of the photoreceptor inner segment–outer segment border, hyporeflective cavities at the level of the inner or outer retina, and atrophy of the retina in later stages. Macular telangiectasia type 2 shows a unique depletion of the macular pigment in the central retina and recent therapeutic trials showed that such depleted areas cannot re-accumulate lutein and zeaxanthin after oral supplementation. There have been various therapeutic approaches with limited or no efficacy. Recent clinical trials with compounds that block vascular endothelial growth factor (VEGF) have established the role of VEGF in the pathophysiology of the disease, but have not shown significant efficacy, at least for the nonneovascular disease stages. Recent progress in structure–function correlation may help to develop surrogate outcome measures for future clinical trials. In this review article, we summarize the current knowledge on macular telangiectasia type 2, including the epidemiology, the genetics, the clinical findings, the staging and the differential diagnosis of the disease. Findings using retinal imaging are discussed, including fluorescein angiography, OCT, adaptive optics imaging, confocal scanning laser ophthalmoscopy, and fundus autofluorescence, as are the findings using visual function testing including visual acuity and fundus-controlled microperimetry. We provide an overview of the therapeutic approaches for both non-neovascular and neovascular disease stages and provide a perspective of future directions including animal models and potential therapeutic approaches.
Issa, Peter Charbel; Gillies, Mark C.; Chew, Emily Y.; Bird, Alan C.; Heeren, Tjebo F.C.; Peto, Tunde; Holz, Frank G.; Scholl, Hendrik P.N.
We have used resonant Raman scattering as a novel, non- invasive, in-vivo optical technique to measure the concentration of macular carotenoid pigments in the living human retina of young and elderly adults. Using a backscattering geometry and resonant molecular excitation in the visible, we measure the Raman peaks originating from the single- and double-bond stretch vibrations of the (pi) - electron conjugated molecule's carbon backbone. The Raman signals scale linearly with carotenoid content while the required laser excitation is well below safety limits for macular exposure. Measured macular pigment levels decline significantly with increasing age. The Raman technique is objective and quantitative and may lead to a new method for rapid screening of carotenoid pigment levels in large populations at risk for vision loss from age-related macular degeneration, the leading cause of blindness in the elderly in the United States.
Gellermann, Werner; Ermakov, Igor V.; Ermakova, Maia R.; McClane, Robert W.; Wintch, Steven W.; Zhao, Da-You; Bernstein, Paul S.
Age-related macular degeneration (ARMD) is the leading cause for visual impairment and blindness in the elder population. Laser photocoagulation, photodynamic therapy and excision of neovascular membranes have met with limited success. Submacular transplantation of autologous iris pigment epithelial (IPE) cells has been proposed to replace the damaged retinal pigment epithelium following surgical removal of the membranes. We tested our hypothesis that the subretinal transplantation of genetically modified autologous IPE cells expressing biological therapeutics might be a promising strategy for the treatment of ARMD and other retinal disorders. Pigment epithelium-derived factor (PEDF) has strong antiangiogenic and neuroprotective activities in the eye. Subretinal transplantation of PEDF expressing IPE cells inhibited pathological choroidal neovascularization in rat models of laser-induced rupture of Bruch's membrane and of oxygen induced ischemic retinopathy. PEDF expressing IPE transplants also increased the survival and preserved rhodopsin expression of photoreceptor cells in the RCS rat, a model of retinal degeneration. These findings suggest a promising concept for the treatment of ARMD and other retinal disorders.
Semkova, Irina; Kreppel, Florian; Welsandt, Gerhard; Luther, Thomas; Kozlowski, Jolanta; Janicki, Hanna; Kochanek, Stefan; Schraermeyer, Ulrich
AIM To investigate the aqueous erythropoietin (EPO) levels and associated factors in patients with acute retinal vein occlusion (RVO). METHODS The aqueous EPO level was measured in patients with macular edema (ME) secondary to acute branched retinal vein occlusion (BRVO) or central retinal vein occlusion (CRVO). Aqueous fluid from cataract patients served as the control. We also evaluated whether aqueous level of EPO was associated with factors such as serum EPO level, non-perfusion area, central macular thickness (CMT), and arterio-venous (AV) transit time RESULTS Twenty-seven RVO patients (16 BRVO, 11 CRVO) and 9 control subjects were enrolled in the study. The aqueous EPO level (mU/mL) was higher in RVO (68.2±54.3) than that in the control subjects (12.9±5.9). More specifically, the aqueous EPO level was higher in CRVO (118.9±52.1) than that in BRVO (33.3±10.8). However, no differences were found in serum EPO levels among three groups. CMT in RVO patients had a positive correlation with the aqueous EPO level (r=0.66). Also, in terms of non-perfusion area, the aqueous EPO levels were more elevated in the ischemic subgroup than in the non-ischemic subgroup in both BRVO and CRVO. CONCLUSION Aqueous EPO levels are elevated in patients with macular edema secondary to recent onset RVO. Patients with CRVO have higher EPO levels than those with BRVO. The aqueous EPO level in RVO has a positive correlation with CMT and is associated with non-perfusion area. These results suggest that the aqueous EPO level could be associated with retinal ischemia and may be involved in the pathogenesis of macular edema secondary to RVO.
Shin, Hyun Jin; Kim, Hyung Chan; Moon, Jun Woong
PurposeClinical data suggest a role for VEGF in uveitic cystoid macular oedema (CME), even though the data on intravitreal VEGF levels in these eyes is still inconclusive. We determined intravitreal VEGF levels and treated uveitis patients with intravitreal bevacizumab.MethodsIntravitreal VEGF levels were measured in eight uveitis patients and 10 controls using cytometric bead array technology. In 11 eyes of a
K Weiss; I Steinbrugger; M Weger; N Ardjomand; R Maier; B J Wegscheider; A Wedrich; Y El-Shabrawi
... understanding vitelliform macular dystrophy? autosomal ; autosomal dominant ; cell ; channel ; chloride ; epithelium ; gene ; incidence ; inheritance ; inheritance pattern ; ions ; juvenile ; lipofuscin ; macula ; peripheral ; photoreceptor ; pigment ; protein ; retina ; ...
Patients with nonexudative ("dry") age-related macular degeneration (AMD) frequently also develop neovascular ("wet") AMD, suggesting a common pathomechanism. Increased vascular endothelial growth factor A (VEGF-A) has been implicated in the pathogenesis of choroidal neovascularization (CNV) in neovascular AMD, while its role in nonexudative AMD that manifests with progressive retinal pigment epithelium (RPE) and photoreceptor degeneration is not well defined. Mice with overall increased VEGF-A levels develop progressive morphological features of both forms of AMD, suggesting that an increase in VEGF-A has a direct age-dependent adverse effect on RPE and photoreceptor function independently of its CNV-promoting proangiogenic effect. Here we provide evidence for this hypothesis and show that morphological RPE abnormalities and retinal thinning in mice with increased VEGF-A levels correlate with progressive age-dependent attenuation of visual function with abnormal electroretinograms and reduced retinal rhodopsin levels. Retinoid profiling revealed a progressive reduction of 11-cis and all-trans retinal in the retinas of these mice, consistent with an impaired retinoid transport between the RPE and photoreceptors. These findings suggest that increased VEGF-A leads to an age-dependent RPE and retinal dysfunction that occurs also at sites where no CNV lesions form. The data support a central role of increased VEGF-A not only in the pathogenesis of neovascular but also of nonexudative AMD. PMID:24558195
Ablonczy, Zsolt; Dahrouj, Mohammad; Marneros, Alexander G
Purpose To investigate the role of serum inflammatory cytokines and vascular endothelial growth factor (VEGF) in diabetic retinopathy (DR) and evaluate their relationship with macular thickness measurements obtained with optical coherence tomography (OCT). Methods The study enrolled 28 healthy subjects (Group 1), 31 patients without DR (Group 2), 49 patients with nonproliferative DR (Group 3), and 46 patients with proliferative DR (Group 4). Macular profile was assessed with Stratus OCT-3 and the serum concentrations of VEGF and interleukin-1? (IL-1?), interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-10 (IL-10), macrophage inflammatory protein (MIP-1?), monocyte chemoattractant protein (MCP-1), and epidermal growth factor (EGF) were measured using multiplex bead immunoassay. Results The median value of the visual acuity was 20/20 (Groups 1 and 2), and 20/100 (Group 3), and 20/125 (Group 4). The median value of central subfield macular thickness was estimated as 165.50 ?m in Group 1, 202.5 ?m in Group 2, 318 ?m in Group 3, and 310 ?m in Group 4. The median serum VEGF level, which was 98.20 pg/ml in Group 1, demonstrated a progressive rise to 125.37 pg/ml in Group 2, to 153.07 pg/ml in Group 3, and to 149.12 pg/ml in Group 4. Statistical significance was found between all groups (p<0.05) except between Groups 3 and 4 (p=0.87). The median levels of IL-1? and IL-6 were zero in all groups. The median serum levels of IL-8, IL-10, MIP-1?, and EGF revealed a wide range within each group but no statistical significance between the groups (p>0.05). The median serum levels of IL-8, IL-10, MIP-1?, and EGF revealed a wide range within each group, however, no statistically significant relationship was found between the groups (p>0.05). The median values of the serum MCP-1 concentrations presented a statistically significant rise with the progression of DR (p=0.02). No correlation was found between macular thickness and serum cytokine and VEGF levels (p>0.05). Conclusions Increased serum levels of VEGF and MCP-1 may act as a key regulator of DR and provide a potential tool for risk assessment in diabetic patients. Further studies that evaluate both vitreous and serum levels in various stages of DR are needed to provide a better understanding of the interaction between systemic and local inflammatory and angiogenic factors.
Bozkurt, Banu; Kerimoglu, Hurkan; Okka, Mehmet; Kamis, Umit; Gunduz, Kemal
Background Age-related macular degeneration (AMD) is a leading cause of blindness that affects the central region of the retinal pigmented epithelium (RPE), choroid, and neural retina. Initially characterized by an accumulation of sub-RPE deposits, AMD leads to progressive retinal degeneration, and in advanced cases, irreversible vision loss. Although genetic analysis, animal models, and cell culture systems have yielded important insights into AMD, the molecular pathways underlying AMD's onset and progression remain poorly delineated. We sought to better understand the molecular underpinnings of this devastating disease by performing the first comparative transcriptome analysis of AMD and normal human donor eyes. Methods RPE-choroid and retina tissue samples were obtained from a common cohort of 31 normal, 26 AMD, and 11 potential pre-AMD human donor eyes. Transcriptome profiles were generated for macular and extramacular regions, and statistical and bioinformatic methods were employed to identify disease-associated gene signatures and functionally enriched protein association networks. Selected genes of high significance were validated using an independent donor cohort. Results We identified over 50 annotated genes enriched in cell-mediated immune responses that are globally over-expressed in RPE-choroid AMD phenotypes. Using a machine learning model and a second donor cohort, we show that the top 20 global genes are predictive of AMD clinical diagnosis. We also discovered functionally enriched gene sets in the RPE-choroid that delineate the advanced AMD phenotypes, neovascular AMD and geographic atrophy. Moreover, we identified a graded increase of transcript levels in the retina related to wound response, complement cascade, and neurogenesis that strongly correlates with decreased levels of phototransduction transcripts and increased AMD severity. Based on our findings, we assembled protein-protein interactomes that highlight functional networks likely to be involved in AMD pathogenesis. Conclusions We discovered new global biomarkers and gene expression signatures of AMD. These results are consistent with a model whereby cell-based inflammatory responses represent a central feature of AMD etiology, and depending on genetics, environment, or stochastic factors, may give rise to the advanced AMD phenotypes characterized by angiogenesis and/or cell death. Genes regulating these immunological activities, along with numerous other genes identified here, represent promising new targets for AMD-directed therapeutics and diagnostics. Please see related commentary: http://www.biomedcentral.com/1741-7015/10/21/abstract
Deimination is a form of protein posttranslational modification carried out by the peptidyl arginine deiminases (PADs) enzymes. PAD2 is the principal deiminase expressed in the retina. Elevated levels of PAD2 and protein deimination are present in a number of human neurological diseases, with or without ocular manifestation. To define the association of deimination with the pathogenesis of age-related macular degeneration (AMD), we studied protein deimination and PAD2 levels in retinas of AMD donor eyes compared to age-matched non-AMD retinas. Eyes from non-AMD and AMD donors were fixed in 4% paraformaldehyde and 0.5% glutaraldehyde in phosphate buffer. Retina and retinal pigment epithelium (RPE) from donor eyes were processed for immunohistochemical detection and western blotting using antibodies to PAD2 and citrulline residues. The ganglion cell, inner plexiform, inner nuclear and outer nuclear layers were labeled by both PAD2 and citrulline antibodies. Changes in the localization of deiminated residues and PAD2 were evident as the retinal layers were remodeled coincident with photoreceptor degeneration in AMD retinas. Immunodetection of either PAD2 or citrulline residues could not be evaluated in the RPE layer due to the high autofluorescence levels in this layer. Interestingly, higher deimination immunoreactivity was detected in AMD retinal lysates. However, no significant changes in PAD2 were detected in the AMD and non-AMD retinas and RPE lysates. Our observations show increased levels of protein deimination but not PAD2 in AMD retinas and RPE, suggesting a reduced rate of turnover of deiminated proteins in these AMD retinas.
Bonilha, Vera L.; Shadrach, Karen G.; Rayborn, Mary E.; Li, Yong; Pauer, Gayle J. T.; Hagstrom, Stephanie A.; Bhattacharya, Sanjoy K.; Hollyfield, Joe G.
Background The A3243G point mutation in mitochondrial DNA (mtDNA) is associated with MELAS (mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes) and MIDD syndromes (maternally inherited diabetes and deafness). Both MELAS and MIDD patients can present with visual symptoms due to a retinopathy, sometimes before the genetic diagnosis is made. Case presentation Patient 1: 46 year-old woman with diabetes mellitus and hearing loss was referred for an unspecified maculopathy detected during screening evaluation for diabetic retinopathy. Visual acuity was 20/20 in both eyes. Fundus examination showed bilateral macular and peripapillary hyperpigmented/depigmented areas. Patient 2: 45 year-old woman was referred for recent vision loss in her left eye. History was remarkable for chronic fatigue, migraine and diffuse muscular pain. Visual acuity was 20/20 in her right eye and 20/30 in her left eye. Fundus exhibited several nummular perifoveal islands of retinal pigment epithelium atrophy and adjacent pale deposits in both eyes. Retinal anatomy was investigated with autofluorescence, retinal angiography and optical coherence tomography. Retinal function was assessed with automated static perimetry, full-field and multifocal electroretinography and electro-oculography. Genetic testing of mtDNA identified a point mutation at the locus 3243. Conclusion Observation of RPE abnormalities in the context of suggestive systemic findings should prompt mtDNA testing.
Background The purpose of this study was to evaluate the effects of intravitreal aflibercept injection for age-related macular degeneration (AMD) with a retinal pigment epithelial (RPE) tear after intravitreal ranibizumab injection (IVR) which finally became resistant to additional IVR. Methods We reviewed the medical records of AMD patients with RPE tears after intravitreal ranibizumab injection who were treated with intravitreal aflibercept injection after acquisition of resistance to additional IVR. Results One eye from three patients, aged 66, 77, and 78 years, was evaluated. All cases started treatment with IVR for AMD. RPE tear developed 1, 4, and 3 months after the first IVR, respectively. Additional IVR was performed seven, seven, and nine times over 10, 19, and 21 months, respectively, but all cases finally became resistant to IVR. Intravitreal aflibercept injection was performed four times, six times, and once over 8, 9, and 6 months, respectively. At the last visit, all patients had complete resolution of subretinal and intraretinal fluid. Conclusion Continued intravitreal aflibercept injection may be beneficial to manage AMD with RPE tear which has become resistant to additional IVR.
Fujii, Ayaka; Imai, Hisanori; Kanai, Michiko; Azumi, Atsushi
Purpose The aim of this study is to report the short-term efficacy of aflibercept in the treatment of neovascular age-related macular degeneration (AMD) with associated retinal pigment epithelial detachment (PED) which is refractory or develops tachyphylaxis to bevacizumab and ranibizumab. Methods The method comprised a retrospective review of the medical records of patients with neovascular AMD and associated PEDs recently treated with aflibercept and previously treated with bevacizumab and ranibizumab. Results Three eyes of three female patients of ages 49, 55, and 65 years old with large serous PEDs and subretinal fluid (SRF) associated with occult choroidal neovascularization and neovascular AMD were treated with aflibercept after intravitreal bevacizumab and/or ranibizumab failed to resolve the lesions. All had complete resolution of SRF and complete or near-complete resolution of the PEDs after aflibercept injections over a 3-month period. Visual acuity improved in all three eyes. Conclusion Intravitreal aflibercept may be an effective treatment option for serous PED in neovascular AMD patients after bevacizumab and ranibizumab have previously failed. Larger studies with longer follow-up are required to determine the role of aflibercept in treatment of PED in neovascular AMD.
Patel, K H; Chow, C C; Rathod, R; Mieler, W F; Lim, J I; Ulanski, L J; Leiderman, Y I; Arun, V; Chau, F Y
Purpose Dietary carotenoids lutein and zeaxanthin may play a protective role against visual loss from age-related macular degeneration (AMD) through antioxidant and light screening mechanisms. We used a novel noninvasive objective method to quantify lutein and zeaxanthin in the human macula using resonance Raman spectroscopy and compared macular pigment levels in AMD and normal subjects. Design Observational study of an ophthalmology clinic-based population. Participants and Controls Ninety-three AMD eyes from 63 patients and 220 normal eyes from 138 subjects. Methods Macular carotenoid levels were quantified by illuminating the macula with a low-power argon laser spot and measuring Raman backscattered light using a spectrograph. This technique is sensitive, specific, and repeatable even in subjects with significant macular pathologic features. Main Outcome Measure Raman signal intensity at 1525 cm?1 generated by the carbon–carbon double-bond vibrations of lutein and zeaxanthin. Results Carotenoid Raman signal intensity declined with age in normal eyes (P < 0.001). Average levels of lutein and zeaxanthin were 32% lower in AMD eyes versus normal elderly control eyes as long as the subjects were not consuming high-dose lutein supplements (P = 0.001). Patients who had begun to consume supplements containing high doses of lutein (?4 mg/day) regularly after their initial diagnosis of AMD had average macular pigment levels that were in the normal range (P = 0.829) and that were significantly higher than in AMD patients not consuming these supplements (P = 0.038). Conclusions These findings are consistent with the hypothesis that low levels of lutein and zeaxanthin in the human macula may represent a pathogenic risk factor for the development of AMD. Resonance Raman measurement of macular carotenoid pigments could play an important role in facilitating large-scale prospective clinical studies of lutein and zeaxanthin protection against AMD, and this technology may someday prove useful in the early detection of individuals at risk for visual loss from AMD.
Bernstein, Paul S.; Zhao, Da-You; Wintch, Steven W.; Ermakov, Igor V.; McClane, Robert W.; Gellermann, Werner
Purpose There is evidence for complement dysfunction in age-related macular degeneration (AMD). Complement activation leads to formation of the membrane attack complex (MAC), known to assemble on retinal pigment epithelial (RPE) cells. Therefore, the effect of sub-lytic MAC on RPE cells was examined with regard to pro-inflammatory or pro-angiogenic mediators relevant in AMD. Methods For sub-lytic MAC induction, RPE cells were incubated with an antiserum to complement regulatory protein CD59, followed by normal human serum (NHS) to induce 5% cell death, measured by a viability assay. MAC formation was evaluated by immunofluorescence and FACS analysis. Interleukin (IL)-6, -8, monocytic chemoattractant protein-1 (MCP-1), and vascular endothelial growth factor (VEGF) were quantified by enzyme-linked immunosorbent assay (ELISA). Intracellular MCP-1 was analysed by immunofluorescence, vitronectin by western blotting, and gelatinolytic matrix metalloproteinases (MMPs) by zymography. Results Incubation of RPE cells with the CD59 antiserum followed by 5% NHS induced sub-lytic amounts of MAC, verified by FACS and immunofluorescence. This treatment stimulated the cells to release IL-6, -8, MCP-1, and VEGF. MCP-1 staining, production of vitronectin, and gelatinolytic MMPs were also elevated in response to sub-lytic MAC. Conclusions MAC assembly on RPE cells increases the IL-6, -8, and MCP-1 production. Therefore, sub-lytic MAC might have a significant role in generating a pro-inflammatory microenvironment, contributing to the development of AMD. Enhanced vitronectin might be a protective mechanism against MAC deposition. In addition, the increased expression of gelatinolytic MMPs and pro-angiogenic VEGF may be associated with neovascular processes and late AMD.
Lueck, K; Wasmuth, S; Williams, J; Hughes, T R; Morgan, B P; Lommatzsch, A; Greenwood, J; Moss, S E; Pauleikhoff, D
Our objective was to investigate antioxidant paraoxonase 1 (PON1) activity together with malondialdehyde (MDA) levels to evaluate oxidative stress in patients with age-related macular degeneration (AMD), an important cause of blindness in the elderly population. Serum PON1 activity and MDA levels were analyzed in 37 patients with AMD and compared with 29 healthy controls using a spectrophotometric method. Serum MDA levels were significantly higher in the patient group (2.76 +/- 1.28 nmol/ml) than controls (1.00 +/- 0.36 nmol/ml; p < 0.001), whereas PON1 activity was lower in the patient group (132.27 +/- 63.39 U/l) than controls (312.13 +/- 136.23 U/l; p < 0.001). There was a negative correlation between MDA and PON1 levels (r = -0.470, p < 0.001). We conclude that the observed increase in MDA levels may be related to decreased PON1 activity; the present data also demonstrated that an obvious negative correlation between PON1 activity and MDA levels exists in patients with AMD. PON1 is also an antioxidant agent, therefore effective antioxidant therapy to inhibit lipid peroxidation is necessary and agents to increase PON1 activity may be a therapeutic option in AMD. PMID:16374043
Baskol, Gulden; Karakucuk, Sarper; Oner, Ayse Ozturk; Baskol, Mevlut; Kocer, Derya; Mirza, Ertugrul; Saraymen, Recep; Ustdal, Muzaffer
Basic studies of human pluripotential stem cells have advanced rapidly and stem cell products are now seeing therapeutic applications. However, questions remain regarding the tumorigenic potential of such cells. Here, we report the tumorigenic potential of induced pluripotent stem cell (iPSC)-derived retinal pigment epithelium (RPE) for the treatment of wet-type, age-related macular degeneration (AMD). First, immunodeficient mouse strains (nude, SCID, NOD-SCID and NOG) were tested for HeLa cells’ tumor-forming capacity by transplanting various cell doses subcutaneously with or without Matrigel. The 50% Tumor Producing Dose (TPD50 value) is the minimal dose of transplanted cells that generated tumors in 50% of animals. For HeLa cells, the TPD50 was the lowest when cells were embedded in Matrigel and transplanted into NOG mice (TPD50?=?101.1, n?=?75). The TPD50 for undifferentiated iPSCs transplanted subcutaneously to NOG mice in Matrigel was 102.12; (n?=?30). Based on these experiments, 1×106 iPSC-derived RPE were transplanted subcutaneously with Matrigel, and no tumor was found during 15 months of monitoring (n?=?65). Next, to model clinical application, we assessed the tumor-forming potential of HeLa cells and iPSC 201B7 cells following subretinal transplantation of nude rats. The TPD50 for iPSCs was 104.73 (n?=?20) and for HeLa cells 101.32 (n?=?37) respectively. Next, the tumorigenicity of iPSC-derived RPE was tested in the subretinal space of nude rats by transplanting 0.8–1.5×104 iPSC-derived RPE in a collagen-lined (1 mm×1 mm) sheet. No tumor was found with iPSC-derived RPE sheets during 6–12 months of monitoring (n?=?26). Considering the number of rodents used, the monitoring period, the sensitivity of detecting tumors via subcutaneous and subretinal administration routes and the incidence of tumor formation from the iPSC-derived RPE, we conclude that the tumorigenic potential of the iPSC-derived RPE was negligible.
Kanemura, Hoshimi; Go, Masahiro J.; Shikamura, Masayuki; Nishishita, Naoki; Sakai, Noriko; Kamao, Hiroyuki; Mandai, Michiko; Morinaga, Chikako; Takahashi, Masayo; Kawamata, Shin
Basic studies of human pluripotential stem cells have advanced rapidly and stem cell products are now seeing therapeutic applications. However, questions remain regarding the tumorigenic potential of such cells. Here, we report the tumorigenic potential of induced pluripotent stem cell (iPSC)-derived retinal pigment epithelium (RPE) for the treatment of wet-type, age-related macular degeneration (AMD). First, immunodeficient mouse strains (nude, SCID, NOD-SCID and NOG) were tested for HeLa cells' tumor-forming capacity by transplanting various cell doses subcutaneously with or without Matrigel. The 50% Tumor Producing Dose (TPD50 value) is the minimal dose of transplanted cells that generated tumors in 50% of animals. For HeLa cells, the TPD50 was the lowest when cells were embedded in Matrigel and transplanted into NOG mice (TPD50?=?10(1.1), n?=?75). The TPD50 for undifferentiated iPSCs transplanted subcutaneously to NOG mice in Matrigel was 10(2.12); (n?=?30). Based on these experiments, 1×10(6) iPSC-derived RPE were transplanted subcutaneously with Matrigel, and no tumor was found during 15 months of monitoring (n?=?65). Next, to model clinical application, we assessed the tumor-forming potential of HeLa cells and iPSC 201B7 cells following subretinal transplantation of nude rats. The TPD50 for iPSCs was 10(4.73) (n?=?20) and for HeLa cells 10(1.32) (n?=?37) respectively. Next, the tumorigenicity of iPSC-derived RPE was tested in the subretinal space of nude rats by transplanting 0.8-1.5×10(4) iPSC-derived RPE in a collagen-lined (1 mm×1 mm) sheet. No tumor was found with iPSC-derived RPE sheets during 6-12 months of monitoring (n?=?26). Considering the number of rodents used, the monitoring period, the sensitivity of detecting tumors via subcutaneous and subretinal administration routes and the incidence of tumor formation from the iPSC-derived RPE, we conclude that the tumorigenic potential of the iPSC-derived RPE was negligible. PMID:24454843
Kanemura, Hoshimi; Go, Masahiro J; Shikamura, Masayuki; Nishishita, Naoki; Sakai, Noriko; Kamao, Hiroyuki; Mandai, Michiko; Morinaga, Chikako; Takahashi, Masayo; Kawamata, Shin
Cannabinoid receptors and the endocannabinoids (anandamide (N-arachidonoylethanolamine—AEA) and 2-arachidonoylglycerol (2-AG)), as well as the AEA congener, palmitoylethanolamide (PEA), are involved in ocular physiology. We measured endocannabinoid and PEA levels by isotope-dilution liquid chromatography-mass spectrometric analysis in post-mortem eye tissues of patients with diabetic retinopathy (DR) or age-related macular degeneration (AMD). In eyes with DR, significantly enhanced levels of AEA were
I. Matias; J. W. Wang; A. Schiano Moriello; A. Nieves; D. F. Woodward; V. Di Marzo
PURPOSE. Ocular melanin synthesis modulates rod photorecep- tor production, because in albino eyes, rod numbers are re- duced by approximately 30%. In this study, rod numbers and ocular rhodopsin concentrations were measured in intermedi- ate pigmentation phenotypes to determine whether propor- tional reductions in melanin are correlated with proportional changes in rod numbers. Further, patterns of cell production and death
Philippe Donatien; Glen Jeffery
Best macular dystrophy (BMD), also known as vitelliform macular dystrophy (VMD2; OMIM 153700), is an autosomal dominant form of macular degeneration characterized by an abnormal accumulation of lipofuscin within and beneath the retinal pigment epithelium cells. In pursuit of the disease gene, we limited the minimum genetic region by recombination breakpoint analysis and mapped to this region a novel retina-specific
Markus J. Koisti; Benjamin Bakall; Wen Li; Guochun Xie; Towa Marknell; Ola Sandgren; Kristina Forsman; Gösta Holmgren; Sten Andreasson; Mihailo Vujic; Arthur A. B. Bergen; Valarie McGarty-Dugan; David Figueroa; Christopher P. Austin; Michael L. Metzker; C. Thomas Caskey; Konstantin Petrukhin; Claes Wadelius
The macula of the primate retina uniquely concentrates high amounts of the xanthophyll carotenoids lutein, zeaxanthin, and meso-zeaxanthin, but the underlying biochemical mechanisms for this spatial- and species-specific localization have not been fully elucidated. For example, despite abundant retinal levels in mice and primates of a binding protein for zeaxanthin and meso-zeaxanthin, the pi isoform of glutathione S-transferase (GSTP1), only human and monkey retinas naturally contain detectable levels of these carotenoids. We therefore investigated whether or not differences in expression, localization, and activity between mouse and primate carotenoid metabolic enzymes could account for this species-specific difference in retinal accumulation. We focused on ?,?-carotene-9',10'-dioxygenase (BCO2, also known as BCDO2), the only known mammalian xanthophyll cleavage enzyme. RT-PCR, Western blot analysis, and immunohistochemistry (IHC) confirmed that BCO2 is expressed in both mouse and primate retinas. Cotransfection of expression plasmids of human or mouse BCO2 into Escherichia coli strains engineered to produce zeaxanthin demonstrated that only mouse BCO2 is an active zeaxanthin cleavage enzyme. Surface plasmon resonance (SPR) binding studies showed that the binding affinities between human BCO2 and lutein, zeaxanthin, and meso-zeaxanthin are 10- to 40-fold weaker than those for mouse BCO2, implying that ineffective capture of carotenoids by human BCO2 prevents cleavage of xanthophyll carotenoids. Moreover, BCO2 knockout mice, unlike WT mice, accumulate zeaxanthin in their retinas. Our results provide a novel explanation for how primates uniquely concentrate xanthophyll carotenoids at high levels in retinal tissue. PMID:24982131
Li, Binxing; Vachali, Preejith P; Gorusupudi, Aruna; Shen, Zhengqing; Sharifzadeh, Hassan; Besch, Brian M; Nelson, Kelly; Horvath, Madeleine M; Frederick, Jeanne M; Baehr, Wolfgang; Bernstein, Paul S
Efficacy of Ethanol Extract of Fructus lycii and Its Constituents Lutein/Zeaxanthin in Protecting Retinal Pigment Epithelium Cells against Oxidative Stress: In Vivo and In Vitro Models of Age-Related Macular Degeneration
Age-related macular degeneration (AMD) is a major cause of blindness worldwide. Oxidative stress plays a large role in the pathogenesis of AMD. The present study was to evaluate the effects of Fructus lycii ethanol extract on AMD in mice and to investigate whether combination of lutein and zeaxanthin, two carotenoid pigments in Fructus lycii, could protect human retinal pigment epithelial ARPE-19 cells treated with hydrogen peroxide (H2O2) in vitro. We found that severe sediment beneath retinal pigment epithelium and thickened Bruch membrane occurred in AMD mice. However, Fructus lycii ethanol extract improved the histopathologic changes and decreased the thickness of Bruch membrane. Furthermore, the gene and protein expression of cathepsin B and cystatin C was upregulated in AMD mice but was eliminated by Fructus lycii ethanol extract. Investigations in vitro showed that ARPE-19 cell proliferation was suppressed by H2O2. However, lutein/zeaxanthin not only stimulated cell proliferation but also abrogated the enhanced expression of MMP-2 and TIMP-1 in H2O2-treated ARPE-19 cells. These data collectively suggested that Fructus lycii ethanol extract and its active components lutein/zeaxanthin had protective effects on AMD in vivo and in vitro, providing novel insights into the beneficial role of Fructus lycii for AMD therapy.
Xu, Xinrong; Hang, Li; Huang, Binglin; Wei, Yuanhua; Zheng, Shizhong
The concentration levels and congener profiles of polychlorinated biphenyls (PCBs), pentachlorobenzene (PeCBz), and hexachlorobenzene (HxCBz) were assessed in commercially available organic pigments. Among the azo-type pigments tested, PCB-11, which is synthesized from 3,3'-dichlorobendizine, and PCB-52, which is synthesized from 2,2',5,5'-tetrachlorobendizine, were the major congeners detected. It is speculated that these were byproducts of chlorobendizine, which has a very similar structure. The total PCB concentrations in this type of pigment ranged from 0.0070 to 740 mg/kg. Among the phthalocyanine-type pigments, highly chlorinated PCBs, mainly composed of PCB-209, PeCBz, and HxCBz were detected. Their concentration levels ranged from 0.011 to 2.5 mg/kg, 0.0035 to 8.4 mg/kg, and 0.027 to 75 mg/kg, respectively. It is suggested that PeCBz and HxCBz were formed as byproducts and converted into PCBs at the time of synthesizing the phthalocyanine green. For the polycyclic-type pigments that were assessed, a distinctive PCB congener profile was detected that suggested an impact of their raw materials and the organic solvent used in the pigment synthesis. PCB pollution from PCB-11, PCB-52, and PCB-209 pigments is of particular concern; therefore, the monthly variations in atmospheric concentrations of these pollutants were measured in an urban area (Sapporo city) and an industrial area (Muroran city). The study detected a certain level of PCB-11, which is not included in PCB technical mixtures, and revealed continuing PCB pollution originating from pigments in the ambient air. PMID:23852585
Anezaki, Katsunori; Nakano, Takeshi
We have used resonance Raman scattering as a non-invasive optical technique to measure the concentration of carotenoid pigments in the human retina. The technique is highly sensitive and specific strength scales linearly with actual macular carotenoid content as measured by high-pressure liquid chromatography. This will facilitate studies of carotenoid distributions and their role in degenerative diseases of the eye and may allow for the rapid screening of carotenoid levels in large populations at risk for vision loss from age-related macular degeneration, the leading cause of blindness in the elderly in the US.
Gellermann, Werner; Yoshida, Mihoko D.; McClane, Robert W.; Balashov, Nikita; Bernstein, Paul S.
Supplementation with carotenoids is proposed to protect against age-related macular degeneration. There is, however, considerable variability in retinal macular pigment response, which may be due to underlying genetic variation. The purpose of this study was to determine whether genetic factors, which have been previously associated with cross-sectional macular pigment levels in the retina or serum lutein, also influence response to supplementation. To this end we conducted an association study in 310 subjects from the TwinsUK cohort between variants in 8 candidate genes and serum lutein and retinal macular pigment optical density (MPOD) levels before and after supplementation. Four variants were associated with MPOD response to supplementation (p < 0.05): rs11057841 (SCARB1), rs4926339 (RPE65), rs1929841 (ABCA1) and rs174534 (FADS1). We also confirmed previous associations between rs6564851 near BMCO1 (p < 0.001) and rs11057841 within SCARB1 (p = 0.01) and baseline measures of serum lutein; while the latter was also associated with MPOD response, none of the BMCO1 variants were. Finally, there was evidence for association between variants near RPE65 and ELOVL2 and changes in lutein concentration after supplementation. This study is the first to show association between genetic variants and response to carotenoids supplementation. Our findings suggest an important link between MP response and the biological processes of carotenoids transport and fatty acid metabolism. PMID:23891863
Yonova-Doing, Ekaterina; Hysi, Pirro G; Venturini, Cristina; Williams, Katie M; Nag, Abhishek; Beatty, Stephen; Liew, S H Melissa; Gilbert, Clare E; Hammond, Christopher J
Complete Resolution of a Giant Pigment Epithelial Detachment Secondary to Exudative Age-Related Macular Degeneration after a Single Intravitreal Ranibizumab (Lucentis) Injection: Results Documented by Optical Coherence Tomography
Aim To describe a patient with a giant pigment epithelial detachment (PED) secondary to exudative age-related macular degeneration (ARMD) successfully treated with a single intravitreal ranibizumab (Lucentis) injection (0.5 mg/0.05 ml). Methods An 89-year-old woman presented with a six-day history of reduced vision and distortion in the left eye. Best-corrected visual acuity in that eye was 6/15. Fundoscopy revealed a giant PED and exudates temporally to the fovea. Optical coherence tomography showed a PED associated with subretinal and intraretinal fluid. Fluorescein angiography confirmed the diagnosis of an occult choroidal neovascularization. Treatment with intravitreal injections of ranibizumab (Lucentis) was recommended, although the increased risk of retinal pigment epithelium (RPE) rip was mentioned. Results Four weeks after the first intravitreal Lucentis injection, the visual acuity in the left eye improved to 6/7.5, with a significant improvement of the distortion and a complete anatomical resolution of the PED confirmed by optical coherence tomography. Conclusion Giant PED secondary to exudative ARMD can be successfully treated with intravitreal ranibizumab, despite the increased risk of RPE rip. To our knowledge, this is the first case presenting with complete resolution of PED after a single ranibizumab injection.
Loukianou, Eleni; Kisma, Nacima; Hamilton, Robin
Retinal pigment epithelium (RPE) arises from neuroectoderm and plays a key role in support of photoreceptor functions. Several degenerative eye diseases, such as macular degeneration or retinitis pigmentosa, are associated with impaired RPE function that may lead to photoreceptor loss and blindness. RPE derived from human embryonic stem (hES) cells can be an important source of this tissue for transplantation
Convergence—the independent evolution of the same trait by two or more taxa—has long been of interest to evolutionary biologists, but only recently has the molecular basis of phenotypic convergence been identified. Here, we highlight studies of rapid evolution of cryptic coloration in vertebrates to demonstrate that phenotypic convergence can occur at multiple levels: mutations, genes and gene function. We first show that different genes can be responsible for convergent phenotypes even among closely related populations, for example, in the pale beach mice inhabiting Florida's Gulf and Atlantic coasts. By contrast, the exact same mutation can create similar phenotypes in distantly related species such as mice and mammoths. Next, we show that different mutations in the same gene need not be functionally equivalent to produce similar phenotypes. For example, separate mutations produce divergent protein function but convergent pale coloration in two lizard species. Similarly, mutations that alter the expression of a gene in different ways can, nevertheless, result in similar phenotypes, as demonstrated by sister species of deer mice. Together these studies underscore the importance of identifying not only the genes, but also the precise mutations and their effects on protein function, that contribute to adaptation and highlight how convergence can occur at different genetic levels.
Manceau, Marie; Domingues, Vera S.; Linnen, Catherine R.; Rosenblum, Erica Bree; Hoekstra, Hopi E.
Purpose This study compares vitreal levels of erythropoietin (EPO) in patients with retinal vein occlusion (RVO) with control subjects. In addition, it investigates different RVO disease parameters (time of vein occlusion, patient age, vitreal vascular endothelial growth factor (VEGF) levels, and extent of central macular edema) for possible correlations with vitreal EPO levels. Methods Serum and vitreal EPO were measured from 6 patients with branch retinal vein occlusion, 6 patients with central retinal vein occlusion, and 12 control subjects (10 macular puckers and 2 macular holes). Results Serum EPO levels (9.8 ± 4.9 mU/mL) did not differ between the RVO and control groups and were significantly lower than vitreal EPO levels in all groups. Vitreal EPO was elevated both in branch RVO (91 ± 59 mU/mL) and central RVO (182 ± 70 mU/mL) compared with controls (35 ± 24 mU/mL). Increased vitreal EPO correlated with higher vitreal VEGF (r = 0.64, P = 0.0008) and more pronounced central macular edema (r = 0.66, P = 0.001). Conclusion The results from this study indicate that EPO is locally expressed in the retina and that it is upregulated together with VEGF in RVO eyes. Because of its role both in neuroprotection and angiogenesis, ocular EPO might represent an interesting target to investigate in patients with RVO, especially in light of the current anti-VEGF treatments.
STAHL, ANDREAS; BUCHWALD, ARMIN; MARTIN, GOTTFRIED; JUNKER, BERND; CHEN, JING; HANSEN, LUTZ L.; AGOSTINI, HANSJURGEN T.; SMITH, LOIS E. H.; FELTGEN, NICOLAS
Stargardt-like macular degeneration (STGD3) is an early onset, autosomal dominant macular degeneration. STGD3 is characterized by a progressive pathology, the loss of central vision, atrophy of the retinal pigment epithelium, and accumulation of lipofuscin, clinical features that are also characteristic of age-related macular degeneration. The onset of clinical symptoms in STGD3, however, is typically observed within the second or third
Vidyullatha Vasireddy; Paul Wong; Radha Ayyagari
Purpose Age-related macular degeneration (AMD) is a condition that progressively reduces central vision in elderly individuals, resulting in a reduced capacity to perform many daily activities and a diminished quality of life. Recent studies identified clinical treatments that can slow or reverse the progression of exudative (wet) AMD and ongoing research is evaluating earlier interventions. Because early diagnosis is critical for an optimal outcome, the goal of this study is to assess psychophysical orientation discrimination for randomly positioned short line segments as a potential indicator of subtle macular changes in eyes with early AMD. Methods Orientation discrimination was measured in a sample of 74 eyes of patients aged 47 to 82 years old, none of which had intermediate or advanced AMD. Amsler-grid testing was performed as well. A masked examiner graded each eye as level 0, 1, 2, or 3 on a streamlined version of the Age-Related Eye Disease Study (AREDS) scale for AMD, based on the presence and extent of macular drusen or retinal pigment epithelium (RPE) changes. Visual acuity in the 74 eyes ranged from 20/15 to 20/40+1, with no significant differences among the grading levels. Humphrey 10–2 and Nidek MP-1 micro-perimetry were used to assess retinal sensitivity at test locations 1° from the locus of fixation. Results Average orientation-discrimination thresholds increased systematically from 7.4° to 11.3° according to the level of macular changes. In contrast, only 3 of 74 eyes exhibited abnormalities on the Amsler grid and central-field perimetric defects occurred with approximately equal probability at all grading levels. Conclusions In contrast to Amsler grid and central-visual-field testing, psychophysical orientation discrimination has the capability to distinguish between eyes with and without subtle age-related macular changes.
Bedell, Harold E.; Tong, Jianliang; Woo, Stanley Y.; House, Jon R.; Nguyen, Tammy
We examined the association of nitrate-nitrogen exposure from rural private drinking water and incidence of age-related macular degeneration (AMD). Participants of the Beaver Dam Eye Study living in rural areas within the 53916 zone improvement plan code but outside the city limits of Beaver Dam, Wisconsin (Beaver Dam Township) completed a questionnaire and ocular examination including standardized, graded fundus photographs at five examinations. Data from an environmental monitoring study with probabilistic-based agro-chemical sampling, including nitrate-nitrogen, of rural private drinking water were available. Incidence of early AMD was associated with elevated nitrate-nitrogen levels in rural private drinking water supply (10.0% for low, 19.2% for medium, and 26.1% for high nitrate-nitrogen level in the right eye). The odds ratios (ORs) were 1.77 (95% confidence interval [CI]: 1.12–2.78) for medium and 2.88 (95% CI: 1.59–5.23) for high nitrate-nitrogen level. Incidence of late AMD was increased for those with medium or high levels of nitrate-nitrogen compared to low levels (2.3% for low and 5.1% for the medium or high nitrate-nitrogen level, for the right eye). The OR for medium or high nitrate-nitrogen groups was 2.80 (95% CI: 1.07–7.31) compared to the low nitrate-nitrogen group.
Klein, Barbara E. K.; McElroy, Jane A.; Klein, Ronald; Howard, Kerri P.; Lee, Kristine E.
We show that high levels of tumor necrosis factor-alpha (TNF-alpha) activity were consistently detected when monocytes were cocultured with Plasmodium falciparum schizont stage-parasitized erythrocytes that subsequently ruptured. Isolated pigment recovere...
S. Pichyangkul P. Saengrai H. K. Webster
We studied the effect of macular grid photocoagulation on the retinal vessels, retina, retinal pigment epithelium, and choroid of normal cynomolgus monkeys. Argon blue-green laser photocoagulation, similar to that employed for treating macular edema due to branch retinal vein occlusion, resulted in a decreased retinal capillary area at both one and five months after treatment. The photoreceptors and retinal pigment epithelium between laser lesions were altered at three days after treatment, but their appearance returned to normal by five months. The significance of these findings is discussed with regard to resolution of macular edema and improvement in vision following grid photocoagulation.
Wilson, D.J.; Finkelstein, D.; Quigley, H.A.; Green, W.R.
Cholecalciferol (vitamin D) might play a physiological role in photo-induced melanogenesis in human skin. We estimated the levels of 25-hydroxy vitamin D [25(OH)D] before, during, and after Narrow Band Ultraviolet B (NBUVB) radiation in patients of vitiligo and their correlation with NBUVB induced pigmentation. Thirty patients of vitiligo and equal number of age and sex matched controls were recruited for the study. Vitiligo patients were treated with NBUVB thrice weekly for 12 weeks. [25(OH)D] levels and Vitiligo Area and Severity Index (VASI) were calculated at 0 (baseline), 6, and 12 weeks. Baseline [25(OH)D] levels were measured in controls. Significant reduction in VASI score was observed after 12 weeks of therapy. Comparison and correlation between mean improvement in VASI and [25(OH)D] levels at 12 weeks showed moderate correlation, and the results were statistically insignificant. Mean reduction in VASI and increase in [25(OH)D] levels after 12 weeks of NBUVB showed moderate correlation. Thus, vitamin D might play a significant role in photo-induced melanogenesis. However, there might be additional effects of the phototherapy on melanogenesis. The complete mechanism of NBUVB induced pigmentation in vitiligo needs to be elucidated.
Sehrawat, Manu; Arora, Tarlok Chand; Chauhan, Amrita; Kar, Hemanta Kumar; Poonia, Amitabh; Jairath, Vijayeeta
... A Search Search Welcome Welcome to the American Macular Degeneration Foundation web site where you can learn about this disease, find valuable resources and help conquer macular degeneration. Macular Degeneration is an incurable eye disease that ...
The inherited macular dystrophies are characterized by different grade central visual loss and different character macula atrophy, because of retinal pigment epithelium lesion. The cause of photoreceptors degeneration is still not known. In this article, we review subjective and objective ophthalmological examines essential to diagnosis and differential diagnosis of inherited autosomal dominant and autosomal recessive macular dystrophies. It is known seven gene mutations (ABCA4, ELOVL4, PROML1, VMD2, Peripherin/RDS, TIMP3, XLRS), which may cause inherited macular dystrophies development. Inheritance type of inherited macular dystrophies, prevalence, beginning of disease, spread of the disease between female and male, clinic, electroretinography, electrooculography, differential diagnosis, genetic research and prognosis are also reviewed. PMID:23168924
Liutkevi?ien?, Rasa; Lesauskait?, Vaiva; Ašmonien?, Virginija; Gelžinis, Arvydas; Zali?nien?, Dalia; Jašinskas, Vytautas
Lipofuscin results from digestion of photoreceptor outer segments by the retinal pigment epithelium (RPE) and is the principal compound that causes RPE fluorescence during autofluorescence imaging. Absorption of the 488-nanometer blue light by macular pigments, especially by the carotenoids lutein and zeaxanthin, causes normal macular hypo-autofluorescence. Fundus autofluorescence imaging is being increasingly employed in ophthalmic practice to diagnose and monitor patients with a variety of retinal disorders. In macular edema for example, areas of hyper-autofluorescence are usually present which are postulated to be due to dispersion of macular pigments by pockets of intraretinal fluid. For this reason, the masking effect of macular pigments is reduced and the natural autofluorescence of lipofuscin can be observed without interference. In cystic types of macular edema, e.g. cystoid macular edema due to retinal vein occlusion, diabetic macular edema and post cataract surgery, hyper-autofluorescent regions corresponding to cystic spaces of fluid accumulation can be identified. In addition, the amount of hyper-autofluorescence seems to correspond to the severity of edema. Hence, autofluorescence imaging, as a noninvasive technique, can provide valuable information on cystoid macular edema in terms of diagnosis, follow-up and efficacy of treatment.
Ebrahimiadib, Nazanin; Riazi-Esfahani, Mohammad
Engineering of human retinal pigment epithelium (RPE) cell monolayer with low level of reactive oxygen species (ROS) is important for regenerative RPE-based therapies. However, it is still challenging to culture RPE monolayer with low ROS level on soft substrates in vitro. To address this, we developed cytocompatible hydrogels to culture human RPE cell monolayer for future use in regenerative RPE-based therapies. The cell adhesion, proliferation, monolayer formation, morphology, survival, and ROS level of human ARPE-19 cells cultured on the surfaces of negatively charged poly (2-acrylamido-2-methyl propane sulfonic sodium) (PNaAMPS) and neutral poly(N,N-dimethylacrylamide) (PDMAAm) hydrogels with different stiffness were investigated. The importance of hydrogel stiffness on the cell function was firstly highlighted on the base of determined optimal Young's modulus for cultivation of RPE cell monolayer with relatively low ROS level. The construction of RPE cell monolayer with low ROS level on the PNaAMPS hydrogel may hold great potential as promising candidates for transplantation of RPE cell monolayer-hydrogel construct into the subretinal space to repair retinal functions. PMID:23913900
Chen, Yong Mei; Liu, Zhen Qi; Feng, Zhi Hui; Xu, Feng; Liu, Jian Kang
Purpose The purpose of this study was to describe the clinical finding of macular subretinal fluid by optical coherence tomography in patients with acute posterior multifocal placoid pigment epitheliopathy. Methods Patients with acute posterior multifocal placoid pigment epitheliopathy were identified, and those with macular serous retinal detachment noted clinically and confirmed by optical coherence tomography are described. Results Of 8 patients with acute posterior multifocal placoid pigment epitheliopathy evaluated by the uveitis service at the Illinois Eye and Ear Infirmary between 2003 and 2008, 4 eyes of 3 patients presented with macular subretinal fluid. Confirmatory optical coherence tomography was performed in two patients. Conclusion Acute posterior multifocal placoid pigment epitheliopathy may present clinically with macular subretinal fluid. This finding can be confirmed and monitored with optical coherence tomography.
BIRNBAUM, ANDREA D.; BLAIR, MICHAEL P.; TESSLER, HOWARD H.; GOLDSTEIN, DEBRA A.
PURPOSE:To determine whether endolaser photocoagulation to the retinal pigment epithelium at the base of a macular hole increases the anatomic success rate of surgery.METHODS:In a prospective consecutive clinical trial, eight eyes of seven patients with idiopathic macular hole underwent vitrectomy with posterior cortical vitreous removal and peeling of visible epiretinal membrane when present. A single shot of argon endolaser photocoagulation
Woog-Ki Min; Jeong-Hee Lee; Don-Il Ham
This study examined the changes of tocopherols (Toc), tocotrienols (T3), ?-oryzanol (GO), and ?-aminobutyric acid (GABA) contents in germinated brown rice (GBR) of pigmented and nonpigmented cultivars under different germination conditions. Results showed that the Toc and T3 contents in GBR were significantly different between treatments in both rice cultivars. The pigmented GBR possessed higher total vitamin E, total Toc, total T3, and GO contents than the nonpigmented GBR; however, its level of GABA was lower. The order of the three highest vitamin E homologues in pigmented and nonpigmented GBR was ?-T3 > ?-Toc > ?-Toc and ?-Toc > ?-T3 > ?-T3, respectively; ?-Toc, ?-T3, ?-Toc, and ?-T3 were present in only small amounts (?1.0 mg/kg) in GBR of both cultivars. Although both cultivars showed an increase in GABA contents with increasing germination time, the GABA content in nonpigmented GBR was higher. PMID:24313881
Ng, Lean-Teik; Huang, Shao-Hua; Chen, Yen-Ting; Su, Chun-Han
· Background: Macular rotation to treat exudative age-related macular degeneration (AMD) involves translocation of the fovea\\u000a to a site with intact retinal pigment epithelium. To avoid the inevitable postoperative cyclotropia we combined this procedure\\u000a with torsional muscle surgery.?· Patients and methods: In 30 eyes the macula was rotated upward by 30–50° following complete\\u000a artificial retinal detachment and a 360° retinotomy.
Claus Eckardt; Ute Eckardt; Hans-Georg Conrad
This article presents information on macular degeneration for professionals helping persons with this disease adjust to their visual loss. It covers types of macular degeneration, the etiology of the disease, and its treatment. Also considered are psychosocial problems and other difficulties that persons with age-related macular degeneration face.…
Chalifoux, L. M.
Macular edema is defined as an accumulation of fluid in the outer plexiform layer and the inner nuclear layer as well as a swelling of Müller cells of the retina. It consists of a localized expansion of the retinal extracellular space (sometimes associated with the intracellular space) in the macular area. Macular edema is a common cause of a sudden
Stefan Scholl; Janna Kirchhof; Albert J. Augustin
Background It has been hypothesised that light skin pigmentation has arisen to ensure adequate levels of vitamin D as human populations moved out of Africa and into higher latitudes. Vitamin D, which is primarily obtained through exposure to sunlight (specifically ultraviolet radiation B (UVR-B)), has been inversely associated with several complex diseases. Greater sun exposure, on the other hand, is a well-known cause of skin cancer. The potential of UVR to be beneficial for some health outcomes but detrimental for others has prompted a public health debate on how to balance the positive and negative consequences of sun exposure. In this study we aimed to determine the validity of the evolutionary hypothesis linking lighter skin with higher vitamin D concentrations in a European population. Additionally, we aimed to examine the influence of pigmentation on personal behaviour towards sunlight exposure and the effects of this behaviour on vitamin D. Methods We combined genetic variants strongly associated with skin colour, tanning or freckling to create genetic scores for each of these phenotypes. We examined the association of the scores with pigmentary traits, sun exposure and serum 25-hydroxyvitamin D (25(OH)D) levels among children of the Avon Longitudinal Study of Parents and Children (ALSPAC, N?=?661 to 5649). Results We found that fairer-skinned children, i.e. those with higher pigmentation score values, had higher levels of 25(OH)D (0.6 nmol/l; 95% CI 0.2, 1.0; per unit increase in skin colour score; N?=?5649). These children also used more protection against the damaging effects of UVR. Conclusions In this population taking protective measures against sunburn and skin cancer does not seem to remove the positive effect that having a less pigmented skin has on vitamin D production. Our findings require further replication as skin pigmentation showed only a small effect on circulating 25(OH)D.
Retinal pigment epithelium (RPE) arises from neuroectoderm and plays a key role in support of photoreceptor functions. Several degenerative eye diseases, such as macular degeneration or retinitis pigmentosa, are associated with impaired RPE function that may lead to photoreceptor loss and blindness. RPE derived from human embryonic stem (hES) cells can be an important source of this tissue for transplantation to cure such degenerative diseases. This chapter describes differentiation of hES cells to RPE, its subsequent isolation, maintenance in culture, and characterization. PMID:17141036
This chapter provides the reader with practical information to be applied to the various remaining causes of macular edema. Some clinical cases of macular edema linked to ocular diseases like postradiotherapy for ocular melanomas remained of poor functional prognosis due to the primary disease. On the contrary, macular edema occurring after retinal detachment or after diverse systemic or local treatment use is often temporary. Macular edema associated with epiretinal membranes or vitreomacular traction is the main cause of poor functional recovery. In other cases, as in tractional myopic vitreoschisis, the delay to observe a significant improvement of the vision after surgery should be long. Finally, macular edema associated with hemangiomas or macroaneurysms should be treated, if symptomatic, using the same current treatment as in diabetic macular edema or exudative macular degeneration. PMID:20703051
Creuzot-Garcher, Catherine; Wolf, Sebastian
This article provides the reader with practical information to be applied to the various remaining causes of macular edema. Some macular edemas linked to ocular diseases like radiotherapy after ocular melanomas remained of poor functional prognosis due to the primary disease. On the contrary, macular edemas occurring after retinal detachment or after some systemic or local treatment use are often temporary. Macular edema associated with epiretinal membranes or vitreomacular traction is the main cause of poor functional recovery. However, the delay to observe a significant improvement of vision after surgery should be long, as usually observed in tractional myopic vitreoschisis. Finally, some circumstances of macular edemas such as hemangiomas or macroaneurysms should be treated, if symptomatic, with the treatments currently used in diabetic macular edema or exudative macular degeneration. PMID:23264332
Creuzot-Garcher, Catherine; Jonas, Jost; Wolf, Sebastian
Background Tunneling nanotubes (TNTs) may offer a very specific and effective way of intercellular communication. Here we investigated TNTs in the human retinal pigment epithelial (RPE) cell line ARPE-19. Morphology of TNTs was examined by immunostaining and scanning electron microscopy. To determine the function of TNTs between cells, we studied the TNT-dependent intercellular communication at different levels including electrical and calcium signalling, small molecular diffusion as well as mitochondrial re-localization. Further, intercellular organelles transfer was assayed by FACS analysis. Methodology and Principal Findings Microscopy showed that cultured ARPE-19 cells are frequently connected by TNTs, which are not attached to the substratum. The TNTs were straight connections between cells, had a typical diameter of 50 to 300 nm and a length of up to 120 µm. We observed de novo formation of TNTs by diverging from migrating cells after a short time of interaction. Scanning electron microscopy confirmed characteristic features of TNTs. Fluorescence microscopy revealed that TNTs between ARPE-19 cells contain F-actin but no microtubules. Depolymerisation of F-actin, induced by addition of latrunculin-B, led to disappearance of TNTs. Importantly, these TNTs could function as channels for the diffusion of small molecules such as Lucifer Yellow, but not for large molecules like Dextran Red. Further, organelle exchange between cells via TNTs was observed by microscopy. Using Ca2+ imaging we show the intercellular transmission of calcium signals through TNTs. Mechanical stimulation led to membrane depolarisation, which expand through TNT connections between ARPE-19 cells. We further demonstrate that TNTs can mediate electrical coupling between distant cells. Immunolabelling for Cx43 showed that this gap junction protein is interposed at one end of 44% of TNTs between ARPE-19 cells. Conclusions and Significance Our observations indicate that human RPE cell line ARPE-19 cells communicate by tunneling nanotubes and can support different types of intercellular traffic.
Wittig, Dierk; Wang, Xiang; Walter, Cindy; Gerdes, Hans-Hermann; Funk, Richard H. W.; Roehlecke, Cora
Spinach (Spinacia oleracea L.) has one of the highest United States per capita consumption rates among leafy vegetable crops, and also ranks second for lutein and ?-carotene carotenoid concentration. The objectives of this study were to determine the effects of nitrogen (N) concentration on elemental and pigment accumulation in spinach. Two spinach cultivars (‘Melody’ and ‘Springer F1’) were greenhouse grown
Mark G. Lefsrud; Dean A. Kopsell; David E. Kopsell
Retinal pigment epithelium transplantation has been proposed as adjunctive treatment for age-related macular degeneration following surgical excision of choroidal neovascular membranes. The goal of this study was to develop a model to evaluate retinal pigment epithelium transplantation onto human Bruch's membrane in vitro. We investigated the ability of cultured fetal human retinal pigment epithelium to colonize human cadaver Bruch's membrane,
ALESSANDRO A. CASTELLARIN; ILENE K. SUGINO; JOSEPH A. VARGAS; BARBARA PAROLINI; GE MING LUI; MARCO A. ZARBIN
Purpose To investigate the influence of the Factor H (CFH) Tyr402His polymorphism on the plasma levels of the alternative pathway proteins CFH, C3, Factor B (FB), Factor D (FD), and Factor I (FI) and the inflammatory marker C-reactive protein (CRP) in 119 patients with age-related macular degeneration (AMD) and 152 unrelated control individuals. Methods Patients with AMD and the control group were separated according to CFH polymorphism, age, and gender. Plasma complement proteins and CRP concentrations were determined with enzyme-linked immunosorbent assay, immunodiffusion, or nephelometry. Results Significant differences in the concentrations of FD and FI were observed between the patients with AMD and the control individuals. We observed significantly reduced FD plasma levels in patients with AMD. We also identified a significant decrease in CFH plasma levels in female patients with AMD in relation to female controls. Plasma FI levels were significantly increased in patients with AMD compared to the control group. Regarding gender, a significant increase in FI plasma levels was observed in male patients. Finally, we found no significant correlation between the CFH Tyr402His polymorphism and the CFH, C3, FB, FD, FI, and CRP plasma levels. Conclusions Patients with AMD present altered levels of FD and FI in a manner independent of this CFH polymorphism, and gender apparently contributes to the plasma levels of these two proteins in patients with AMD and control individuals.
Silva, Aldacilene Souza; Teixeira, Anderson Gustavo; Bavia, Lorena; Lin, Fabio; Velletri, Roberta; Belfort, Rubens
We have used resonance Raman scattering as a novel, non- invasive, in-vivo optical technique to measure the concentration of carotenoid pigment in the human retina. Using argon laser excitation we are able to measure two strong carotenoid resonance Raman signals at 1159 and 1525 wave numbers, respectively. The required laser power levels are within the limits given by safety standards for ocular exposure. Of the approximately ten carotenoid pigment found in normal human serum, the species lutein and zeaxanthin are concentrated in high amounts in the cells of the human macula, which is an approximately 5 mm diameter area of the retina in which the visual acuity is highest. These carotenoids give the macula a characteristic yellow coloration, and it is speculated that these molecules function as filter to attenuate photochemical damage and/or image degradation under bright UV/blue light exposures. In addition, they are thought to act as free-radical scavenging antioxidants. Studies have shown that there may be a link between macular degenerative diseases, the leading cause of blindness in the elderly in the US, and the presence or absence of the carotenoids. We describe an instrument capable of measuring the macular carotenoids in human subjects in a non-invasive, rapid and quantitative way.
Gellermann, Werner; Ermakov, Igor V.; McClane, Robert W.; Bernstein, Paul S.
Objective To report findings in asymptomatic family members of patients with macular telangiectasia type 2. Design Prospective, observational, cross-sectional case series. Participants Four patients with symptomatic macular telangiectasia type 2 (index patients) and 5 relatives, including 2 sets of monozygotic twins. Methods Screening of family members of participants in a non-interventional natural history study of macular telangiectasia type 2. Ophthalmologic examination included best-corrected visual acuity testing, fundus biomicroscopy, fluorescein angiography (FA), optical coherence tomography (OCT), and fundus autofluorescence (FAF) imaging. Main Outcome Measures Evidence for macular telangiectasia type 2 in any of the imaging methods used and visual function of the family members studied. Results In the first family, 2 of 3 daughters of a severely affected 68-year-old woman had features of macular telangiectasia type 2. Although one of the daughters was diagnosed by biomicroscopic examination, the second daughter was diagnosed only by subtle changes on OCT and FAF imaging. Both affected daughters were asymptomatic and were unaware that they had the condition. In the second family, clinical examination showed that the 60-year-old brother of the 75-year-old index patient obviously was affected, despite a lack of any subjective visual dysfunction. The 65-year-old monozygotic twin of the third index patient showed a slight retinal thinning within a small area temporal to the foveola in both eyes as well as minor staining on FA and a subtle monocular loss of macular pigment. The 56-year-old asymptomatic monozygotic twin of the last proband had opacification of the retina with leakage on FA in the right eye. The fellow eye was unremarkable except for an abnormal FAF signal that was present in both eyes. Conclusions Macular telangiectasia type 2 may be more common than previously assumed, but patients may not seek ophthalmic care if their visual function is normal. The study of these early, asymptomatic cases may yield valuable insights into the pathogenesis of the condition. Further research is warranted to determine whether there is an underlying, dominantly inherited genetic abnormality in macular telangiectasia type 2 of variable penetrance and expressivity.
Gillies, Mark C.; Zhu, Meidong; Chew, Emily; Barthelmes, Daniel; Hughes, Edward; Ali, Haipha; Holz, Frank G.; Scholl, Hendrik P. N.; Issa, Peter Charbel
Two healthy Japanese patients developed bilateral pigment epitheliopathy. No inflammatory sign was observed at the time of onset. Multiple yellowish-white placoid lesions developed in the macular region after which vision was seriously disturbed. Fluorescein angiography showed hypofluorescence at the early stage and hyperfluorescence at the later stage--a finding coincident with the placoid lesions. In Case 1 a similar attack in the right eye occurred half a year later, and of the left eye seven years later. New placoid lesions were observed at sites of previous lesions and also at new sites. Lesions of both fundi resolved, rapidly leaving pigment clumps, and visual prognosis was good. The clinical experience of Case 1 were quite similar to acute posterior multifocal placoid pigment epitheliopathy (APMPPE). In Case 2 the placoid lesions spontaneously resolved within a month. However, fluorescein angiography showed multiple pinpoint leaks occurring at the level of the pigment epithelium, and at the resolved stage a "sunset glow" fundal appearance was observed. The second attack was observed four months after the first onset, with iridocyclitis accompanying it. These clinical features were similar to Harada's disease while some were similar to APMPPE. PMID:6830097
Kayazawa, F; Takahashi, H
Patients with a specific subtype of atopic dermatitis (AD) display particular patterns of pigmentation, such as ripple pattern pigmentation on the neck, pigmented macules on the lip and diffuse pigmentation. However, the mechanism underlying these patterns has not been determined. The purpose of our research is to investigate the factors influencing this type of pigmentation in AD. We observed that AD model mice (NC/Nga mice) displayed an increase in the number of 3, 4-dihydroxyphenylalanine (Dopa)-positive melanocytes in the epidermis and intestine (jejunum and colon) while in the inflammatory state. The plasma levels of alpha-melanocyte-stimulating hormone (alpha-MSH) and adrenocoticotropin (ACTH) also increased in NC/Nga mice with dermatitis. Furthermore, the expression of melanocortin receptor 5 and melanocortin receptor 1 (MC1R) increased in the skin, and melanocortin receptor 3 (MC3R) expression increased in the intestine. However, the changes in the Dopa-positive cells of conventional NC/Nga mice were not induced by treatment with either agouti (an MC1R antagonist) or agouti-related protein (an MC3R antagonist). These results indicate that the pigmentation of AD is related to increased levels of alpha-MSH, MC1R (in the skin) and MC3R (in the intestines). PMID:19889022
Hiramoto, Keiichi; Kobayashi, Hiromi; Ishii, Masamitsu; Sato, Eisuke; Inoue, Masayasu
Purpose The presented case raises questions regarding the favorable scheduling of planned postoperative care and the ideal observation interval to decide for reoperations in macular hole surgery. Furthermore a discussion about the use of short- and long-acting gas tamponades in macular hole surgery is encouraged. Methods We present an interventional case report and a short review of the pertinent literature. Results We report a case of spontaneous delayed macular hole closure after vitreoretinal surgery had been performed initially without the expected success. A 73-year-old male Caucasian patient presented at our clinic with a stage 2 macular hole in his left eye. He underwent 23-gauge pars plana vitrectomy and internal limiting membrane peeling with a 20% C2F6-gas tamponade. Sixteen days after the procedure, an OCT scan revealed a persistent stage 2 macular hole, and the patient was scheduled for reoperation. Surprisingly, at the date of planned surgery, which was another 11 days later, the macular hole had resolved spontaneously without any further intervention. Conclusions So far no common opinion exists regarding the use of short- or long-acting gas in macular hole surgery. Our case of delayed macular hole closure after complete resorption of the gas tamponade raises questions about the need and duration of strict prone positioning after surgery. Furthermore short-acting gas might be as efficient as long-acting gas. We suggest to wait with a second intervention at least 4 weeks after the initial surgery, since a delayed macular hole closure is possible.
Distelmaier, Peter; Meyer, Linda M.; Fischer, Marie T.; Philipp, Sebastian; Paquet, Patrick; Mammen, Antje; Haller, Katharina; Schonfeld, Carl-Ludwig
Age-related macular degeneration (AMD) is a common condition that leads to severe vision loss and dysregulation of the complement system is thought to be associated with the disease. To investigate associations of polymorphisms in AMD susceptibility genes with systemic complement activation, 2655 individuals were genotyped for 32 single nucleotide polymorphisms (SNPs) in or near 23 AMD associated risk genes. Component 3 (C3) and its catabolic fragment C3d were measured in serum and AMD staging was performed using multimodal imaging. The C3d/C3 ratio was calculated and associations with environmental factors, SNPs and various haplotypes of complement factor H (CFH) genes and complement factor B (CFB) genes were analyzed. Linear models were built to measure the influence of genetic variants on the C3d/C3 ratio. The study cohort included 1387 patients with AMD and 1268 controls. Higher C3d/C3 ratios were found for current smoker (p = 0.002), higher age (p = 1.56 × 10(-7)), AMD phenotype (p = 1.15 × 10(-11)) and the two SNPs in the C3 gene rs6795735 (p = 0.04) and rs2230199 (p = 0.04). Lower C3d/C3 ratios were found for diabetes (p = 2.87 × 10(-6)), higher body mass index (p = 1.00 × 10(-13)), the SNPs rs1410996 (p = 0.0001), rs800292 (p = 0.003), rs12144939 (p = 4.60 × 10(-6)) in CFH, rs4151667 (p = 1.01 × 10(-5)) in CFB and individual haplotypes in CFH and CFB. The linear model revealed a corrected R-square of 0.063 including age, smoking status, gender, and genetic polymorphisms explaining 6.3% of the C3d/C3 ratio. After adding the AMD status the corrected R-square was 0.067. In conclusion, none of the evaluated genetic polymorphisms showed an association with increased systemic complement activation apart from two SNPs in the C3 gene. Major genetic and non-genetic factors for AMD were not associated with systemic complement activation. PMID:24675670
Ristau, Tina; Paun, Constantin; Ersoy, Lebriz; Hahn, Moritz; Lechanteur, Yara; Hoyng, Carel; de Jong, Eiko K; Daha, Mohamed R; Kirchhof, Bernd; den Hollander, Anneke I; Fauser, Sascha
... Dry, or atrophic, macular degeneration (also called non-neovascular macular degeneration) with drusen Most people who have ... immediately. Wet, or exudative, macular degeneration (also called neovascular macular degeneration) About 10 percent of people who ...
The role of foliar nitrogen (N) in the seasonal dynamics and vertical canopy distribution of photosynthetic pigments, photosynthetic capacity, and carbon (C) storage was investigated in boreal broadleaved species. The study was conducted at two different aged stands (60 y and 15 y) in 1994 and 1996 in Saskatchewan, Canada as part of the Boreal Ecosystem-Atmosphere Study (BOREAS). Foliage in upper and lower strata was examined for aspen (Populus tremuloides Michx.) and its associated hazelnut shrub (Corylus americana Walt.). We determined that C accumulation, expressed as dry mass per unit leaf area (mg C cm (exp -2)), was linearly dependent on N content (approximately 0.3- 3.5 mg N cm (exp -2))(r (exp 2) = 0.93, n=383, P less than 0.001) when eleven foliage groups were defined according to species, site, and developmental stage. C assembly was greatest in the upper aspen strata of both sites (seasonal average, 40.1 plus or minus 0.6 mg C cm (exp -2)), intermediate in the lower aspen strata (32.7 plus or minus 0.6), and considerably lower, and similar, in the hazelnut shrub layers (23.7 plus or minus 0.6) and in expanding aspen leaves (23.8 plus or minus 0.5); the lowest C assembly per unit N occurred in the two youngest, emerging leaf groups (17.1 plus or minus 0.6). Other relationships among physiological and biochemical variables were typically non-linear and were confounded by inclusion of the three groups of young (i.e., emerging or expanding) leaves, unless these were separately identified. Net C uptake, measured as photosynthetic capacity (A (sub max), micromole CO2 m (exp -2) s (exp -1)), was greater in aspen throughout the season, and optimal in mid-summer at a C:N ratio of approximately 18 (approximately 2.3 %N). When young leaves were excluded and logarithms of both variables were used, A (sub max) was approximately linearly dependent on N (mg N cm (exp-2) (r (exp 2) = 0.85, n= 193, P less than 0.001), attributed to incorporation of N into photosynthetic complexes and enzymes. In mature leaves, differences in pigment content vs. N among canopy strata were accentuated when N was expressed per unit leaf area (Mg cm (exp -2)) . However, the simplest log-linear relationship between a pigment variable and N was obtained for a ratio describing the relative allocation of photosynthetic pigment to Chl a (Chl a/[Chl b + carotenoids], microgram cm (exp -2)/ microgram cm-2) vs. %N (r (exp 2) = 0.90, n=343, P less than 0.001). Attainment of comparable A (sub max) Chl a content and relative Chl a allocation per unit N (mg cm (exp -2)) was achieved at different foliar N levels per canopy group: the lowest N requirement was for hazelnut leaves in the lowest, shaded stratum at the older, closed canopy site; the highest N requirement was in aspen leaves of the upper-most stratum at the younger, more open canopy site. These results highlight the differences in physiological responses between young and fully expanded leaves and show that sustaining those foliar constituents and processes important to C balance may require higher foliar N levels in leaves of establishing vs. mature aspen stands. There may be implications for remote-sensing assessments made for carbon balance in springtime, or over a landscape mosaic comprised of different aged stands.
Middleton, Elizabeth M.; Sullivan, Joseph H.; Papagno, Andrea J.
Abstract Aim: To explore the relationship between plasma total homocysteine concentration and diabetic macular edema in patients with type 2 diabetes. Methods: Patients with type 2 diabetes (n?=?176) were enrolled in a cross-sectional hospital-based study. Diabetic macular edema status was documented by fundus photographs. Plasma total homocysteine concentration was measured using fluorescence polarization immunoassay. Normal control plasma homocysteine was established in 115 healthy subjects. Risk factors for diabetic macular edema were obtained from fasting blood samples and interviewer questionnaire. Results: Diabetic patients had increased plasma homocysteine compared with normal control. Plasma homocysteine levels were higher in subjects with diabetic macular edema than without ((11.4?±?2.7) versus (8.5?±?1.9)?(?mol/l), p?=?0.000). The association of homocysteine with diabetic macular edema was independent of major risk factors for diabetic macular edema (duration of diabetes, HbA1c, lipid) and determinants of higher homocysteine concentration (age, gender, serum folate and vitamin B12, renal status, and biguanide use) (OR: 1.63 (1.02-2.14), p?=?0.018). Furthermore, per increase of 5.0??mol/l plasma homocysteine was related to macular edema, after controlling for per unit increase of other factors (OR: 1.64 (1.04-2.16), p?=?0.019). Conclusions: Plasma total homocysteine concentration is independently associated with the occurrence of macular edema in type 2 diabetes. Future prospective studies are warranted to clarify the relationship. PMID:24502555
Li, Jianbo; Zhang, Hongman; Shi, Min; Yan, Lingfei; Xie, Min
The visibility and continuity of the inner segment outer segment (ISOS) junction layer of the photoreceptors on spectral domain optical coherence tomography images is known to be related to visual acuity in patients with age-related macular degeneration (AMD). Automatic detection and segmentation of lesions and pathologies in retinal images is crucial for the screening, diagnosis, and follow-up of patients with retinal diseases. One of the challenges of using the classical level-set algorithms for segmentation involves the placement of the initial contour. Manually defining the contour or randomly placing it in the image may lead to segmentation of erroneous structures. It is important to be able to automatically define the contour by using information provided by image features. We explored a level-set method which is based on the classical Chan-Vese model and which utilizes image feature information for automatic contour placement for the segmentation of pathologies in fluorescein angiograms and en face retinal images of the ISOS layer. This was accomplished by exploiting a priori knowledge of the shape and intensity distribution allowing the use of projection profiles to detect the presence of pathologies that are characterized by intensity differences with surrounding areas in retinal images. We first tested our method by applying it to fluorescein angiograms. We then applied our method to en face retinal images of patients with AMD. The experimental results included demonstrate that the proposed method provided a quick and improved outcome as compared to the classical Chan-Vese method in which the initial contour is randomly placed, thus indicating the potential to provide a more accurate and detailed view of changes in pathologies due to disease progression and treatment.
Mohammad, Fatimah; Ansari, Rashid; Shahidi, Mahnaz
Background Mitochondrial dysfunction is associated with the development and progression of age-related macular degeneration (AMD). Recent studies using populations from the United States and Australia have demonstrated that AMD is associated with mitochondrial (mt) DNA haplogroups (as defined by combinations of mtDNA polymorphisms) that represent Northern European Caucasians. The aim of this study was to use the cytoplasmic hybrid (cybrid) model to investigate the molecular and biological functional consequences that occur when comparing the mtDNA H haplogroup (protective for AMD) versus J haplogroup (high risk for AMD). Methodology/Principal Findings Cybrids were created by introducing mitochondria from individuals with either H or J haplogroups into a human retinal epithelial cell line (ARPE-19) that was devoid of mitochondrial DNA (Rho0). In cybrid lines, all of the cells carry the same nuclear genes but vary in mtDNA content. The J cybrids had significantly lower levels of ATP and reactive oxygen/nitrogen species production, but increased lactate levels and rates of growth. Q-PCR analyses showed J cybrids had decreased expressions for CFH, C3, and EFEMP1 genes, high risk genes for AMD, and higher expression for MYO7A, a gene associated with retinal degeneration in Usher type IB syndrome. The H and J cybrids also have comparatively altered expression of nuclear genes involved in pathways for cell signaling, inflammation, and metabolism. Conclusion/Significance Our findings demonstrate that mtDNA haplogroup variants mediate not only energy production and cell growth, but also cell signaling for major molecular pathways. These data support the hypothesis that mtDNA variants play important roles in numerous cellular functions and disease processes, including AMD.
Kenney, M. Cristina; Chwa, Marilyn; Atilano, Shari R.; Pavlis, Janelle M.; Falatoonzadeh, Payam; Ramirez, Claudio; Malik, Deepika; Hsu, Tiffany; Woo, Grace; Soe, Kyaw; Nesburn, Anthony B.; Boyer, David S.; Kuppermann, Baruch D.; Jazwinski, S. Michal; Miceli, Michael V.; Wallace, Douglas C.; Udar, Nitin
2 Abstract: We have previously reported that pearl millet (PM) could substitute corn and reduce the amount of flaxseed (8%, FS) needed to produce omega-3 enriched eggs in a 6 week trial, but reduced yolk pigmentation. In this experiment we evaluated egg fatty acid (FA) profile, yolk pigmentation, laying performance, and liver integrity in a 12 week experiment using PM-based
K. Amini; C. A. Ruiz-Feria
Trace elements might play a role in the complex multifactorial pathogenesis of age-related macular degeneration (AMD). The aim of this study was to measure alterations of trace elements levels in aqueous humor of patients with non-exsudative (dry) AMD. For this pilot study, aqueous humor samples were collected from patients undergoing cataract surgery. 12 patients with dry AMD (age 77.9±6.62, female 8, male 4) and 11 patients without AMD (age 66.6±16.7, female 7, male 4) were included. Aqueous levels of cadmium, cobalt, copper, iron, manganese, selenium, and zinc were measured by use of Flow-Injection-Inductively-Coupled-Plasma-Mass-Spectrometry (FI-ICP-MS), quality controlled with certified standards. Patients with AMD had significantly higher aqueous humor levels of cadmium (median: 0.70 µmol/L, IQR: 0.40–0.84 vs. 0.06 µmol/L; IQR: 0.01–.018; p?=?0.002), cobalt (median: 3.1 µmol/L, IQR: 2.62–3.15 vs. 1.17 µmol/L; IQR: 0.95–1.27; p<0.001), iron (median: 311 µmol/L, IQR: 289–329 vs. 129 µmol/L; IQR: 111–145; p<0.001) and zinc (median: 23.1 µmol/L, IQR: 12.9–32.6 vs. 5.1 µmol/L; IQR: 4.4–9.4; p?=?0.020) when compared with patients without AMD. Copper levels were significantly reduced in patients with AMD (median: 16.2 µmol/L, IQR: 11.4–31.3 vs. 49.9 µmol/L; IQR: 32.0–.142.0; p?=?0.022) when compared to those without. No significant differences were observed in aqueous humor levels of manganese and selenium between patients with and without AMD. After an adjustment for multiple testing, cadmium, cobalt, copper and iron remained a significant factor in GLM models (adjusted for age and gender of the patients) for AMD. Alterations of trace element levels support the hypothesis that cadmium, cobalt, iron, and copper are involved in the pathogenesis of AMD.
Junemann, Anselm G. M.; Stopa, Piotr; Michalke, Bernhard; Chaudhri, Anwar; Reulbach, Udo; Huchzermeyer, Cord; Schlotzer-Schrehardt, Ursula; Kruse, Friedrich E.; Zrenner, Eberhart; Rejdak, Robert
Background: Age-related macular degeneration (AMD), the leading cause of irreversible blindness and low vi- sion among the elderly, has not been well studied with regard to its impact on daily life. This study was de- signed to demonstrate the impact of AMD on quality of life, emotional distress, and functional level. Participants: The study sample consisted of 86 elderly adults
Rebecca A. Williams; Barbara L. Brody; Ronald G. Thomas; Robert M. Kaplan; Stuart I. Brown
Purpose Age-related macular degeneration (AMD) and polypoidal choroidal vasculopathy (PCV) are the leading causes of vision loss in the elderly Asian population. Previous studies have confirmed that abnormal extracellular matrix (ECM) metabolism plays an important role in the pathogenesis of AMD and PCV. However, the dynamic metabolism of the ECM is closely regulated by matrix metalloproteinases (MMPs) and tissue metalloproteinase inhibitors (TIMPs). Whether MMPs and TIMPs participate in the pathogenesis of AMD and PCV remains unclear. The aim of this study was to investigate the correlation between circulating MMP and TIMP levels and AMD and PCV. Methods The serum levels of MMPs (MMP1, MMP2, MMP3, and MMP9) and TIMPs (TIMP1 and TIMP3) were quantified using enzyme-linked immunosorbent assays in four groups of subjects (n=342): early AMD (group 1, n=75), neovascular AMD (group 2, n=89), PCV (group 3, n=98), and age- and gender-matched controls (group 4, n=80). Results The mean concentrations of the two gelatinases, MMP2 and MMP9, in the PCV group were significantly higher than that of the control (p=0.001, p<0.001, respectively), early AMD (both p<0.001), and neovascular AMD (p=0.005, p=0.001, respectively) groups. Moreover, the serum MMP2 concentration was positively correlated with the serum MMP9 concentration in the PCV group (r=0.822, p<0.001). However, the mean concentrations of MMP2 and MMP9 in the early AMD and neovascular AMD groups were not significantly different from that of the control group (p>0.05). The mean serum levels of MMP1, MMP3, TIMP1, and TIMP3 were not significantly different among the four groups. Conclusions This pilot study first reveals a link between increased levels of circulating gelatinases (MMP2 and MMP9) and PCV but not AMD, which may provide a biologically relevant marker of ECM metabolism in patients with PCV. This finding suggests that the two disorders may have different molecular mechanisms.
Zeng, Renpan; Zhang, Xiongze; Su, Yu
The optical coherence tomography (OCT), a noninvasive and noncontact diagnostic method, was introduced in 1995 for imaging macular diseases. In diabetic macular edema (DME), OCT scans show hyporeflectivity, due to intraretinal and/or subretinal fluid accumulation, related to inner and/or outer blood-retinal barrier breakdown. OCT tomograms may also reveal the presence of hard exudates, as hyperreflective spots with a shadow, in the outer retinal layers, among others. In conclusion, OCT is a particularly valuable diagnostic tool in DME, helpful both in the diagnosis and follow-up procedure.
Lobo, Conceiçăo; Pires, Isabel; Cunha-Vaz, José
One contributing factor in the worldwide decline in amphibian populations is thought to be the exposure of eggs to UV light.\\u000a Enrichment of pigment in the animal hemisphere of eggs laid in the sunlight defends against UV damage, but little is known\\u000a about the cell biological mechanisms controlling such polarized pigment patterns. Even less is known about how such mechanisms
Chanjae Lee; Minh-Phuong Le; David Cannatella; John B. Wallingford
Stem cells, with their capacity to regenerate and replace diseased tissues, have recently been proposed as having great potential in the treatment of age-related macular degeneration (AMD). A stem cell therapeutic approach could operate to replace either the retinal pigment epithelium (RPE), the neurosensory retina or a combination of both. From the scientific perspective, RPE replacement alone is likely to
E Lee; R E MacLaren
There is growing evidence that high levels of the macular xanthophyll carotenoids lutein and zeaxanthin may be protective against visual loss from age-related macular degeneration. To study this protective effect further, it is important to measure macular carotenoid levels noninvasively in a wide variety of subjects. We have developed and validated resonance Raman spectroscopy as a sensitive and specific objective method to measure macular carotenoid levels in the living human eye. In this minireview, the principles and implementation of ocular carotenoid resonance Raman spectroscopy are reviewed, and the results of observational cross-sectional studies and of prospective supplementation studies on subjects with and without macular pathology are summarized. We have recently extended this technology to an imaging mode which will further enhance our understanding of the roles of lutein and zeaxanthin in normal macular function and in the prevention of age-related visual loss. PMID:15369814
Bernstein, Paul S; Zhao, Da-You; Sharifzadeh, Mohsen; Ermakov, Igor V; Gellermann, Werner
Clinical and pathological examination was performed on 378 eyes from 216 patients aged 43 to 97 years. This series represented eyes in which the fundi were normal or showed various manifestations of senile macular degeneration. The eyes were divided into six groups according to the histological appearance of a linear deposit at the base of the retinal pigment cells. Groups
S H Sarks
Best macular dystrophy (BMD) is an autosomal dominant retinopathy caused by mutations in the VMD2 gene that encodes a chloride channel in the basolateral membrane of the retinal pigment epithelium (RPE). BMD patients were studied using optical coherence tomography (OCT) to understand the disease process in the macula leading to vision loss. BMD patients (ages 5–61), representing four families with
Michael J. Pianta; Tomas S. Aleman; Artur V. Cideciyan; Janet S. Sunness; Yuanyuan Li; Betsy A. Campochiaro; Peter A. Campochiaro; Donald J. Zack; Edwin M. Stone; Samuel G. Jacobson
The pigment epithelium cell structure and therapeutic effect of antioxidant SkQ1, selectively penetrating into mitochondria from eye drops, were studied upon development in OXYS rats of age-related retinopathy as a model of macular degeneration. The characteristic dynamics and ultrastructural peculiarities of the layer of electron-dense cytoplasmic structures of the pigment epithelium apex part and incorporated lipofuscin granules were revealed. The therapy of OXYS animals for 68 days using 250 nM SkQ1 drops decreased the extent of development of age-related macular degeneration. Electron-microscopic investigation showed that SkQ1 prevented development of ultrastructural changes in the pigment epithelium characteristic of macular degeneration, the condition of which after therapy with SkQ1 drops corresponded to ultrastructure of pigment epithelium in Wistar rats of the same age having no symptoms of retinal damage. It is supposed that ultrastructural changes in the electron-dense layer upon development of age-related macular degeneration are indicative of disturbances in the optical cycle functioning, especially of disturbances in functioning of photoreceptor membranes. PMID:20367599
Saprunova, V B; Pilipenko, D I; Alexeevsky, A V; Fursova, A Zh; Kolosova, N G; Bakeeva, L E
Best macular dystrophy (BMD) is an autosomal dominant retinopathy caused by mutations in the VMD2 gene that encodes a chloride channel in the basolateral membrane of the retinal pigment epithelium (RPE). BMD patients were studied using optical coherence tomography (OCT) to understand the disease process in the macula leading to vision loss. BMD patients (ages 5-61), representing four families with known VMD2 mutations, were included. OCT scans were recorded in the central retina and longitudinal reflectivity profiles were analysed. The central retina in BMD showed different OCT abnormalities at or near the level of the highly reflective deep retinal band termed the outer retina-choroid complex (ORCC). Two types of ORCC change were noted to occur either separately or together: (1) splitting with or without intervening hyporeflective areas; and (2) elevation. Longitudinal study of a BMD patient indicated that such abnormalities were dynamic and changed in type and degree with time. The pathogenetic sequence in BMD may begin with defective fluid transport across the RPE secondary to the channelopathy in the basolateral membrane. In the macula, this leads to an abnormal interface with adjacent structures at both apical and basal surfaces of the RPE. The disease process results in detachments of the neurosensory retina, such as in central serous chorioretinopathy, and sub-RPE pathology resembling some stages of age-related macular degeneration, with eventual loss of photoreceptors, inner retina and central vision. PMID:12565808
Pianta, Michael J; Aleman, Tomas S; Cideciyan, Artur V; Sunness, Janet S; Li, Yuanyuan; Campochiaro, Betsy A; Campochiaro, Peter A; Zack, Donald J; Stone, Edwin M; Jacobson, Samuel G
A case is reported of a traumatic macular hole caused by a high-energy Nd:YAG laser. The initial ocular examination revealed an explosive, crater-shaped, full-thickness macular hole surrounded by local edema and detachment. By the 12th day after the injury, the hole had shrunk progressively and was covered by a thin fibrin-like membrane. A thick epiretinal membrane covered the injured area 1 month after the injury. Nine months after the injury, the macular hole closed spontaneously with a partially detached epiretinal membrane. This case demonstrates one of the natural healing processes of a traumatic macular hole. Although the hole finally closed, the patient did not regain his vision because of the severe damage to the photoreceptors, retinal pigment epithelium, and choroid. PMID:11195748
Chuang, L H; Lai, C C; Yang, K J; Chen, T L; Ku, W C
An 18 year-old male with no antecedent of trauma, systemic syndrome or myopia was referred for surgical treatment of a full thickness macular hole in the left eye. A more careful inspection revealed discrete foveal cystic changes in the fellow eye and subtle peripheral depigmented retinal pigment epithelial changes in both eyes. A spectral-domain optical coherence tomography (SD-OCT) scan confirmed, in addition to the full thickness macular hole in the left eye, microcystic spaces in the nuclear layers of both retinae. The diagnosis of X-linked retinoschisis was confirmed with a full field electroretinogram displaying the typical negative ERG. Macular holes are uncommon in the young and those complicating X-linked retinoschisis are rare. This report highlights the importance of investigating the presence of a macular hole in a young patient and illustrates the clinical and SD-OCT clues beyond the foveal center which led to the correct diagnosis of X-linked juvenile retinoschisis.
Al-Swaina, Nayef; Nowilaty, Sawsan R.
The current treatment of macular oedema remains unsatisfactory. The dissection of the molecular mechanisms responsible for\\u000a the formation of macular oedema will lead to the identification of specific therapeutic targets, and the successful application\\u000a of this knowledge will result in the generation of more effective treatment modalities.
Antonia M. Joussen; Bernd Kirchhof
Among macular diseases, choroidal neovascularization (CNV) is one of the most common causes of visual loss, especially in the form associated with age-related macular degeneration and pathologic myopia. Research on these diseases has recently evaluated new treatment modalities that use laser light differently; among these, photodynamic therapy (PDT) has been introduced in the clinical practice, allowing us to expand the
Ugo Menchini; Gianni Virgili; Fabrizio Giansanti; Giovanni Giacomelli; Stefania Cappelli
Purpose: To describe six patients (six eyes) who developed an eccentric macular hole after surgery for idiopathic epimacular proliferation. Materials and Methods: Review of records from six patients who developed eccentric macular holes postoperatively following vitrectomy in 107 consecutive cases with peeling of the epimacular proliferation and internal limiting membrane (ILM) from June 2004 to January 2009 Results: Eccentric macular holes were developed from nine days to eight months (mean, 3.1 months) after epimacular proliferation peeling. The ILM was peeled in addition to the epimacular proliferation in five of the six cases. Of the six eccentric macular holes, four were located temporal to the fovea, one was located superior to the fovea, and one was located nasal to the fovea. Final visual acuities after a mean follow-up period of 17.3 months were 20/20 in two eyes, 20/25 in one eye, 20/40 in two eyes, and 5/200 in one eye. The eye with the eccentric macular hole nasal to the fovea had the poorest final visual acuity of 5/200. Conclusion: Eccentric macular holes occurring after vitrectomy to remove epimacular proliferation is an uncommon postoperative finding. Various explanations have been suggested for the etiology of these holes, but there is no consensus. We suggested that the ILM tear should be initiated with a diamond dusted knife to reduce the likelihood of injury to the underlying Muller cells that may contribute to the formation of eccentric macular holes.
Abo EL Enin, Mostafa Abdellatif; El-Toukhy, Hesham M; Swelam, Ahmed
Recent increasing concern regarding the use of edible coloring agents has banned various synthetic coloring agents, which\\u000a have a potential of carcinogenicity and terratogenicity. This circumstance has inevitably increased the demands for safe and\\u000a naturally occurring natural (edible) coloring agents, one of which is pigment from the fungus Monascus purpureus. It has long been known that the microorganisms of the
The adaptive function of melanin-based coloration is a long-standing debate. A recent genetic model suggested that pleiotropy could account for covariations between pigmentation, behaviour, morphology, physiology and life history traits. We explored whether the expression levels of genes belonging to the melanocortin system (MC1R, POMC, PC1/3, PC2 and the antagonist ASIP), which have many pleiotropic effects, are associated with melanogenesis (through variation in the expression of the genes MITF, SLC7A11, TYR, TYRP1) and in turn melanin-based coloration. We considered the tawny owl (Strix aluco) because individuals vary continuously from light to dark reddish, and thus, colour variation is likely to stem from differences in the levels of gene expression. We measured gene expression in feather bases collected in nestlings at the time of melanin production. As expected, the melanocortin system was associated with the expression of melanogenic genes and pigmentation. Offspring of darker reddish fathers expressed PC1/3 to lower levels but tended to express PC2 to higher levels. The convertase enzyme PC1/3 cleaves the POMC prohormone to obtain ACTH, while the convertase enzyme PC2 cleaves ACTH to produce ?-melanin-stimulating hormone (?-MSH). ACTH regulates glucocorticoids, hormones that modulate stress responses, while ?-MSH induces eumelanogenesis. We therefore conclude that the melanocortin system, through the convertase enzymes PC1/3 and PC2, may account for part of the interindividual variation in melanin-based coloration in nestling tawny owls. Pleiotropy may thus account for the covariation between phenotypic traits involved in social interactions (here pigmentation) and life history, morphology, behaviour and physiology. PMID:24033481
Emaresi, Guillaume; Ducrest, Anne-Lyse; Bize, Pierre; Richter, Hannes; Simon, Celine; Roulin, Alexandre
Immune function can be modulated by multiple physiological factors, including nutrition and reproductive state. Because these factors can vary throughout an individual's lifetime as a result of environmental conditions (affecting nutrition) or life-history stage (e.g. entering the adult reproduction stage), we must carefully examine the degree to which developmental versus adult conditions shape performance of the immune system. We investigated how variation in dietary access to carotenoid pigments - a class of molecules with immunostimulatory properties that females deposit into egg yolks - during three different developmental time points affected adult immunological and reproductive traits in female mallard ducks (Anas platyrhynchos). In males and females of other avian species, carotenoid access during development affects carotenoid assimilation ability, adult sexual ornamentation and immune function, while carotenoid access during adulthood can increase immune response and reproductive investment (e.g. egg-laying capacity, biliverdin deposition in eggshells). We failed to detect effects of developmental carotenoid supplementation on adult immune function [phytohemagglutinin-induced cutaneous immune response, antibody production in response to the novel antigen keyhole limpet hemocyanin (KLH), or oxidative burst, assessed by changes in circulating nitric oxide levels], carotenoid-pigmented beak coloration, ovarian development, circulating carotenoid levels or concentration of bile pigments in the gall bladder. However, we did uncover positive relationships between circulating carotenoid levels during adulthood and KLH-specific antibody production, and a negative relationship between biliverdin concentration in bile and KLH-specific antibody production. These results are consistent with the view that adult physiological parameters better predict current immune function than do developmental conditions, and highlight a possible, previously unstudied relationship between biliverdin and immune system performance. PMID:23531827
Butler, Michael W; McGraw, Kevin J
Since the recognition of the toxic potential of heavy metals, their concentration levels in the environmentally sensitive places are being monitored rigorously. In addition, their biological effects are being studied to better assess their impact on the environment, and to identify suitable test systems for biomonitoring low level contaminations. Photosynthetic processes are widely studied endpoints in metal toxicity testing involving plants. Considering the importance of photosynthetic pigments in energy transduction, variations in their levels, especially that of chlorophylls, in response to heavy metals have also been studied by some workers. However, a detailed and comparative study of such variations giving importance not only to chlorophylls but also to carotenoids is lacking. The present study was designed to study the same. Keeping in view the report of Patro (1993) that the cultivated lands in and around the Angul-Talcher industrial belt, adjacent to Bhubaneswar, are under severe threats of pollution by heavy metals released from a thermal power plant and various industrial and mining activities in the region, a widely cultivated legume, Phaseolus aureus Roxb., was selected as the test species. The metals used were Hg and Cd which are well recognized land pollutants from secondary sources. This study also reports how the changes in pohotsynthetic pigments and the toxicity of the two metals are dependent on the stage of development at which the test species is exposed to the metals, information on which is scant. 20 refs., 1 fig., 1 tab.
Shaw, B.P. [Institute of Life Sciences, Orissa (Indonesia)
A2E, an important constituent of lipofuscin in human retinal pigment epithelium (RPE), is thought to mediate light-induced oxidative damage associated with aging and other ocular disorders. Ocular carotenoids in overlying retinal tissues were measured by HPLC and mass spectrometry and were correlated with levels of RPE A2E. We observed a statistically significant increase in total A2E levels in human RPE/choroid with age, and A2E levels in macular regions were approximately 1/3 lower than in peripheral retinal regions of the same size. There was a statistically significant inverse correlation between peripheral retina carotenoids and peripheral RPE/choroid A2E. Prospective carotenoid supplementation studies in Japanese quail demonstrated nearly complete inhibition of A2E formation and oxidation. These findings support current recommendations to increase dietary intake of xanthophyll carotenoids in individuals at risk for macular degeneration and highlight a new potential mechanism for their protective effects-inhibition of A2E formation and oxidation in the eye. PMID:18926795
Bhosale, Prakash; Serban, Bogdan; Bernstein, Paul S
Progressive macular hypomelanosis (PMH) is a common skin disorder that is often misdiagnosed. Various authors have written about similar skin disorders, referring to them by different names, but we believe that all these similar disorders are part of the same entity.PMH is characterized by ill-defined nummular, non-scaly hypopigmented spots on the trunk, often confluent in and around the midline, and rarely extending to the proximal extremities and neck/head region. There is no itch, pain, or preceding inflammation. PMH has a worldwide distribution; however, it is more often identified in Black people living in or originating from tropical countries. It is also more often seen in young females. The natural history of PMH is stable disease or perhaps slow progression over decades, with spontaneous disappearance after mid-life. Extensive pityriasis alba is probably identical with PMH and we suggest discontinuation of use of the former term on the grounds that extensive pityriasis alba is histologically and clinically different from classical pityriasis alba, which is basically an eczematous type of disorder.PMH is characterized histologically by diminished pigment in the epidermis and a normal-looking dermis. Electron microscopy shows a shift from large melanosomes in normal-looking skin to small aggregated, membrane-bound melanosomes in hypopigmented skin. PMH should be differentiated from other disorders with hypopigmentation on the trunk such as pityriasis versicolor. We propose that Propionibacterium acnes bacteria living in hair follicles are the cause of PMH as a result of production of a hypothetical depigmenting factor. This hypothesis is based on: (i) the presence of a red follicular fluorescence in the hypopigmented spots and the absence of this phenomenon in normal skin when examined under a Wood's light in a dark room; (ii) cultivation of P. acnes from the follicles in the hypopigmented spots but not from follicles in normal-looking skin; and (iii) improvement of the disorder after elimination of these micro-organisms with topical antimicrobial treatment in combination with UVA light.Currently, the treatment of choice of PMH is application of 1% clindamycin lotion during the daytime, 5% benzoyl peroxide gel at night-time, and UVA light irradiation three times a week for a period of 12 weeks. There is insufficient information available as yet to comment on the recurrence rate after therapy. PMID:17298102
Relyveld, Germaine N; Menke, Henk E; Westerhof, Wiete
All major studies on the absorption of the human macular pigment are gathered and evaluated, and compared with a weighted mean curve. A new standard density spectrum is proposed, which slightly deviates in shape from this weighted mean curve, but has sign...
J. J. Vos
The clinical outcome within one month after phacoemulsification cataract extraction with implantation of the blue-blocking SN60AT IOL was examined prospectively and compared to a retrospectively examined material of implantations of the equivalent SA30AL without blue-blocker. There was no difference in best corrected visual acuity gain between the two lenses. In addition, the subjective color perception was examined for with a questionnaire after the first implantation of blue-blocking IOL and after the second implantation of blue-blocking IOL. Only one patient noted a changed color perception. There are thus strong theoretical reasons to block blue light in IOLs and no short term clinical inconvenience. But, it remains to be proven in long term follow up studies that the blue-blocking IOL protects against macular degeneration.
Soderberg, Per G.; Lofgren, Stefan; Ayala, Marcelo; Dong, Xiuqin; Kakar, Manoj; Mody, Vino; Meyer, Linda; Laurell, Carl-Gustaf
Background Vitamin D plays a critical role in bone metabolism and many cellular and immunological processes. Recent research indicates that concentrations of serum 25-hydroxyvitamin D [25(OH)D], the main indicator of vitamin D status, should be in excess of 75 nmol/L. Low levels of 25(OH)D have been associated with several chronic and infectious diseases. Previous studies have reported that many otherwise healthy adults of European ancestry living in Canada have low vitamin D concentrations during the wintertime. However, those of non-European ancestry are at a higher risk of having low vitamin D levels. The main goal of this study was to examine the vitamin D status and vitamin D intake of young Canadian adults of diverse ancestry during the winter months. Methods One hundred and seven (107) healthy young adults self-reporting their ancestry were recruited for this study. Each participant was tested for serum 25(OH)D concentrations and related biochemistry, skin pigmentation indices and basic anthropometric measures. A seven-day food diary was used to assess their vitamin D intake. An ANOVA was used to test for significant differences in the variables among groups of different ancestry. Linear regression was employed to assess the impact of relevant variables on serum 25(OH)D concentrations. Results More than 93% of the total sample had concentrations below 75 nmol/L. Almost three-quarters of the subjects had concentrations below 50 nmol/L. There were significant differences in serum 25(OH)D levels (p < 0.001) and vitamin D intake (p = 0.034) between population groups. Only the European group had a mean vitamin D intake exceeding the current Recommended Adequate Intake (RAI = 200 IU/day). Total vitamin D intake (from diet and supplements) was significantly associated with 25(OH)D levels (p < 0.001). Skin pigmentation, assessed by measuring skin melanin content, showed an inverse relationship with serum 25(OH)D (p = 0.033). Conclusion We observe that low vitamin D levels are more prevalent in our sample of young healthy adults than previously reported, particularly amongst those of non-European ancestry. Major factors influencing 25(OH)D levels were vitamin D intake and skin pigmentation. These data suggest a need to increase vitamin D intake either through improved fortification and/or supplementation.
Gozdzik, Agnes; Barta, Jodi Lynn; Wu, Hongyu; Wagner, Dennis; Cole, David E; Vieth, Reinhold; Whiting, Susan; Parra, Esteban J
Background To assess the efficacy, clinical outcomes, visual acuity (VA), incidence of adverse effects, and complications of peripheral iris fixation of 3-piece acrylic IOLs in eyes lacking capsular support. Thirteen patients who underwent implantation and peripheral iris fixation of a 3-piece foldable acrylic PC IOL for aphakia in the absence of capsular support were followed after surgery. Clinical outcomes and macular SD-OCT (Cirrus OCT; Carl Zeiss Meditec, Germany) were analyzed. Findings The final CDVA was 20/40 or better in 8 eyes (62%), 20/60 or better in 12 eyes (92%), and one case of 20/80 due to corneal astigmatism and mild persistent edema. No intraoperative complications were reported. There were seven cases of medically controlled ocular hypertension after surgery due to the presence of viscoelastic in the AC. There were no cases of cystoid macular edema, chronic iridocyclitis, IOL subluxation, pigment dispersion, or glaucoma. Macular edema did not develop in any case by means of SD-OCT. Conclusions We think that this technique for iris suture fixation provides safe and effective results. Patients had substantial improvements in UDVA and CDVA. This surgical strategy may be individualized however; age, cornea status, angle structures, iris anatomy, and glaucoma are important considerations in selecting candidates for an appropriate IOL fixation method.
PurposeTo evaluate long-term morphologic and functional changes after intravitreal ranibizumab in avascular pigment epithelial detachment (PED) secondary to age-related macular degeneration (AMD).Patients and methodsInterventional, prospective case series; the first group of six patients received three and the second group of six patients received six intravitreal injections of ranibizumab (0.5 mg) at monthly intervals. Outcome measures included the change of PED
M Ritter; M Bolz; S Sacu; G G Deák; C Kiss; C Pruente; U M Schmidt-Erfurth
Examinations of 202 patients (337 eyes) with different forms of macular dystrophies, such as idiopathic flat detachment of the retina in the macular area, central sclerotic dystrophy of the retina, tapetoretinal macular degeneration, outcome of local inflammation of pigmented epithelium, post-traumatic central chorioretinitis, etc., allowed to receive data confirming high information value of a method based on the phenomenon of dynamic scotoma of disadaptation as compared with examinations on the Amsler's grid and campimetry. Thus, metamorphopsias were revealed on the Amsler's grid in 193 eyes (57%), changes by means of campimetry--in 171 eyes (51%), while dynamic scotoma disadaptation was revealed in 337 eyes (100%). The method is most effective at early stages of the disease because it allows to reveal it in the presence of high visual acuity and negative data of the Amsler's grid and campimetry. PMID:2636343
Shigina, R P
Age-related macular degeneration, a major cause of blindness for which no satisfactory treatments exist, leads to a gradual decrease in central high acuity vision. The accumulation of fluorescent materials, called lipofuscin, in retinal pigment epithelial cells of the aging retina is most pronounced in the macula. One of the fluorophores of retinal pigment epithelial lipofuscin has been characterized as A2E,
Craig A. Parish; Masaru Hashimoto; Koji Nakanishi; James Dillon; Janet Sparrow
Human retinal pigment epithelium cells were used to investigate the mechanisms underlying blood-retinal barrier disruption under conditions of chronic hyperglycemia. The treatment with 25 mM glucose caused a rapid drop in the transepithelial electrical resistance (TEER), which was reversed by the addition of either a methanolic extract from Goji (Lycium barbarum L.) berries or its main component, taurine. Intracellular cAMP levels increased concurrently with the high glucose-induced TEER decrease, and were correlated to an increased activity of the cytosolic isoform of the enzyme adenylyl cyclase. The treatment with plant extract or taurine restored control levels. Data are discussed in view of a possible prevention approach for diabetic retinopathy. PMID:24345371
Pavan, Barbara; Capuzzo, Antonio; Forlani, Giuseppe
The Macular Photocoagulation Study (MPS) was designed to determine, by means of multicenter randomized controlled clinical trials, whether laser photocoagulation is of benefit in preventing visual acuity loss in eyes with senile macular degeneration or pr...
... dpi (5M, TIFF) Description: A fundus photo showing neovascular age-related macular degeneration. Credit: National Eye Institute, ... Ref#: EDA17 72 dpi (1.1M, TIFF) Description: Neovascular age-related macular degeneration. Credit: National Eye Institute, ...
The Macular Photocoagulation Study (MPS) is a set of randomized, controlled clinical trials designed to evaluate the effectiveness of laser photocoagulation of neovascular lesions, secondary to age-related (senile) macular degeneration, ocular histoplasmo...
BACKGROUNDMost idiopathic macular holes can be closed by a surgical procedure combining vitrectomy, posterior hyaloid ablation, and fluid-gas exchange followed by postoperative positioning. Reopening of closed macular holes has been reported, but its frequency is not known. Here the incidence of reopening after successful macular hole surgery is reported.METHODS77 consecutive cases of idiopathic macular holes operated with autologous platelet injection
Michel Paques; Pascale Massin; Pierre-Yves Santiago; Alain C Spielmann; Jean-François Le Gargasson; Alain Gaudric
Purpose: Full macular translocation surgery relocates the fovea away from choroidal neovascularization, inducing significant postoperative torsional diplopia. In “limited macular translocation,” a saline-induced retinal detachment is followed by scleral imbrication with mattress sutures and spontaneous retinal reattachment. In this study, diplopia was characterized in patients treated with limited macular translocation. Methods: Two surgeons performed retinal translocation surgery on 250 patients
Angela N. Buffenn; Eugene de Juan; Gildo Fujii; David G. Hunter
PURPOSE : To report eight cases of spontaneous closure of traumatic macular hole.DESIGN : Consecutive observational case series.PATIENTS AND METHODS : In a consecutive series of 18 eyes of 18 patients with traumatic macular hole, eight patients achieved spontaneous closure of traumatic macular hole. Clinical records of the eight eyes of eight patients were reviewed, together with the results of
Takehiro Yamashita; Akinori Uemara; Eisuke Uchino; Norihito Doi; Norio Ohba
Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in the elderly population in the Western world. AMD is a clinically heterogeneous disease presenting with drusen, pigmentary changes, geographic atrophy and/or choroidal neovascularization. Due to its heterogeneous presentation, it can be challenging to distinguish AMD from several macular diseases that can mimic the features of AMD. This clinical overlap may potentially lead to misdiagnosis. In this review, we discuss the characteristics of AMD and the macular dystrophies that can mimic AMD. The appropriate use of clinical and genetic analysis can aid the clinician to establish the correct diagnosis, and to provide the patient with the appropriate prognostic information. An overview is presented of overlapping and distinguishing clinical features. PMID:24291520
Saksens, Nicole T M; Fleckenstein, Monika; Schmitz-Valckenberg, Steffen; Holz, Frank G; den Hollander, Anneke I; Keunen, Jan E E; Boon, Camiel J F; Hoyng, Carel B
AimTo assess the impact of early and late age-related macular degeneration (AMD) on vision-specific functioning in Singapore Malays.MethodsAMD was assessed from fundus photographs. The following endpoints were considered for (a) AMD: no AMD, early AMD, and late AMD; (b) drusen: absence and presence; and (c) retinal pigment epithelium (RPE) abnormality: absence and presence. Vision functioning was assessed using the modified
Ecosse L Lamoureux; Paul Mitchell; Gwyn Rees; Gemmy Cheung; Ian Yeo; Shu Yen Lee; Erica Liu; Tien Y Wong
Summary Post-surgical macular oedema results from blood-retinal barrier breakdown, but it is not accompanied by structural abnormalities in the retinal vessels or retinal pigmented epithelium. Previous studies, using horseradish peroxidase in a primate model, suggested that leakage occurs primarily through this epithelium. This study was conducted to localize sites of the barrier breakdown in humans following different types of intra-ocular surgery
Abha Amin; Nancy L. Derevjanik; W. Richard Green; Peter A. Campochiaro
Background: Transplantation of autologous iris pig- ment epithelium (IPE) into the subretinal space has been suggested as one approach for the treatment of age-re- lated macular degeneration, as well as for other condi- tions in which loss of retinal pigment epithelium (RPE) occurs. Surgical removal of choroidal neovascular mem- branes is associated with traumatic loss of the RPE cell layer,
Gabriele Thumann; Sabine Aisenbrey; Ulrich Schraermeyer; Bart Lafaut; Peter Esser; Peter Walter; Karl Ulrich Bartz-Schmidt
A case of acute posterior multifocal placoid pigment epitheliopathy (APMPPE) complicated by a central retinal vein occlusion five weeks after presentation is described. After eight months' follow-up there was mild residual visual impairment, macular scarring, and angiographic changes. The association of these two conditions is discussed. PMID:2804034
Charteris, D G; Khanna, V; Dhillon, B
A case of acute posterior multifocal placoid pigment epitheliopathy (APMPPE) complicated by a central retinal vein occlusion five weeks after presentation is described. After eight months' follow-up there was mild residual visual impairment, macular scarring, and angiographic changes. The association of these two conditions is discussed. Images
Charteris, D G; Khanna, V; Dhillon, B
Age-related macular degeneration is the leading cause of blindness in elderly populations of European descent. The most consistent risk factors associated with this ocular condition are increasing age and cigarette smoking. Genetic investigations have shown that complement factor H, a regulator of the alternative complement pathway, and LOC387715/HtrA1 are the most consistent genetic risk factors for age-related macular degeneration. Although the pathogenesis of this disease is unknown, oxidative stress might have an important role. Treatment with antioxidant vitamins and zinc can reduce the risk of developing advanced age-related macular degeneration by about a quarter in those at least at moderate risk. Intravitreal injections of ranibizumab, a monoclonal antibody that inhibits all forms of vascular endothelial growth factor, have been shown to stabilise loss of vision and, in some cases, improve vision in individuals with neovascular age-related macular degeneration. These findings, combined with assessments of possible environmental and genetic interactions and new approaches to modulate inflammatory pathways, will hopefully further expand our ability to understand and treat age-related macular degeneration.
Coleman, Hanna R; Chan, Chi-Chao; Ferris, Frederick L; Chew, Emily Y
Purpose The goal of the present research was to study post-treatment changes in polypoidal choroidal vasculopathy (PCV) shown by optical coherence tomography (OCT). Methods The study included 12 patients with naive PCV. Photodynamic therapy and 3 consecutive intravitreal bevacizumab injections at 6-week intervals were given. Best corrected visual acuity, subretinal fluid (SRF), pigment epithelium detachment (PED), central macular thickness (CMT), and total macular volume (TMV) were measured before and after treatment as assessed by Stratus OCT3. Results After treatment, the SRF height decreased earlier than the PED height. The SRF diameter decreased with statistical significance. However, the PED diameter did not show a statistically significant improvement, persisting at pre-treatment levels. Both CMT and TMV decreased significantly after treatment. Conclusions After PCV treatment, SRF and PED stabilized, as shown by OCT. However, the PED treatment response was both delayed and refractory compared to the SRF response. The small change in post-treatment PED diameter may suggest the possibility of PCV recurrence.
Chae, Ju Byung; Lee, Joo Yong; Yang, Sung Jae; Kim, June-Gone
Lutein and zeaxanthin are two dietary carotenoids that compose the macular pigment of the primate retina. Another carotenoid, meso-zeaxanthin, is formed from lutein in the retina. A membrane location is one possible site where these dipolar, terminally dihydroxylated carotenoids, named macular xanthophylls, are accumulated in the nerve fibers and photoreceptor outer segments. Macular xanthophylls are oriented perpendicular to the membrane surface, which ensures their high solubility, stability, and significant effects on membrane properties. It was recently shown that they are selectively accumulated in membrane domains that contain unsaturated phospholipids, and thus are located in the most vulnerable regions of the membrane. This location is ideal if they are to act as lipid antioxidants, which is the most accepted mechanism through which lutein and zeaxanthin protect the retina from age-related macular degeneration. In this mini-review, we examine published data on carotenoid-membrane interactions and present our hypothesis that the specific orientation and location of macular xanthophylls maximize their protective action in membranes of the eye retina.
Subczynski, Witold K.; Wisniewska, Anna; Widomska, Justyna
Purpose: To identify OCT-based anatomical features and clinical characteristics for poor central retinal thickness (CRT) response to ranibizumab in neovascular age-related macular degeneration (AMD). Patients and Methods: Investigating our electronic patient records (Eyeswide), patients with neovascular AMD treated with intravitreal injections of 0.5mg/0.05ml ranibizumab were identified and their notes reviewed. Data collected included gender, age, initial best-corrected visual acuity (BCVA), prior photodynamic therapy, lesion type (classic versus occult), type of macular edema (intraretinal fluid, subretinal fluid, pigment epithelium detachment) and the total number of previous ranibizumab injections. Results: A total of 210 eyes of 182 patients with neovascular AMD were identified. Mean follow-up time was 1.34 years (SD ± 0.77). Central retinal thickness reduction in women was significantly inferior to that in men (p=0.05). Patients with cystoid type macular edema had significantly greater reduction in CRT compared to patients with subretinal fluid (p<0.001) or pigment epithelium detachment (p<0.001). The percentage drop of CRT was no longer statistically significant after the sixth injection. Age, initial BCVA, prior photodynamic therapy and lesion type had no statistically effect on CRT response. Conclusion: Risk factors for poor central retinal thickness response to ranibizumab include female gender and patients with predominant subretinal fluid or pigment epithelium detachment. Furthermore, the anatomical response decreased after the sixth injection of ranibizumab.
Guber, Josef; Josifova, Tatjana; Henrich, Paul Bernhard; Guber, Ivo
Provided are methods of using levels of markers of systemic inflammation, e.g., CRP, to predict a subject's risk of development or progression of Age-Related Macular Degeneration (AMD), and methods of treating, delaying or preventing the development or pr...
J. M. Seddon
Age-related macular degeneration (AMD)--a common eye disease causing vision loss--can be detected early through regular eye-health examinations, and measures can be taken to prevent visual decline. Getting eye examinations requires certain levels of awareness, knowledge, and concern related to AMD. However, little is known about AMD-related…
Cimarolli, Verena R.; Laban-Baker, Allie; Hamilton, Wanda S.; Stuen, Cynthia
A non-invasive in vivo method for assessing macular carotenoids includes performing Optical Coherence Tomography (OCT) on a retina of a subject. A spatial representation of carotenoid levels in the macula based on data from the OCT of the retina can be generated.
Lambert, James L. (Inventor); Borchert, Mark S. (Inventor)
We studied 175 eyes of 175 patients who had successful repair of primary rhegmatogenous retinal detachment. Patients were randomly assigned to be treated with cryotherapy and episcleral sponges or with diathermy, scleral dissection, and encircling silicone bands. Fundus photography and fluorescein angiography were performed six weeks after successful reattachment surgery. Macular complications were discovered in 48 (27%) of the 175 eyes. The most frequent changes were cystoid macular edema in 28 (16%) and preretinal macular membrane in 13 eyes (8%). No significant differences in the incidence of cystoid macular edema were observed between diathermy and cryotherapy. Macular detachment, increased duration of macular detachment, cryotherapy, and pseudophakia were identified as risk factors for certain macular complications. PMID:2750831
Sabates, N R; Sabates, F N; Sabates, R; Lee, K Y; Ziemianski, M C
Transplantation of pigment epithelial cells in patients with age-related macular degeneration and Parkinson's disease has the potential to improve functional rehabilitation. Genetic modification of cells before transplantation may allow the delivery of neuroprotective factors to achieve functional improvement. As transplantation of cells modified using viral vectors is complicated by the possible dissemination of viral particles and severe immune reactions, we have explored non-viral methods to insert genetic material in pigment epithelial cells. Using lipofection or nucleofection ARPE-19 cells, freshly isolated and primary retinal and iris pigment epithelial (IPE) cells were transfected with plasmids encoding green fluorescent protein (GFP) and with three plasmids encoding recombinant pigment epithelium-derived factor (PEDF) and GFP. Transfection efficiency was evaluated by fluorescence microscopy and stability of protein expression by immunoblotting. Pigment epithelial cells were successfully transfected with plasmid encoding GFP. Expression of GFP in ARPE-19 was transient, but was observed for up to 1 year in IPE cells. Analysis of pigment epithelial cells transfected with PEDF plasmids revealed that PEDF fusion proteins were successfully expressed and functionally active. In conclusion, efficient transfer of genetic information in pigment epithelial cells can be achieved using non-viral transfection protocols. PMID:19741732
Thumann, G; Stöcker, M; Maltusch, C; Salz, A K; Barth, S; Walter, P; Johnen, S
Recessive Stargardt's macular degeneration is a blinding disease of children caused by mutations in the ABCA4 (ABCR) gene. Mice with a knockout mutation in abcr accumulate toxic lipofuscin pigments in ocular tissues, similar to affected humans. The major fluorophore of lipofuscin is the bis-retinoid, N-retinylidene-N-retinylethanolamine (A2E). In the current study, we sought to define the effect of increasing light on A2E accumulation. We crossed the abcr–/– mutation onto an albino background. The retinoid profiles in albino mice indicated higher retinal illuminance than in pigmented mice exposed to similar ambient light. Unexpectedly, A2E levels were not higher in the albino mice. Also, A2E levels in abcr–/– mice reared under cyclic light at 30, 120, or 1,700 lux were similar. Thus, increased retinal illuminance was not correlated with higher A2E. A2E has been shown to undergo light-dependent oxidation to yield a series of A2E epoxides or oxiranes. These oxiranes react with DNA in vitro, suggesting a potential mechanism for A2E cytotoxicity. We analyzed ocular tissues from abcr–/– mice for A2E oxiranes by mass spectrometry. Unlike A2E, the oxiranes were more abundant in albino vs. pigmented abcr–/– mice, and in abcr–/– mice exposed to increasing ambient light. These observations suggest that both the biosynthesis of A2E and its conversion to oxiranes are accelerated by light. Finally, we showed that the formation of A2E oxiranes is strongly suppressed by treating the abcr–/– mice with Accutane (isotretinoin), an inhibitor of rhodopsin regeneration.
Radu, Roxana A.; Mata, Nathan L.; Bagla, Aarti; Travis, Gabriel H.
... related macular degeneration is one of the most common, and it affects people generally over the age of 50. The risk factors for it are very similar as the risk factors for heart disease, so smoking is really a biggy, it’s the ...
Pigmentation, defined as the placement of pigment in skin, hair, and eyes for coloration, is distinctive because the location, amount, and type of pigmentation provides a visual manifestation of genetic heterogeneity in pathways regulating the pigment-producing cells, melanocytes. The scope of this genetic heterogeneity in humans ranges from normal to pathological pigmentation phenotypes. Clinically normal human pigmentation encompasses a variety of skin and hair color as well as with punctate pigmentation such as melanocytic nevi (moles) or ephelides (freckles), while clinically abnormal human pigmentation exhibits markedly reduced or increased pigment levels, known as hypopigmentation and hyperpigmentation, respectively. Elucidation of the molecular genetics underlying pigmentation has revealed genes important for melanocyte development and function. Furthermore, many pigmentation disorders show additional defects in cells other than melanocytes, and identification of the genetic insults in these disorders has revealed pleiotropic genes, where a single gene is required for various functions, often in different cell types. Thus unravelling the genetics of easily visualized pigmentation disorders has identified molecular similarities between melanocytes and less visible cell types/tissues, revealing a common cellular origin and/or common genetic regulatory pathways. Herein we discuss notable human pigmentation disorders and their associated genetic alterations, focusing on the fact that the developmental genetics of pigmentation abnormalities is instructive for understanding normal pathways governing development and function of melanocytes.
Baxter, Laura L.; Pavan, William J.
The highly radioresistant Rubrobacter radiotolerans, contains red pigments. Since the pigments could not be extracted by usual methods, a new method was developed in which the\\u000a pigments were extracted with organic solvents after addition of 10 N KOH to the intact cells, followed by neutralization.\\u000a These pigments were also extracted after treatment with achromopeptidase, but not with lysozyme. The extracted
T. Saito; H. Terato; O. Yamamoto
Age-related macular degeneration (AMD) is the most frequent cause of irreversible blindness in the elderly in developed countries. Our previous studies implicated activation of complement in the formation of drusen, the hallmark lesion of AMD. Here, we show that factor H (HF1), the major inhibitor of the alternative complement pathway, accumulates within drusen and is synthesized by the retinal pigmented
Gregory S. Hageman; Don H. Anderson; Lincoln V. Johnson; Lisa S. Hancox; Andrew J. Taiber; Lisa I. Hardisty; Jill L. Hageman; Heather A. Stockman; James D. Borchardt; Karen M. Gehrs; Richard J. H. Smith; Giuliana Silvestri; Stephen R. Russell; Caroline C. W. Klaver; Irene Barbazetto; Stanley Chang; Lawrence A. Yannuzzi; Gaetano R. Barile; John C. Merriam; R. Theodore Smith; Adam K. Olsh; Julie Bergeron; Jana Zernant; Joanna E. Merriam; Bert Gold; Michael Dean; Rando Allikmets
• Background: Iris pigment epithelium (IPE) cells and retinal pigment epithelium (RPE) cells possess the same embryonic origin. It is also known that the pigmented epithelial cells in the eye have a high transdifferentiation potential. In this study we transplanted IPE cells into the subretinal space of albino Royal College of Surgeons (RCS) rats and evaluated their influence on the
Kourous A. Rezai; Leon Kohen; Peter Wiedemann; Klaus Heimann
This lesson will examine the two major classes of phototsynthetic pigments, chlorophylls and carotenoids, their biochemical structures and their biosynthesis. The organization of these pigments into photosynthetic pigment, which are protein complexes that harvest light and convert its energy into biochemical energy will be explained.
Pathogenesis of age-related macular degeneration (AMD), the leading cause of blindness in the world, remains poorly understood. This makes it necessary to create animal models for studying AMD pathogenesis and to design new therapeutic approaches. Here we showed that retinopathy in OXYS rats is similar to human AMD according to clinical signs, morphology, and vascular endothelium growth factor (VEGF) and pigment epithelium-derived factor (PEDF) genes expression. Clinical signs of retinopathy OXYS rats manifest by the age 3 months against the background of significantly reduced expression level of VEGF and PEDF genes due to the decline of the amount of retinal pigment epithelium (RPE) cells and alteration of choroidal microcirculation. The disruption in OXYS rats' retina starts at the age of 20 days and appears as reduce the area of RPE cells but does not affect their ultrastructure. Ultrastructural pathological alterations of RPE as well as develop forms of retinopathy are observed in OXYS rats from age 12 months and manifested as excessive accumulation of lipofuscin in RPE regions adjacent to the rod cells, whirling extentions of the basement membrane into the cytoplasm. These data suggest that primary cellular degenerative alterations in the RPE cells secondarily lead to choriocapillaris atrophy and results in complete loss of photoreceptor cells in the OXYS rats' retina by the age of 24 months.
Markovets, Anton M.; Saprunova, Valeriya B.; Zhdankina, Anna A.; Fursova, Anzhella Zh.; Bakeeva, Lora E.; Kolosova, Natalia G.
The retinal pigmented epithelium (RPE) is composed of retinal pigmented epithelial cells joined by tight junctions and represents the outer blood-retinal barrier (BRB). The inner BRB is made of endothelial cells joined by tight junctions and glial extensions surrounding all the retinal blood vessels. One of the functions of the RPE is to maintain an osmotic transepithelial gradient created by ionic pumps and channels, avoiding paracellular flux. Under such physiological conditions, transcellular water movement follows the osmotic gradient and flows normally from the retina to the choroid through the RPE. Several diseases, such as diabetic retinopathy, are characterized by the BRB breakdown leading to leakage of solutes, proteins, and fluid from the retina and the choroid. The prevailing hypothesis explaining macular edema formation during diabetic retinopathy incriminates the inner BRB breakdown resulting in increased osmotic pressure leading in turn to massive water accumulation that can affect vision. Under these conditions, it has been hypothesized that RPE is likely to be exposed to hyperosmolar stress at its apical side. This review summarizes the origins and consequences of osmotic stress in the RPE. Ongoing and further research advances will clarify the mechanisms, at the molecular level, involved in the response of the RPE to osmotic stress and delineate potential novel therapeutic targets and tools. PMID:24910616
Willermain, François; Libert, Sarah; Motulsky, Elie; Salik, Dany; Caspers, Laure; Perret, Jason; Delporte, Christine
The retinal pigmented epithelium (RPE) is composed of retinal pigmented epithelial cells joined by tight junctions and represents the outer blood-retinal barrier (BRB). The inner BRB is made of endothelial cells joined by tight junctions and glial extensions surrounding all the retinal blood vessels. One of the functions of the RPE is to maintain an osmotic transepithelial gradient created by ionic pumps and channels, avoiding paracellular flux. Under such physiological conditions, transcellular water movement follows the osmotic gradient and flows normally from the retina to the choroid through the RPE. Several diseases, such as diabetic retinopathy, are characterized by the BRB breakdown leading to leakage of solutes, proteins, and fluid from the retina and the choroid. The prevailing hypothesis explaining macular edema formation during diabetic retinopathy incriminates the inner BRB breakdown resulting in increased osmotic pressure leading in turn to massive water accumulation that can affect vision. Under these conditions, it has been hypothesized that RPE is likely to be exposed to hyperosmolar stress at its apical side. This review summarizes the origins and consequences of osmotic stress in the RPE. Ongoing and further research advances will clarify the mechanisms, at the molecular level, involved in the response of the RPE to osmotic stress and delineate potential novel therapeutic targets and tools.
Willermain, Francois; Libert, Sarah; Motulsky, Elie; Salik, Dany; Caspers, Laure; Perret, Jason; Delporte, Christine
Purpose To describe clinical characteristics and visual and anatomic outcomes of a syndrome clinically similar to acute posterior multifocal placoid pigment epitheliopathy (APMPPE) in older patients. Methods We retrospectively reviewed medical records and photographic studies of consecutive patients over the age of 50 who presented to an academic tertiary care center with acute-onset visual symptoms associated with flat, gray-white lesions at the level of the retinal pigment epithelium reminiscent of APMPPE. Main outcome measures were visual acuity and macular anatomic status at the final follow-up visit. Results The cohort included 4 men and 2 women with a median age of 72.5 (range, 58–82) years. The disease course was characterized by recurrent episodes in 6 of 11 eyes (55%), with initial or eventual bilaterality in all 5 binocular patients. Five of 6 patients were treated with corticosteroids, and all 6 patients experienced significant short-term improvement in visual acuity. However, 8 of 11 eyes (73%) developed progressive geographic atrophy, and 7 (64%) developed choroidal neovascularization. With a mean (± SD) follow-up time of 6.6 ± 5.5 years, the final visual acuity was 20/200 or worse in 8 of 11 eyes (73%). Conclusions Although older patients presenting with APMPPE-like lesions are likely to experience visual improvement as acute lesions resolve, progression to geographic atrophy and choroidal neovascular membrane formation is the usual long-term outcome.
Taich, Alexander; Johnson, Mark W.
Current management of age-related macular degeneration (AMD) can be divided into two categories: first, anti-vasoendothelial growth factor (anti-VEGF) injection for wet macular degeneration; second, anti-oxidant vitamins for dry macular degeneration. New therapies are being developed for both of these diseases using novel technologies and different modes of administration. The hope is that some of these therapies will achieve significant improvement to current management and prevent future loss of vision in this devastating eye condition.
A 27-year-old man with progressive bilateral visual decline was diagnosed to have Bietti's crystalline dystrophy (BCD). Fluorescein angiography revealed bilateral petaloid type late hyperfluorescence implicating concurrent cystoid macular edema (CME). Optical coherence tomography exhibited cystoid foveal lacunas OU. During the follow-up of six years, intraretinal crystals reduced in amount but CME persisted angiographically and tomographically. CME is among the rare macular features of BCD including subfoveal sensorial detachment, subretinal neovascular membrane, and macular hole.
Background Polycystic ovary syndrome (PCOS) has been recognized as a metabolic disorder, manifested by abdominal obesity, insulin resistance, dyslipidemia and hypertension. Pigment epithelium-derived factor (PEDF), a member of the serine protease inhibitor family, is a pleiotropic protein known for its antiangiogenic, antioxidant, and neuroprotective properties and has been shown to induce insulin resistance and play a role in glucose metabolism. Recent studies investigating circulating PEDF levels show elevated serum PEDF in association with insulin resistance in normal-weight women with PCOS, but not in obese PCOS patients. The aims of this study were 1) to assess PEDF gene expression in subcutaneous adipose tissue (scAT) from women with PCOS and nonhirsute, ovulatory controls, and 2) to determine the circulating levels of PEDF in these groups. Methods Total RNA was extracted from adipose tissue biopsy samples and reverse-transcribed to cDNA. Real-time quantitative PCR was performed to determine relative gene expression levels. Results The 22 women with PCOS and 14 non-PCOS controls included in the study had similar age, BMI, and fasting glucose, triglycerides, and HDL-cholesterol levels. Participants with PCOS exhibited higher 2 h oral glucose tolerance test levels (p?=?0.006), total (p?=?0.026) and LDL-cholesterol (p?=?0.036), Ferriman-Gallwey score (p?=?0.003) and total testosterone (p?=?0.001) as compared to controls. BMI-adjusted PEDF serum levels and scAT gene expression were similar in the PCOS and control groups (p?=?0.622 and p?=?0.509, respectively). Circulating PEDF levels were not associated with scAT PEDF gene expression. Multiple regression analysis revealed that, in women with PCOS, insulin contributed positively and significantly to serum PEDF (p = 0.027), independently of testosterone. Conclusion Serum PEDF levels and scAT gene expression were associated with metabolic risk factors, but did not differ between women with PCOS and age- and BMI-matched controls. Circulating levels and scAT gene expression of PEDF were not associated in the study subjects, suggesting additional sources for PEDF in addition to or instead of fat tissue.
Physiological stress response and oxidative damage are factors for aging processes and, as such, are thought to contribute to neovascular age-related macular degeneration (AMD). Paraoxonase 1 (PON1) is an enzyme that plays an important role in oxidative stress and aging. We investigated association of DNA sequence variants (SNP) within the upstream regulatory region of the PON1 gene with neovascular AMD in 305 patients and 288 controls. Four of the seven tested SNPs (rs705379, rs705381, rs854573, and rs757158) were more frequently found in AMD patients compared to controls (P = 0.0099, 0.0295, 0.0121, and 0.0256, respectively), and all but one (SNP rs757158) are in linkage disequilibrium. Furthermore, haplotype TGGCCTC conferred protection (odds ratio (OR) = 0.76, (CI) = 0.60-0.97) as it was more frequently found in control individuals, while haplotype CGATGCT increased the risk (OR = 1.55, CI = 1.09-2.21) for AMD. These results were also reflected when haplotypes for the untranscribed and the 5'untranslated regions (5'UTR) were analyzed separately. To assess haplotype correlation with levels of gene expression, the three SNPs within the 5'UTR were tested in a luciferase reporter assay. In retinal pigment epithelium-derived ARPE19 cells, we were able to measure significant differences in reporter levels, while this was not observed in kidney-derived HEK293 cells. The presence of the risk allele A (SNP rs705381) caused an increase in luciferase activity of approximately twofold. Our data support the view that inflammatory reactions mediated through anti-oxidative activity may be relevant to neovascular age-related macular degeneration. PMID:22956172
Oczos, Jadwiga; Grimm, Christian; Barthelmes, Daniel; Sutter, Florian; Menghini, Moreno; Kloeckener-Gruissem, Barbara; Berger, Wolfgang
Purpose. Lipofuscin, a fluorescent lysosomal pigment made of lipophilic molecules, is associated with age-related pathophysiological processes in the retinal pigment epithelium (RPE). The best-characterized components of lipofuscin are A2E and its oxides, but a direct spatial correlation with lipofuscin has not previously been possible. Methods. Lipofuscin fluorescence was mapped across the RPE of Abca4?/? and Sv129 (background strain control) mice. In the same tissues, they determined the spatial distribution of A2E and its oxides by using the high molecular specificity of matrix-assisted laser desorption-ionization imaging mass spectrometry (MALDI-IMS). The fluorescence and tandem mass spectra taken directly from the tissue were compared with those of synthetic A2E standard. Results. In 2-month-old mice, A2E was found in the center of the retinal pigment epithelial tissue; with age, A2E increased across the tissue. With high levels of A2E, there was a marked correlation between A2E and lipofuscin, but with low levels this correlation diminished. The distributions of the oxidized forms of A2E were also determined. The amount of oxidation on A2E remained constant over 6 months, implying that A2E does not become increasingly oxidized with age in this time frame. Conclusions. This report is the first description of the spatial imaging of a specific retinoid from fresh tissue and the first description of a direct correlation of A2E with lipofuscin. The molecule-specific imaging of lipofuscin components from the RPE suggests wide applicability to other small molecules and pharmaceuticals for the molecular characterization and treatment of age-related macular degeneration.
Grey, Angus C.; Crouch, Rosalie K.; Koutalos, Yiannis; Schey, Kevin L.
Macular amyloidosis causes an eruption of brown pigment in the skin when keratin is altered. The resulting hyperpigmentation, which often leads to patient distress, generally has unsatisfactory treatment options. Among the treatment modalities that have been used for amyloidosis, the pulsed dye laser (PDL) has shown success in the treatment of nodular amyloidosis, and the Q-switched Nd:YAG laser has reduced the appearance of amyloid plaques in macular amyloidosis. We investigated the effects of repeated PDL treatments in a 57-year-old man with recalcitrant macular amyloidosis. The patient was treated with 3 treatment sessions of PDL at 2-week intervals. Based on patient self-assessment and our own photographic analysis, improvement of the lesions was noted with each treatment. Macular amyloidosis can be successfully treated using the PDL, which decreases amyloid aggregation and skin hyperpigmentation. This effect from a decrease in collagen and dermatan sulfate synthesis is similar to the mechanism behind the reduction of size of hypertrophic scars using PDL. PMID:24818178
Barsky, Maya; Buka, Robert L
Diffuse electrical currents delivered to the eye were investigated in a rat model of retinitis pigmentosa for potentially therapeutic effects. Low-level currents were passed between electrodes placed on the cornea and in the mouth during 30-min sessions two times per week from 4 to 16 weeks of age. Single-flash electroretinograms (ERG) were recorded and analyzed for amplitude and measures of sensitivity, and basic histology was performed. ERG a-wave amplitudes were slightly greater in treated vs. age-matched controls at 16 weeks of age, but the combined thicknesses of the outer nuclear layer and outer segment layer were similar at this age. Treated animals exhibited a significant preservation of b-wave amplitudes, and a striking preservation of rod sensitivity, measured as the stimulus strength required to reach half-saturation of the a-wave. Analysis of the leading edge of the a-wave using a delayed Gaussian function revealed a decrease in the parameter reflecting gain of the phototransduction cascade over the 12-week course of treatment, and no significant change in control animals over the same period. These results suggest that while the exogenous currents failed to preserve the number or gross structure of rods, the responsivity of individual photoreceptors was relatively preserved, perhaps via an increase in efficiency of photon capture (R/photon). This preserved functionality may delay the retraction of bipolar cell dendrites from degenerating photoreceptors. PMID:23147691
Rahmani, Safa; Bogdanowicz, Les; Thomas, Joel; Hetling, John R
The common variant in the human complement Factor H gene (CFH), with Tyr402His, is linked to age-related macular degeneration (AMD), a prevalent disorder leading to visual impairment and irreversible blindness in elderly patients. Here we show that the risk variant CFH 402His displays reduced binding to C reactive protein (CRP), heparin and retinal pigment epithelial cells. This reduced binding can
Christine Skerka; Nadine Lauer; Andreas A. W. A. Weinberger; Claudia N. Keilhauer; Jürgen Sühnel; Richard Smith; Lars Fritsche; Stefan Heinen; Andrea Hartmann; Bernhard H. F. Weber; Peter F. Zipfel
Pseudophakic cystoid macular edema (PCME) is the most common complication following cataract surgery. In 1-3% of cases it is associated with a decrease in visual acuity. However, PCME has a good prognosis, persisting in only 10% of the patients beyond 2 years. The prophylactic therapy of eyes without additional disease with non-steroidal antiphlogistic drugs or steroids does not influence the final visual acuity. Under certain circumstances, prophylaxis can be a reasonable option. Risk factors that promote the formation of PCME are discussed. The course of acute or chronic PCME can be influenced by drug treatment, but in general the level of evidence for the treatment of this widespread problem is low. We would therefore like to present the Freiburg treatment scheme for PCME for discussion. PMID:17443332
Agostini, H T; Hansen, L L; Feltgen, N
Bone morphogenetic protein-4 (BMP4) may be involved in the molecular switch that determines which late form of age-related macular degeneration (AMD) an individual develops. BMP4 expression is high in retinal pigment epithelium (RPE) cells in late, dry AMD patients, while BMP4 expression is low in the wet form of the disease, characterized by choroidal neovascularization (CNV). Here, we sought to determine the mechanism by which BMP4 is down-regulated in CNV. BMP4 expression was decreased within laser-induced CNV lesions in mice at a time when tumor necrosis factor (TNF) expression was high (7 d postlaser) and was reexpressed in RPE when TNF levels declined (14 d postlaser). We found that TNF, an important angiogenic stimulus, significantly down-regulates BMP4 expression in cultured human fetal RPE cells, ARPE-19 cells, and RPE cells in murine posterior eye cup explants. We identified two specificity protein 1 (Sp1) binding sites in the BMP4 promoter that are required for basal expression of BMP4 and its down-regulation by TNF. Through c-Jun NH2-terminal kinase (JNK) activation, TNF modulates Sp1 phosphorylation, thus decreasing its affinity to the BMP4 promoter. The down-regulation of BMP4 expression by TNF in CNV and mechanisms established might be useful for defining novel targets for AMD therapy.—Xu, J., Zhu, D., He, S., Spee, C., Ryan, S. J., Hinton, D. R. Transcriptional regulation of bone morphogenetic protein 4 by tumor necrosis factor and its relationship with age-related macular degeneration.
Xu, Jing; Zhu, Danhong; He, Shikun; Spee, Christine; Ryan, Stephen J.; Hinton, David R.
BACKGROUND\\/AIMSMost surgeons performing macular hole surgery using long acting gas recommend strict postoperative face down posturing for 10–15 days. Patients with chronic systemic illness such as arthritis may be unable to carry out this postoperative regime. Thus there is a need for alternative techniques that would eliminate such a regime. The authors review a series of patients who underwent macular
N Karia; A Laidlaw; E Ezra; M Z Gregor
BACKGROUND—Most idiopathic macular holes can be closed by a surgical procedure combining vitrectomy, posterior hyaloid ablation, and fluid-gas exchange followed by postoperative positioning. Reopening of closed macular holes has been reported, but its frequency is not known. Here the incidence of reopening after successful macular hole surgery is reported.?METHODS—77 consecutive cases of idiopathic macular holes operated with autologous platelet injection between July 1993 and October 1995 were reviewed. The procedure consisted of three port vitrectomy, posterior hyaloid removal, non-expansile fluid-gas exchange, and autologous platelet injection followed by face down positioning. The incidence of reopening was analysed in the cohort of the 72 anatomical successes.?RESULTS—Mean follow up was 12.3 months. The macular hole reopened in five eyes of five patients (five out of 72 patients, 6.9%), in four cases after cataract extraction. In four cases too, an epiretinal membrane was noted, either clinically or during reoperation, and fluorescein leakage in the macular area was present in two cases. Three of the five cases of reopening were reoperated and all three were anatomical successes.?CONCLUSION—Late macular hole reopening occurred in five out of 72 patient, and in four cases after cataract surgery. The presence of an epiretinal membrane around the hole in four of them suggested that tractional forces were responsible for the reopening. Reoperation, performed in three cases, again closed the macular holes.??
Paques, M.; Massin, P.; Santiago, P.; Spielmann, A.; Le Gargasson, J.-F.; Gaudric, A.
Age-related macular degeneration (AMD) is the leading cause of blindness in the Western world. In advanced AMD, new vessels from choriocapillaris (CC) invade through the Bruch's membrane (BrM) into the retina, forming choroidal neovascularization (CNV). BrM, an elastic lamina that is located between the retinal pigment epithelium (RPE) and CC, is thought to act as a physical and functional barrier against CNV. The BrM of patients with early AMD are characterized by decreased levels of antiangiogenic factors, including endostatin, thrombospondin-1 (TSP-1), and pigment epithelium-derived factor (PEDF), as well as by degeneration of the elastic layer. Motivated by a previous report that heat increases elastin expression in human skin, we examined the effect of heat on human ARPE-19 cell production of BrM components. Heat treatment stimulated the production of BrM components, including TSP-1, PEDF, and tropoelastin in vitro and increased the antiangiogenic activity of RPE measured in a mouse corneal pocket assay. The effect of heat on experimental CNV was investigated by pretreating the retina with heat via infrared diode laser prior to the induction of CNV. Heat treatment blocked the development of experimental CNV in vivo. These findings suggest that heat treatment may restore BrM integrity and barrier function against new vessel growth.—Sekiyama, E., Saint-Geniez, M., Yoneda, K., Hisatomi, T., Nakao, S., Walshe, T. E., Maruyama, K., Hafezi-Moghadam, A., Miller, J. W., Kinoshita, S., D'Amore, P. A. Heat treatment of retinal pigment epithelium induces production of elastic lamina components and anti-angiogenic activity.
Sekiyama, Eiichi; Saint-Geniez, Magali; Yoneda, Kazuhito; Hisatomi, Toshio; Nakao, Shintaro; Walshe, Tony E.; Maruyama, Kazuichi; Hafezi-Moghadam, Ali; Miller, Joan W.; Kinoshita, Shigeru; D'Amore, Patricia A.
Age-related macular degeneration (AMD) is the leading cause of vision loss in older adults and ultimately leads to the death of photoreceptor cells in the macular area of the neural retina. Currently, treatments are only available for patients with the wet form of AMD. In this review, we describe recent approaches to develop cell-based therapies for the treatment of AMD. Recent research has focused on replacing the retinal pigment epithelium (RPE), a monolayer of cells vital to photoreceptor cell health. We discuss the various methods used to differentiate and purify RPE from human embryonic stem cells (HESC), and describe the surgical approaches being used to transplant these cells in existing and forthcoming clinical trials. PMID:23601133
Carr, Amanda-Jayne F; Smart, Matthew J K; Ramsden, Conor M; Powner, Michael B; da Cruz, Lyndon; Coffey, Peter J
Stargardt-like macular degeneration (STGD3) is an early onset, autosomal dominant macular degeneration. STGD3 is characterized by a progressive pathology, the loss of central vision, atrophy of the retinal pigment epithelium, and accumulation of lipofuscin, clinical features that are also characteristic of age-related macular degeneration. The onset of clinical symptoms in STGD3, however, is typically observed within the second or third decade of life (i.e., starting in the teenage years). The clinical profile at any given age among STGD3 patients can be variable suggesting that, although STGD3 is a single gene defect, other genetic or environmental factors may play a role in moderating the final disease phenotype. Genetic studies localized the STGD3 disease locus to a small region on the short arm of human chromosome 6, and application of a positional candidate gene approach identified protein truncating mutations in the elongation of very long chain fatty acids-4 gene (ELOVL4) in patients with this disease. The ELOVL4 gene encodes a protein homologous to the ELO group of proteins that participate in fatty acid elongation in yeast. Pathogenic mutations found in the ELOVL4 gene result in altered trafficking of the protein and behave with a dominant negative effect. Mice carrying an Elovl4 mutation developed photoreceptor degeneration and depletion of very long chain fatty acids (VLCFA). ELOVL4 protein participates in the synthesis of fatty acids with chain length longer than 26 carbons. Studies on ELOVL4 indicate that VLCFA may be necessary for normal function of the retina, and the defective protein trafficking and/or altered VLCFA elongation underlies the pathology associated with STGD3. Determining the role of VLCFA in the retina and discerning the implications of abnormal trafficking of mutant ELOVL4 and depleted VLCFA content in the pathology of STGD3 will provide valuable insight in understanding the retinal structure, function, and pathology underlying STGD3 and may lead to a better understanding of the process of macular disease in general.
Vasireddy, Vidyullatha; Wong, Paul; Ayyagaria, Radha
Macular hole formation is a well-known complication following ocular trauma. Less commonly recognised is the spontaneous closure of such holes. A 27-year-old man presented with a history of blunt trauma to his left eye. Eye evaluation showed conjunctival laceration, diffuse retinal oedema and multiple retinal haemorrhages in that eye. A month later, he developed a full thickness macular hole. Two months later, there was spontaneous complete closure of the full-thickness macular hole in the left eye as confirmed on optical coherence tomography. Spontaneous closure of hole is not uncommon. Observation for a period of up to 12 months is a reasonable management option. Macular hole surgery for traumatic macular holes may be delayed in such cases. PMID:23961017
Sanjay, Srinivasan; Yeo, Tun Kuan; Au Eong, Kah-Guan
Macular hole formation is a well-known complication following ocular trauma. Less commonly recognised is the spontaneous closure of such holes. A 27-year-old man presented with a history of blunt trauma to his left eye. Eye evaluation showed conjunctival laceration, diffuse retinal oedema and multiple retinal haemorrhages in that eye. A month later, he developed a full thickness macular hole. Two months later, there was spontaneous complete closure of the full-thickness macular hole in the left eye as confirmed on optical coherence tomography. Spontaneous closure of hole is not uncommon. Observation for a period of up to 12 months is a reasonable management option. Macular hole surgery for traumatic macular holes may be delayed in such cases.
Sanjay, Srinivasan; Yeo, Tun Kuan; Au Eong, Kah-Guan
A 42-year-old man was admitted to our clinic complaining of visual distortion in his left eye two months after bilateral myopic photorefractive keratectomy (PRK). Macular optical coherence tomography (OCT) showed a stage II macular hole in the left eye. Simultaneous OCT in the right eye showed vitreous traction and distortion of the outer retina. One month later, the patient underwent vitrectomy for the left eye, and the macular hole was closed. Two months after that, the patient complained of visual distortion in the right eye, and OCT revealed increased traction and accentuated outer retinal distortion indicating a stage IB macular hole. Traction attenuated later without any intervention. The short interval between PRK and hole formation, bilateral involvement, and the moderate refractive error in this case highlight the possible role of PRK in aggravating vitreoretinal interface abnormalities. We recommend the addition of PRK to the list of procedures that may be associated with the formation of a macular hole.
Shoeibi, Nasser; Abrishami, Majid; Ansari-Astaneh, Mohammad-reza
Purpose: The purpose of this study was to evaluate the safety and efficacy of intravitreal triamcinolone acetonide injection in patients with diffuse diabetic macular edema. We also compared the effect of intravitreal triamcinolone with macular grid laser photocoagulation in macular edema. Patients and Methods: Thirty patients with diabetic diffuse macular edema unresponsive to grid laser photocoagulation for at least 4
Abstract Context: Lutein (LUT) and zeaxanthin (ZEA) are currently under investigation in clinical trials as prophylactic nutritional agents for age-related macular degeneration (AMD). However, dose used in these trials is empirical and not been investigated in in vitro studies. Objective: In this study, we investigated the dose-response effect of LUT and ZEA in protecting retinal pigment epithelium (RPE) from oxidative stress, a common underlying pathology in AMD. Methods: Three thousand cultured human retinal pigment epithelial cells (ARPE-19) were plated in 72-well plate and after 24?h were exposed to increasing concentrations of hydrogen peroxide (H2O2). ARPE-19 cells were exposed to four different concentrations of LUT (0.5, 1, 2 and 4?µg/mL) and ZEA (0.1, 0.2, 0.4 and 0.8?µg/mL). After 24?h incubation, cells were subjected to oxidative stress induced with H2O2. Cultures containing saline solution and dichloromethane served as controls. Cell viability was assessed using the WST-1 assay. Pathophysiological pathways were evaluated by measuring caspase-3 levels as an indicator of apoptosis induction. Reactive oxygen species (ROS) levels were measured using dihydrorhodamine-123. Results: Cell viability as a percentage of control was 81.3%, 81.1%, and 88.8% at 0.5, 1, and 2?µg/ml, respectively of LUT (p?0.001). The maximum cytoprotective effect was seen with LUT at 2??g/mL. ZEA did not show any cytoprotective effect at all concentrations used in the study. Caspase-3 showed a corresponding decrease in levels with LUT (1 and 2?µg/ml). Significant decrease in ROS levels were measured only with LUT at 4?µg/ml (p?=?0.02). Discussion and conclusions: Results from our study provide in vitro data to support the epidemiologic studies, which are currently underway to provide evidence that lutein may act as cofactor that modulates processes implicated in AMD pathogenesis. PMID:23862688
Murthy, Ravi K; Ravi, Kavitha; Balaiya, Sankarathi; Brar, Vikram S; Chalam, Kakarla V
Two patients with choroidal neovascularization secondary to age-related macular degeneration (AMD) developed a retinal pigment epithelial (RPE) tear following intravitreal injection of ranibizumab. One patient developed the RPE tear within 2 weeks of the injection, the other within 6 weeks of a second injection. Both patients presented with vision loss of one line at diagnosis of the RPE tear. During long-term follow-up, visual acuity improved in one patient by one line and deteriorated in the second patient by three lines. RPE tears may occur after intravitreal injection of ranibizumab in patients with neovascular AMD, probably because of the rapid regression of the fibrovascular membrane. PMID:17408387
Kiss, Christopher; Michels, Stephan; Prager, Franz; Geitzenauer, Wolfgang; Schmidt-Erfurth, Ursula
Age-related macular degeneration and cataract are the most frequent eye disorders of elderly people worldwide. The aim of this systematic review was to evaluate the effect of cataract surgery on the development and progression of age-related macular degeneration. Data were collected by means of a systematic literature search in 28 databases and an additional update in Pubmed. Search results were evaluated using pre-defined inclusion and exclusion criteria. All relevant publications were rated in terms of scientific quality and analyzed regarding their results. The literature search generated a total of 2,827 hits. Seven publications on five observational studies and two non-randomized clinical trials were eligible for analysis. The observational studies provided some evidence for an increased incidence of late age-related macular degeneration, respectively, for a promoting influence of cataract surgery on the progression of early types of age-related macular degeneration. The clinical trials did yield inconsistent results. In conclusion, only a small number of published studies investigated the development or progression of age-related macular degeneration following cataract surgery. The scientific level of evidence of these articles was not high and results were inconsistent, nevertheless a promoting influence of cataract surgery on the progression of early age-related macular degeneration can be assumed. PMID:18572053
Bockelbrink, Angelina; Roll, Stephanie; Ruether, Klaus; Rasch, Andrej; Greiner, Wolfgang; Willich, Stefan N
Age-related macular degeneration (AMD) causes severe vision loss in the elderly; early identification of AMD risk could help slow or prevent disease progression. Toward the discovery of AMD biomarkers, we quantified plasma protein N?-carboxymethyllysine (CML) and pentosidine from 58 AMD and 32 control donors. CML and pentosidine are advanced glycation end products that are abundant in Bruch membrane, the extracellular matrix separating the retinal pigment epithelium from the blood-bearing choriocapillaris. We measured CML and pentosidine by LC-MS/MS and LC-fluorometry, respectively, and found higher mean levels of CML (?54%) and pentosidine (?64%) in AMD (p < 0.0001) relative to normal controls. Plasma protein fructosyl-lysine, a marker of early glycation, was found by amino acid analysis to be in equal amounts in control and non-diabetic AMD donors, supporting an association between AMD and increased levels of CML and pentosidine independent of other diseases like diabetes. Carboxyethylpyrrole (CEP), an oxidative modification from docosahexaenoate-containing lipids and also abundant in AMD Bruch membrane, was elevated ?86% in the AMD cohort, but autoantibody titers to CEP, CML, and pentosidine were not significantly increased. Compellingly higher mean levels of CML and pentosidine were present in AMD plasma protein over a broad age range. Receiver operating curves indicate that CML, CEP adducts, and pentosidine alone discriminated between AMD and control subjects with 78, 79, and 88% accuracy, respectively, whereas CML in combination with pentosidine provided ?89% accuracy, and CEP plus pentosidine provided ?92% accuracy. Pentosidine levels appeared slightly altered in AMD patients with hypertension and cardiovascular disease, indicating further studies are warranted. Overall this study supports the potential utility of plasma protein CML and pentosidine as biomarkers for assessing AMD risk and susceptibility, particularly in combination with CEP adducts and with concurrent analyses of fructosyl-lysine to detect confounding factors.
Ni, Jiaqian; Yuan, Xianglin; Gu, Jiayin; Yue, Xiuzhen; Gu, Xiaorong; Nagaraj, Ram H.; Crabb, John W.
Light toxicity is suspected to enhance certain retinal degenerative processes such as age-related macular degeneration. Death of photoreceptors can be induced by their exposure to the visible light, and although cellular processes within photoreceptors have been characterized extensively, the role of the retinal pigment epithelium (RPE) in this model is less well understood. We demonstrate that exposition to intense light causes the immediate breakdown of the outer blood–retinal barrier (BRB). In a molecular level, we observed the slackening of adherens junctions tying up the RPE and massive leakage of albumin into the neural retina. Retinal pigment epithelial cells normally secrete vascular endothelial growth factor (VEGF) at their basolateral side; light damage in contrast leads to VEGF increase on the apical side – that is, in the neuroretina. Blocking VEGF, by means of lentiviral gene transfer to express an anti-VEGF antibody in RPE cells, inhibits outer BRB breakdown and retinal degeneration, as illustrated by functional, behavioral and morphometric analysis. Our data show that exposure to high levels of visible light induces hyperpermeability of the RPE, likely involving VEGF signaling. The resulting retinal edema contributes to irreversible damage to photoreceptors. These data suggest that anti-VEGF compounds are of therapeutic interest when the outer BRB is altered by retinal stresses.
Cachafeiro, M; Bemelmans, A-P; Samardzija, M; Afanasieva, T; Pournaras, J-A; Grimm, C; Kostic, C; Philippe, S; Wenzel, A; Arsenijevic, Y
Light toxicity is suspected to enhance certain retinal degenerative processes such as age-related macular degeneration. Death of photoreceptors can be induced by their exposure to the visible light, and although cellular processes within photoreceptors have been characterized extensively, the role of the retinal pigment epithelium (RPE) in this model is less well understood. We demonstrate that exposition to intense light causes the immediate breakdown of the outer blood-retinal barrier (BRB). In a molecular level, we observed the slackening of adherens junctions tying up the RPE and massive leakage of albumin into the neural retina. Retinal pigment epithelial cells normally secrete vascular endothelial growth factor (VEGF) at their basolateral side; light damage in contrast leads to VEGF increase on the apical side--that is, in the neuroretina. Blocking VEGF, by means of lentiviral gene transfer to express an anti-VEGF antibody in RPE cells, inhibits outer BRB breakdown and retinal degeneration, as illustrated by functional, behavioral and morphometric analysis. Our data show that exposure to high levels of visible light induces hyperpermeability of the RPE, likely involving VEGF signaling. The resulting retinal edema contributes to irreversible damage to photoreceptors. These data suggest that anti-VEGF compounds are of therapeutic interest when the outer BRB is altered by retinal stresses. PMID:23990021
Cachafeiro, M; Bemelmans, A P; Samardzija, M; Afanasieva, T; Pournaras, J A; Grimm, C; Kostic, C; Philippe, S; Wenzel, A; Arsenijevic, Y
By 2050 the prevalence of diabetes will more than triple globally, dramatically increasing the societal and financial burden of this disease worldwide. As a consequence of this growth, it is anticipated that there will be a concurrent rise in the numbers of patients with diabetic macular edema (DME), already among the most common causes of severe vision loss worldwide. Recent available therapies for DME target the secreted cytokine, vascular endothelial growth factor (VEGF). This review focuses on the treatment of DME using the first humanized monoclonal antibody targeting VEGF that has been Food and Drug Administration-approved for the use in the eye, ranibizumab (Lucentis(®)). PMID:24379922
Krispel, Claudia; Rodrigues, Murilo; Xin, Xiaoban; Sodhi, Akrit
Clinical question: Is there any new knowledge about the pathogenesis and treatment of age-related macular degeneration (AMD)? Results: We now understand better the biochemical and pathological pathways involved in the genesis of AMD. Treatment of exudative AMD is based on intravitreal injection of new antivascular endothelial growth factor drugs for which there does not yet exist a unique recognized strategy of administration. No therapies are actually available for atrophic AMD, despite some experimental new pharmacological approaches. Implementation: strategy of administration, safety of intravitreal injection
Querques, Giuseppe; Avellis, Fernando Onofrio; Querques, Lea; Bandello, Francesco; Souied, Eric H
Cone visual pigments are visual opsins that are present in vertebrate cone photoreceptor cells and act as photoreceptor molecules responsible for photopic vision. Like the rod visual pigment rhodopsin, which is responsible for scotopic vision, cone visual pigments contain the chromophore 11-cis-retinal, which undergoes cis-trans isomerization resulting in the induction of conformational changes of the protein moiety to form a G protein-activating state. There are multiple types of cone visual pigments with different absorption maxima, which are the molecular basis of color discrimination in animals. Cone visual pigments form a phylogenetic sister group with non-visual opsin groups such as pinopsin, VA opsin, parapinopsin and parietopsin groups. Cone visual pigments diverged into four groups with different absorption maxima, and the rhodopsin group diverged from one of the four groups of cone visual pigments. The photochemical behavior of cone visual pigments is similar to that of pinopsin but considerably different from those of other non-visual opsins. G protein activation efficiency of cone visual pigments is also comparable to that of pinopsin but higher than that of the other non-visual opsins. Recent measurements with sufficient time-resolution demonstrated that G protein activation efficiency of cone visual pigments is lower than that of rhodopsin, which is one of the molecular bases for the lower amplification of cones compared to rods. In this review, the uniqueness of cone visual pigments is shown by comparison of their molecular properties with those of non-visual opsins and rhodopsin. This article is part of a Special Issue entitled: Retinal Proteins - You can teach an old dog new tricks. PMID:24021171
Imamoto, Yasushi; Shichida, Yoshinori
The pathogenesis of acute posterior multifocal placoid pigment epitheliopathy (APMPPE) is not fully understood. Some believe it to be a primary dysfunction of the retinal pigment epithelium while others assume that its development follows a choroidal vasculitis. It generally presents as a bilateral condition and shows no sex predilection. The visual prognosis is generally good, though severe and permanent visual loss occasionally occurs. The funduscopic presentation consists of multiple flat, yellow-white lesions of the posterior pole at the level of the retinal pigment epithelium. This paper discusses a case of APMPPE and reviews and summarizes the current literature on this disorder. PMID:3819293
Goen, T M; Terry, J E
In this effort, an approach was devised and utilized to theoretically predict optimum coating compositions using two parameters, the maximum pigment packing factor and the coating critical pigment volume concentration, CPVC. Five binary pigment systems we...
A. T. Eng C. R. Hegedus
This study was conducted to describe the dose-response curve relating the concentration of carotenoid pigments in plasma and reflectance spectrum characteristics of fat to the carotenoid intake level in sheep, and to investigate the extent to which incorporation of dehydrated alfalfa in the diet affects the reliability of the discrimination between concentrate-fed and pasture-fed lambs based on these measurements. In Exp. 1, 6 treatments were compared in individually penned lambs: feeding 0, 250, 500, 750, 1,000, or 1,250 g/d of dehydrated alfalfa for 60 d before slaughter. Each treatment (T0 to T1,250) consisted of 8 male Romanov x Berrichon lambs with an initial average BW of 24.8 kg (SD 2.6). All lambs received straw for ad libitum intake and T0 to T1,000 lambs received a concentrate free of green vegetative matter in amounts to produce similar ADG in all treatments. In Exp. 2, 33 male Romanov x Berrichon lambs grazed a natural pasture maintained in a leafy green vegetative stage for at least 59 d before slaughter. Initial BW when turning out to pasture was 14.2 kg (SD 2.3). Plasma carotenoid concentration was measured at slaughter by spectrophotometry. Reflectance spectrum, lightness, redness, and yellowness were measured after 24 h of shrinkage in subcutaneous caudal and perirenal fat. The spectra were translated to 0 reflectance at 510 nm, and the integral of the translated spectrum was calculated between 450 and 510 nm (i.e., the range of light absorption by carotenoids). Reflectance measurement was replicated 5 times, from which we calculated the absolute value of the mean integral (AVMI). In Exp. 1, plasma carotenoid concentration at slaughter (PCCS) increased linearly with mean daily carotenoid intake (P < 0.01). Both subcutaneous caudal and perirenal fat AVMI increased linearly (P < 0.01) with mean daily carotenoid intake and PCCS, the slopes of the regressions being greater for perirenal than for subcutaneous caudal fat. The mean PCCS was greater for lambs of Exp. 2 than for lambs on any treatment of Exp. 1 (P < 0.01). We established the dose-response curves relating PCCS and AVMI of subcutaneous and perirenal fat to carotenoid intake level. The combined use of PCCS and of perirenal fat AVMI enabled discrimination of pasture-fed lambs of Exp. 2 from the lambs of Exp. 1 that received up to 500 g/d of dehydrated alfalfa. PMID:17609467
Dian, P H M; Chauveau-Duriot, B; Prado, I N; Prache, S
Lipofuscin accumulates with age in the retinal pigment epithelium (RPE) in discrete granular organelles and may contribute to age-related macular degeneration. Because previous studies suggest that lipofuscin contains protein that may impact pathogenic mechanisms, we pursued proteomics analysis of lipofuscin. The composition of RPE lipofuscin and its mechanisms of pathogenesis are poorly understood in part because of the heterogeneity of isolated preparations. We purified RPE lipofuscin granules by treatment with proteinase K or SDS and showed by light, confocal, and transmission electron microscopy that the purified granules are free of extragranular material and associated membranes. Crude and purified lipofuscin preparations were quantitatively compared by (i) LC MS/MS proteomics analyses, (ii) immunoanalyses of oxidative protein modifications, (iii) amino acid analysis, (iv) HPLC of bisretinoids, and (v) assaying phototoxicity to RPE cells. From crude lipofuscin preparations 186 proteins were identified, many of which appeared to be modified. In contrast, very little protein ( approximately 2% (w/w) by amino acid analysis) and no identifiable protein were found in the purified granules, which retained full phototoxicity to cultured RPE cells. Our analyses showed that granules in purified and crude lipofuscin preparations exhibit no statistically significant differences in diameter or circularity or in the content of the bisretinoids A2E, isoA2E, and all-trans-retinal dimer-phosphatidylethanolamine. The finding that the purified granules contain minimal protein yet retain phototoxic activity suggests that RPE lipofuscin pathogenesis is largely independent of associated protein. The purified granules also exhibited oxidative protein modifications, including nitrotyrosine generated from reactive nitrogen oxide species and carboxyethylpyrrole and isolevuglandin E(2) adducts generated from reactive lipid fragments. This finding is consistent with previous studies demonstrating RPE lipofuscin to be a potent generator of reactive oxygen species and supports the hypothesis that such species, including reactive fragments from lipids and retinoids, contribute to the mechanisms of RPE lipofuscin pathogenesis. PMID:18436525
Ng, Kwok-Peng; Gugiu, Bogdan; Renganathan, Kutralanathan; Davies, Matthew W; Gu, Xiaorong; Crabb, John S; Kim, So Ra; Rózanowska, Malgorzata B; Bonilha, Vera L; Rayborn, Mary E; Salomon, Robert G; Sparrow, Janet R; Boulton, Michael E; Hollyfield, Joe G; Crabb, John W
Along the Mexican coast, harmful algae blooms (HAB) have become more frequent, and therefore, there is an urgent need to establish monitoring programs to avoid the undesired consequences of HAB in human and natural ecosystems. In this work, we analyzed the pigment signatures and the species composition from phy- toplankton samples to evaluate the utility of the specific pigment \\
J. Bustillos-Guzmán; I. Gárate-Lizárraga; D. López-Cortés; F. Hernández-Sandoval
Age-related macular degeneration (ARMD) is the leading cause of blindness in the occidental world. Patients suffering this process have an important reduction on their quality of life being handicapped to read, to write, to recognise faces of their friends, or even to watch the television. One of the main problems of that disease is the absence of an effective treatment able to revert the process. Laser treatment is only useful in a limited number of patients, and even in these cases recurrent lesions are frequent. These facts and the progressive ageing of our society establish the ARMD as one of the biggest aim of medical investigations for the next century, and currently is focus of attention in the most industrialised countries. One of the most promising pieces of research is focused in the investigation of the risk factors associated with the age-related macular degeneration, in order to achieve a prophylactic treatment avoiding its appearance. Diet elements such as fat ingestion or reduced antioxidant intakes are being investigated as some of these factors, what open a new possibility for a prophylactic treatment. Finally, research is looking for new therapeutic modalities such as selective radiotherapy in order to improve or maintain the vision of these patients. PMID:10420956
Garcia Layana, A
The aryl hydrocarbon receptor (AhR) is a nuclear receptor that regulates xenobiotic metabolism and detoxification. Herein, we report a previously undescribed role for the AhR signaling pathway as an essential defense mechanism in the pathogenesis of early dry age-related macular degeneration (AMD), the leading cause of vision loss in the elderly. We found that AhR activity and protein levels in human retinal pigment epithelial (RPE) cells, cells vulnerable in AMD, decrease with age. This finding is significant given that age is the most established risk factor for development of AMD. Moreover, AhR(-/-) mice exhibit decreased visual function and develop dry AMD-like pathology, including disrupted RPE cell tight junctions, accumulation of RPE cell lipofuscin, basal laminar and linear-like deposit material, Bruch's membrane thickening, and progressive RPE and choroidal atrophy. High-serum low-density lipoprotein levels were also observed in AhR(-/-) mice. In its oxidized form, this lipoprotein can stimulate increased secretion of extracellular matrix molecules commonly found in deposits from RPE cells, in an AhR-dependent manner. This study demonstrates the importance of cellular clearance via the AhR signaling pathway in dry AMD pathogenesis, implicating AhR as a potential target, and the mouse model as a useful platform for validating future therapies. PMID:24106308
Hu, Peng; Herrmann, Rolf; Bednar, Amanda; Saloupis, Peter; Dwyer, Mary A; Yang, Ping; Qi, Xiaoping; Thomas, Russell S; Jaffe, Glenn J; Boulton, Michael E; McDonnell, Donald P; Malek, Goldis
The retinal pigment epithelial cell (RPE cell) layer protects the photoreceptors of the retina against oxidative stress. The decline of this capacity is believed to be a major factor in the impairment of vision in age-related macular degeneration. Exposure of human adult RPE cells to UV light at predominantly 320-400 nm (UVA light) in the presence of all-trans-retinaldehyde results in
Xiangqun Gao; Paul Talalay
Hydroxytyrosol (HTS) is a natural polyphenol abundant in olive oil. Increasing evidence indicates HTS has beneficial effect on human health for preventing various diseases. In the present study, we investigated the protective effects of HTS on acrolein-induced toxicity in human retinal pigment epithelial cell line, ARPE-19, a cellular model of smoking- and age-related macular degeneration. Acrolein, a major compo- nent
Zhongbo Liu; Lijuan Sun; Lu Zhu; Xu Jia; Xuesen Li; Haiqun Jia; Ying Wang; Peter Weber; Jiangang Long; Jiankang Liu
This work reports a 3D parylene scaffold cage for culturing stem-cell-differentiated retinal pigment epithelial (RPE) cells for the therapy of age-related macular degeneration, which is caused by degenerated permeability of the Bruch's membrane first and then the loss of RPE cells. This reported cage can support sufficient nutrient permeation to nourish the RPE cells inside with in vivo like morphology.
Bo Lu; Danhong Zhu; David Hinton; Mark S. Humayun; Yu-Chong Tai
Whereas cigarette smoking (CS) and dysregulated complement are thought to play central roles in age-related macular degeneration (AMD), their exact roles are unknown. The aim of this study was to determine if CS activates complement and if the antioxidant transcription factor Nrf2 modulates this response. In AMD specimens, Nrf2 immunolabeling was strong in the cytoplasm, with scattered nuclear labeling of macular retinal pigmented epithelial (RPE) cells that appeared normal, but was decreased and without nuclear labeling in dysmorphic cells overlying drusen, a hallmark AMD lesion. Cigarette smoke extract (CSE) induced Nrf2 nuclear translocation in RPE cells with increased antioxidant and complement gene expression. Whereas CFH protein was not altered by CSE, the cell membrane regulator proteins CD46, CD55, and CD59 were decreased, and C3a and C3b, but not iC3b, were increased compared to controls. C5b-9 was increased by CSE, but at sublytic levels, only after addition of normal human serum. Nrf2 knockdown enhanced the increase in C3a and C3b from CSE, but not iC3b, C5a, or C5b-9. CSE also increased IL-1b expression and secretion after C3a generation and was reduced by a C3aR antagonist. In contrast, the Nrf2 activator CDDO-Im restored complement gene expression in RPE cells exposed to CSE. We provide evidence of altered Nrf2 in human AMD and that CSE induces a proinflammatory environment specifically by generating C3a and C3b, and Nrf2 deficiency magnifies this specific complement response. PMID:24440594
Wang, Lei; Kondo, Naoshi; Cano, Marisol; Ebrahimi, Katayoon; Yoshida, Takeshi; Barnett, Bradley P; Biswal, Shyam; Handa, James T
The authors describe two cases of bilateral simultaneous stage 1 macular hole diagnosed via optical coherence tomography (OCT). Vitreomacular traction, foveal pseudo cysts, and outer retinal changes were present initially. Resolution of the foveal pseudo cysts and outer retinal changes occurred in cases where a complete posterior vitreous detachment was noted. The initial step in the pathogenesis of macular holes is “traction” from the detaching posterior hyaloid. However, there are missing links in the exact inciting events and in the progression of the disease. The development of bilateral stage 1 macular holes simultaneously is unique and interesting because an unknown common inciting factor might be at play in these cases.
Alwassia, Ahmad A.; Adhi, Mehreen; Duker, Jay S.
The retina exhibits an inherent autofluorescence that is imaged ophthalmoscopically as fundus autofluorescence. In clinical settings, fundus autofluorescence examination aids in the diagnosis and follow-up of many retinal disorders. Fundus autofluorescence originates from the complex mixture of bisretinoid fluorophores that are amassed by retinal pigment epithelial (RPE) cells as lipofuscin. Unlike the lipofuscin found in other cell-types, this material does not form as a result of oxidative stress. Rather, the formation is attributable to non-enzymatic reactions of vitamin A aldehyde in photoreceptor cells; transfer to RPE occurs upon phagocytosis of photoreceptor outer segments. These fluorescent pigments accumulate even in healthy photoreceptor cells and are generated as a consequence of the light capturing function of the cells. Nevertheless, the formation of this material is accelerated in some retinal disorders including recessive Stargardt disease and ELOVL-4-related retinal degeneration. As such, these bisretinoid side-products are implicated in the disease processes that threaten vision. In this article, we review our current understanding of the composition of RPE lipofuscin, the structural characteristics of the various bisretinoids, their related spectroscopic features and the biosynthetic pathways by which they form. We will revisit factors known to influence the extent of the accumulation and therapeutic strategies being used to limit bisretinoid formation. Given their origin from vitamin A aldehyde, an isomer of the visual pigment chromophore, it is not surprising that the bisretinoids of retina are light sensitive molecules. Accordingly, we will discuss recent findings that implicate the photodegradation of bisretinoid in the etiology of age-related macular degeneration.
Sparrow, Janet R.; Gregory-Roberts, Emily; Yamamoto, Kazunori; Blonska, Anna; Ghosh, Shanti Kaligotla; Ueda, Keiko; Zhou, Jilin
Chlorophyll pigment concentrations and proportions, nitrogen (N), and needle morphology traits, are important components of\\u000a growth and were examined in five hybrid index categories from controlled crosses of various crosstypes, ranging from pure\\u000a black spruce (BS) [Picea mariana (Mill.) B.S.P.] to pure red spruce (RS) (Picea rubens Sarg.) grown under controlled light and water environments. Black spruce had on average
Debby C. Barsi; John E. Major; Alex Mosseler; Moira Campbell
Ocimum tenuiflorum L. exposed to various concentrations of chromium (0.0, 10.0, 20.0, 50.0, 100.0?M) accumulated high amount of chromium in various plant parts in a concentration and duration dependent manner. Chromium induced lipid peroxidation coupled with potassium leakage. Toxic effects of chromium on O. tenuiflorum were reflected by the reductions in photosynthetic pigments, protein, cysteine, ascorbic acid and non-protein thiol
Vartika Rai; Poornima Vajpayee; Shri Nath Singh; Shanta Mehrotra
The rs1061170T/C variant encoding the Y402H change in complement factor H (CFH) has been identified by genome-wide association studies as being significantly associated with age-related macular degeneration (AMD). However, the precise mechanism by which this CFH variant impacts the risk of AMD remains largely unknown. Oxidative stress plays an important role in many aging diseases, including cardiovascular disease and AMD. A large amount of oxidized phospholipids (oxPLs) are generated in the eye because of sunlight exposure and high oxygen content. OxPLs bind to the retinal pigment epithelium and macrophages and strongly activate downstream inflammatory cascades. We hypothesize that CFH may impact the risk of AMD by modulating oxidative stress. Here we demonstrate that CFH binds to oxPLs. The CFH 402Y variant of the protective rs1061170 genotype binds oxPLs with a higher affinity and exhibits a stronger inhibitory effect on the binding of oxPLs to retinal pigment epithelium and macrophages. In addition, plasma from non-AMD subjects with the protective genotype has a lower level of systemic oxidative stress measured by oxPLs per apolipoprotein B (oxPLs/apoB). We also show that oxPL stimulation increases expression of genes involved in macrophage infiltration, inflammation, and neovascularization in the eye. OxPLs colocalize with CFH in drusen in the human AMD eye. Subretinal injection of oxPLs induces choroidal neovascularization in mice. In addition, we show that the CFH risk allele confers higher complement activation and cell lysis activity. Together, these findings suggest that CFH influences AMD risk by modulating oxidative stress, inflammation, and abnormal angiogenesis.
Shaw, Peter X.; Zhang, Li; Zhang, Ming; Du, Hongjun; Zhao, Ling; Lee, Clara; Grob, Seanna; Lim, Siok Lam; Hughes, Guy; Lee, Janet; Bedell, Matthew; Nelson, Mark H.; Lu, Fang; Krupa, Martin; Luo, Jing; Ouyang, Hong; Tu, Zhidan; Su, Zhiguang; Zhu, Jin; Wei, Xinran; Feng, Zishan; Duan, Yaou; Yang, Zhenglin; Ferreyra, Henry; Bartsch, Dirk-Uwe; Kozak, Igor; Zhang, Liangfang; Lin, Feng; Sun, Hui; Feng, Hong; Zhang, Kang
We studied retrospectively the clinical features of 18 eyes of 18 patients with traumatic macular hole. The macular hole was elliptical with irregular edges in 17 eyes (94%) and its size ranged from 1/5 to 1/2 of the disc diameter. Posterior vitreous detachment was found in 3 eyes (17%); the vitreous was detached from the macula in only one of these 3 eyes. Commotio retinae, vitreous hemorrhage, hyphema, or choroidal rupture was also found in several eyes. These findings suggest that traumatic macular hole develops usually in the absence of posterior vitreous detachment and its pathogenesis is independent of the occurrence of posterior vitreous detachment. We speculate that blunt trauma-induced deformity of the eyeball or impact on the posterior pole provides a mechanical cause for the macular rupture. PMID:7484503
Yanagiya, N; Akiba, J; Takahashi, M; Kakehashi, A; Kado, M; Yoshida, A
The clinical characteristics of 20 eyes of 20 consecutive patients with traumatic macular hole were studied retrospectively. The macular holes were elliptical with irregular edges in 19 eyes (95%) and ranged in size from 0.2 to 0.5 DD (disc diameter). Posterior vitreous detachment (PVD) was found in only 3 eyes (15%); the vitreous was detached from the macula in only one of these 3. Other conditions found in the 20 patients included commotio retinae, vitreous hemorrhage, hyphema, and choroidal rupture. These findings strongly suggest that most traumatic macular holes develop in the absence of PVD and that the pathogenesis is independent of the occurrence of PVD. We believe that the macular rupture (hole) is caused mechanically by the force of the impact on the posterior pole and the ocular deformity which result from blunt trauma. PMID:9130060
Yanagiya, N; Akiba, J; Takahashi, M; Shimizu, A; Kakehashi, A; Kado, M; Hikichi, T; Yoshida, A
... susceptibility gene for age-related macular degeneration. CD36 – Cluster of Differentiation 36 (CD36) is a “scavenger receptor,” ... your doctor if you notice vision changes. “Vision” Foods to Include in Your Diet Dark green, yellow, ...
Background: Macular translocation is a new treatment option in age-related maculopathy. The aim of this study was to report experience\\u000a with the handling of the sensory problems concerning subjective cyclorotation and binocularity that arise with this technique.\\u000a Methods: The data of 33 patients who had undergone macular translocation and counterrotation of the globe by muscle surgery in a first\\u000a operation,
Julia Fricke; Antje Neugebauer; Heike Nobis; Karl U. Bartz-Schmidt; W. Rüßmann
Purpose To find the gene(s) responsible for macular telangiectasia type 2 (MacTel) by a candidate-gene screening approach. Methods Candidate genes were selected based on the following criteria: those known to cause or be associated with diseases with phenotypes similar to MacTel, genes with known function in the retinal vasculature or macular pigment transport, genes that emerged from expression microarray data from mouse models designed to mimic MacTel phenotype characteristics, and genes expressed in the retina that are also related to diabetes or hypertension, which have increased prevalence in MacTel patients. Probands from eight families with at least two affected individuals were screened by direct sequencing of 27 candidate genes. Identified nonsynonymous variants were analyzed to determine whether they co-segregate with the disease in families. Allele frequencies were determined by TaqMan analysis of the large MacTel and control cohorts. Results We identified 23 nonsynonymous variants in 27 candidate genes in at least one proband. Of these, eight were known single nucleotide polymorphisms (SNPs) with allele frequencies of >0.05; these variants were excluded from further analyses. Three previously unidentified missense variants, three missense variants with reported disease association, and five rare variants were analyzed for segregation and/or allele frequencies. No variant fulfilled the criteria of being causal for MacTel. A missense mutation, p.Pro33Ser in frizzled homolog (Drosophila) 4 (FZD4), previously suggested as a disease-causing variant in familial exudative vitreoretinopathy, was determined to be a rare benign polymorphism. Conclusions We have ruled out the exons and flanking intronic regions in 27 candidate genes as harboring causal mutations for MacTel.
Parmalee, Nancy L.; Schubert, Carl; Merriam, Joanna E.; Allikmets, Kaija; Bird, Alan C.; Gillies, Mark C.; Peto, Tunde; Figueroa, Maria; Friedlander, Martin; Fruttiger, Marcus; Greenwood, John; Moss, Stephen E.; Smith, Lois E.H.; Toomes, Carmel; Inglehearn, Chris F.
Brucellosis is a significant health problem especially in developing countries as Turkey. Skeletal system involvement is relatively a common complication of human brucellosis, however genitourinary, cardiovascular, neurovascular and skin involvements are less frequent. In this case report, a 36-years-old female patient with fever, arthralgia, disseminated macular rash at the extremities and body and peripheral polineuropathy has been presented. The patient, living at a rural area, had a history of consumption of raw milk products. Polyneuropathy of the patient presenting as glove-sock type paresthesia was evaluated with electromyography and reported as mild demyelinated sensorial polyneuropathy and radiculopathy compatible with right L(4-5) involvement. Brucella agglutination test was found to be positive at a titer of 1/1280 in the serum sample. Other bacterial and viral agents presenting with maculopapular rash were ruled out by serological tests. Bacterial growth was detected in the blood culture by automated BacT/ALERT 3D system (bioMerieux, USA) and the bacteria was identified as Brucella melitensis by automated VITEK-2 system (bioMerieux, France). Microbiologic diagnosis was confirmed by detection of agglutination with polyvalent and monovalent anti-M Brucella sera. The patient was successfully treated with rifampicin and doxycycline combination for six weeks. The macular rash was recruited leaving a brown pigmentation in the first week of treatment, whereas the neurologic signs and symptoms disappeared at the end of the first month. Brucella infection should be considered in the differential diagnosis of skin rash and neurologic disorders especially in endemic areas such as Turkey. PMID:19334392
Kaya, Selçuk; Kostako?lu, U?ur
BackgroundAge-related macular degeneration (AMD) is the leading cause of legal blindness in the elderly population. Debris (termed drusen) below the retinal pigment epithelium (RPE) have been recognized as a risk factor for dry AMD and its progression to wet AMD, which is characterized by choroidal neovascularization (CNV). The underlying mechanism of how drusen might elicit CNV remains undefined. Cigarette smoking,
Marianne Pons; Maria E. Marin-Castańo; Carlo Gaetano
Stem cell regeneration of damaged tissue has recently been reported in many different organs. Since the loss of retinal pigment epithelium (RPE) in the eye is associated with a major cause of visual loss – specifically, age-related macular degeneration – we investigated whether hematopoietic stem cells (HSC) given systemically can home to the damaged subretinal space and express markers of
Pelin Atmaca-Sonmez; Yang Li; Yasuyuki Yamauchi; Carrie L. Schanie; Suzanne T. Ildstad; Henry J. Kaplan; Volker Enzmann
Ophthalmic fundus imaging plays an important role in the advances in the pathophysiology of retinal diseases. Using fundus imaging, we studied morphological changes in the choroid, subretinal pathophysiology and photoreceptor and retinal pigment epithelial (RPE) cell damage, and functional abnormalities of photoreceptor cells in macular diseases. To evaluate the choroidal changes, we performed enhanced depth imaging optical coherence tomography (EDI-OCT) for macular diseases. Choroidal thickness both in the affected eyes and in the fellow eyes with choroidal vascular hyperpermeability was thicker in patients with central serous chorioretinopathy (CSC). Photodynamic therapy (PDT) reduced the hyperpermeability and led to choroidal thinning in eyes with CSC, whereas laser photocoagulation did not result in any change in choroidal thickness, suggesting different mechanism of action for these two forms of treatment. PDT also decreased choroidal thickness in eyes with polypoidal choroidal vasculopathy. These findings will help to elucidate the pathophysiologic features of CSC as well as responses to treatment. Patients with acute Vogt-Koyanagi-Harada (VKH) disease have markedly thickened choroids. Both the choroidal thickness and the retinal detachment in these patients decreased quickly with corticosteroid treatment. EDI-OCT can be used to evaluate the choroidal involvement in VKH disease in acute stages and may prove useful in the diagnosis and management of this disease. Dome-shaped macula is the result of a localized thickening of the sclera under the macula in highly myopic patients, and it cannot be categorized into any known type of staphyloma. EDI-OCT is helpful in monitoring the proposed site of pathophysiologic changes in the choroid and the sclera, and provides noninvasively information not available by other means. To clarify the subretinal changes and the mechanism of cell damage in macular detachment, we studied the clinical characteristics of yellow deposits (multiple dot-like yellow precipitates and subretinal yellow material) seen in CSC using fundus autofluorescence and OCT. The yellow deposits had highly reflective tissue in the intraretinal and subretinal spaces seen on OCT and hyperfluorescence on short-wave autofluorescence (SW-AF) examinations during the follow-up period. These findings may indicate that formations of yellow deposits are associated with the accumulation of the photoreceptor outer segments and metabolism and phagocytosis by macrophages or RPE cells. SW-AF also demonstrated a hypofluorescence corresponding to the accumulated areas of yellow deposits during the long term followup period. Another study using infrared autofluorescence examination demonstrated that the yellow deposits induced a decrease in melanin and the functional decline of RPE cells in CSC. These may indicate that the existence of depositions in eyes with CSC is associated with photoreceptor and RPE cells damage. Similar yellow deposits can also be seen in eyes with macular detachment, e. g. branch retinal vein occlusion. We report a new method of retinal densitometry using SW-AF examination by scanning laser ophthalmoscope. We named the technique autofluorescence densitometry (AFD). This technique can evaluate photopigment density from serial SW-AF images during exposure to excitation light. This new technique can examine a much broader macular area and create a distribution map of optical density of the photopigments. It is also easy to compare the distribution of the photopigment densities with other retinal imaging devices such as OCT. To investigate functional abnormalities in eyes with CSC, we measured the optical density of the photopigments using AFD in both the acute and quiescent phase. The photopigment density decreased at the serous retinal detachment. The density remained decreased immediately after resolution and showed delayed recovery. The photopigments decreased even in eyes with a morphologic recovery of the outer retina. AFD could identify the functional impairment of the outer retina as characterized by
Background Congenital macular coloboma is a rare ocular disease that consists of atrophic lesions in the macula with well-circumscribed borders. We report the findings of spectral domain optical coherence tomography (SD-OCT) at the fixation point in a case of bilateral macular coloboma. Case report The subject is a 4-year-old boy. He visited our hospital at age 1 year and 4 months for the evaluation of strabismus. The fundus examination of both eyes showed round-shaped sharply-demarcated atrophic lesions involving the macula with large choroidal vessels and bared sclera at the base. Immunologic tests including toxoplasmosis, rubella, varicella, herpes virus, and human T-cell leukemia virus were all negative. At age 4 years and 1 month, cycloplegic refraction showed insignificant refractive errors and his best corrected visual acuity was 0.6 bilaterally. The SD-OCT showed a crater-like depression accompanying atrophic neurosensory retina, and the absence of retinal pigment epithelium and choroid. Examination of the fixation behavior by visuscope showed steady fixation with an area 0.5° nasal to the nasal edge of the atrophic lesion bilaterally. The SD-OCT findings at fixation area showed remaining normal retinal structures involving inner segment-outer segment (IS/OS) junction line. Conclusion The findings of SD-OCT have been shown to be useful in the diagnosis of macular coloboma. In the fixation point, the structure of retina and choroid were well preserved.
Abe, Kosuke; Shirane, Jumi; Sakamoto, Masuo; Tanabe, Fumi; Kuniyoshi, Kazuki; Matsumoto, Chota; Shimomura, Yoshikazu
Pigment epithelium-derived factor is well known as a secreted glycoprotein with multiple functions, such as anti-angiogenic, neuroprotective and anti-tumor activities. However, its intracellular role remains unknown. The present study was performed to demonstrate the intracellular function of pigment epithelium-derived factor on triglyceride degradation. Hepatic pigment epithelium-derived factor levels increased at the early stage and subsequently decreased after 16 weeks in high-fat-diet-fed mice compared to those in chow-fed mice. Similarly, oleic acid led to long-term downregulation of pigment epithelium-derived factor in HepG2 cells. Endogenous pigment epithelium-derived factor was an intracellular protein with cytoplasmic distribution in hepatocytes by immunostaining. Exogenous FITC-labeled pigment epithelium-derived factor could be absorbed into hepatocytes. Both signal peptide deletion and full-length pigment epithelium-derived factor transfection HeLa cells and hepatocytes promoted triglyceride degradation. Intracellular pigment epithelium-derived factor co-immunoprecipitated with adipose triglyceride lipase and promoted triglyceride degradation in an adipose triglyceride lipase-dependent manner. Additionally, pigment epithelium-derived factor bound to the C-terminal of adipose triglyceride lipase (aa268-504) and adipose triglyceride lipase-G0/G1 switch gene-2 complex simultaneously, which facilitated adipose triglyceride lipase-G0/G1 switch gene-2 translocation onto lipid droplet using bimolecular fluorescence complementation assay. Moreover, knockdown of endogenous pigment epithelium-derived factor in hepatocytes diminished triglyceride degradation. Taken together, these results indicate that hepatic pigment epithelium-derived factor was decreased in obese mice accompanied with hepatic steatosis. Intracellular pigment epithelium-derived factor binds to and facilitates adipose triglyceride lipase translocation onto lipid droplet, which promotes triglyceride degradation. These findings suggest that a decreased level of hepatic pigment epithelium-derived factor may contribute to hepatic steatosis in obesity. PMID:23886488
Dai, Zhiyu; Zhou, Ti; Li, Cen; Qi, Weiwei; Mao, Yuling; Lu, Juling; Yao, Yachao; Li, Lei; Zhang, Ting; Hong, Honghai; Li, Shuai; Cai, Weibin; Yang, Zhonghan; Ma, Jianxing; Yang, Xia; Gao, Guoquan
Purpose: To assess visual and anatomical outcomes following the surgical removal of subfoveal choroidal neovascular membranes (CNVMs) in older patients without clinical evidence of diffuse disease of the retinal pigment epithelium (RPE). Methods: We retrospectively reviewed records of consecutive patients aged 50 years or older who underwent surgical removal of subfoveal CNVMs. Patients with clinical evidence for age-related macular degeneration (AMD) (>5 small drusen), angioid streaks, and myopic degeneration were excluded. Results: Twenty-two patients (8 women) ranged in age from 50 to 85 years (median, 67 years). All membranes were 100% classic, with a mean size of 2.5 MPS disc areas (range, 1 to 6.5). Best postoperative visual acuity (VA), measured a median 12.5 weeks after surgery, improved (>3 Snellen lines) in 10 eyes (45%) and worsened in 0 eyes, with 8 eyes (36%) achieving 20/50 or better. Over a mean follow-up of 37 months (range, 6 to 114 months), CNVM recurrence was seen in 13 eyes (59%), causing loss of VA from best postoperative levels in 5 eyes (23%). On final follow-up, 4 eyes (18%) retained acuity of 20/50 or better, 12 eyes (55%) had disciform scarring, and 5 eyes (23%) had geographic atrophy. Improvement in best postoperative VA occurred in a higher percentage of eyes with focal (58%) compared with idiopathic (30%) disease, but this trend was not statistically significant (p = 0.23, Fisher’s exact test). Conclusions: Surgical removal of subfoveal CNVMs may result in substantial visual improvement in older patients without other clinical evidence for AMD, particularly in eyes with focal diseases of the RPE-Bruch’s membrane complex.
Wu, Rebecca A; Best, Richard M; Musch, David C; Johnson, Mark W
Abstract Age-related macular degeneration (AMD) is the leading cause of permanent, irreversible, central blindness (scotoma in the central visual field that makes reading and writing impossible, stereoscopic vision, recognition of colors and details) in patients over the age of 50 years in European and North America countries, and an important role is attributed to disorders in the regulation of the extracellular matrix (ECM). The main aim of this article is to present the crucial processes that occur on the level of Bruch's membrane, with special consideration of the metalloproteinase substrates, metalloproteinase, and tissue inhibitor of metalloproteinase (TIMP). A comprehensive review of the literature was performed through MEDLINE and PubMed searches, covering the years 2005-2012, using the following keywords: AMD, extracellular matrix, metalloproteinases, tissue inhibitors of metalloproteinases, Bruch's membrane, collagen, elastin. In the pathogenesis of AMD, a significant role is played by collagen type I and type IV; elastin; fibulin-3, -5, and -6; matrix metalloproteinase (MMP)-2, MMP-9, MMP-14, and MMP-1; and TIMP-3. Other important mechanisms include: ARMS2 and HTR1 proteins, the complement system, the urokinase plasminogen activator system, and pro-renin receptor activation. Continuous rebuilding of the extracellular matrix occurs in both early and advanced AMD, simultaneously with the dysfunction of retinal pigment epithelium (RPE) cells and endothelial cells. The pathological degradation or accumulation of ECM structural components are caused by impairment or hyperactivity of specific MMPs/TIMPs complexes, and is also endangered by the influence of other mechanisms connected with both genetic and environmental factors. PMID:24938626
Nita, Ma?gorzata; Strza?ka-Mrozik, Barbara; Grzybowski, Andrzej; Mazurek, Urszula; Romaniuk, Wanda
Age-related macular degeneration (AMD) is the leading cause of permanent, irreversible, central blindness (scotoma in the central visual field that makes reading and writing impossible, stereoscopic vision, recognition of colors and details) in patients over the age of 50 years in European and North America countries, and an important role is attributed to disorders in the regulation of the extracellular matrix (ECM). The main aim of this article is to present the crucial processes that occur on the level of Bruch’s membrane, with special consideration of the metalloproteinase substrates, metalloproteinase, and tissue inhibitor of metalloproteinase (TIMP). A comprehensive review of the literature was performed through MEDLINE and PubMed searches, covering the years 2005–2012, using the following keywords: AMD, extracellular matrix, metalloproteinases, tissue inhibitors of metalloproteinases, Bruch’s membrane, collagen, elastin. In the pathogenesis of AMD, a significant role is played by collagen type I and type IV; elastin; fibulin-3, -5, and -6; matrix metalloproteinase (MMP)-2, MMP-9, MMP-14, and MMP-1; and TIMP-3. Other important mechanisms include: ARMS2 and HTR1 proteins, the complement system, the urokinase plasminogen activator system, and pro-renin receptor activation. Continuous rebuilding of the extracellular matrix occurs in both early and advanced AMD, simultaneously with the dysfunction of retinal pigment epithelium (RPE) cells and endothelial cells. The pathological degradation or accumulation of ECM structural components are caused by impairment or hyperactivity of specific MMPs/TIMPs complexes, and is also endangered by the influence of other mechanisms connected with both genetic and environmental factors.
Nita, Malgorzata; Strzalka-Mrozik, Barbara; Grzybowski, Andrzej; Mazurek, Urszula; Romaniuk, Wanda
The classification and, therefore, identification of Chromobacterium violaceum has been based upon its ability to produce a violet pigment. Although the organism may yield non-pigmented variants when subcultured on artificial media, the isolation of non-pigmented strains from pathological tissues or from nature had not been reported. With a method established for the identification of C. violaceum regardless of violet pigmentation, non-pigmented strains were isolated from nature. The presence of non-pigmented strains of C. violaceum in nature is of significance to taxonomy and clinical bacteriology. Pigmentation cannot be held as an essential characteristic of the definition of the genus Chromobacterium and gives credence to the suspicion of Sneath (1960, 1966) that the genus is not a natural one. Non-pigmented strains may have been isolated from clinical material but wrongly identified as belonging to other genera of non-pigmented Gram-negative bacilli and regarded as not being pathogenic. PMID:1236933
Sivendra, R; Lo, H S
Macular degeneration is a heterogeneous group of disorders characterized by photoreceptor degeneration and atrophy of the retinal pigment epithelium (RPE) in the central retina. An autosomal dominant form of Stargardt macular degeneration (STGD) is caused by mutations in ELOVL4, which is predicted to encode an enzyme involved in the elongation of long-chain fatty acids. We generated transgenic mice expressing a mutant form of human ELOVL4 that causes STGD. In these mice, we show that accumulation by the RPE of undigested phagosomes and lipofuscin, including the fluorophore, 2-[2,6-dimethyl-8-(2,6,6-trimethyl-1-cyclohexen-1-yl)-1E,3E,5E,7E-octatetraenyl]-1-(2-hyydroxyethyl)-4-[4-methyl-6-(2,6,6,-trimethyl-1-cyclohexen-1-yl)-1E,3E,5E-hexatrienyl]-pyridinium (A2E) is followed by RPE atrophy. Subsequently, photoreceptor degeneration occurs in the central retina in a pattern closely resembling that of human STGD and age-related macular degeneration. The ELOVL4 transgenic mice thus provide a good model for both STGD and dry age-related macular degeneration, and represent a valuable tool for studies on therapeutic intervention in these forms of blindness.
Karan, G.; Lillo, C.; Yang, Z.; Cameron, D. J.; Locke, K. G.; Zhao, Y.; Thirumalaichary, S.; Li, C.; Birch, D. G.; Vollmer-Snarr, H. R.; Williams, D. S.; Zhang, K.
Age-related macular degeneration, a neurodegenerative and vascular retinal disease, is the most common cause of blindness in the Western countries. Evidence accumulates that target of rapamycin is involved in aging and age-related diseases, including neurodegeneration. The target of rapamycin inhibitor, rapamycin, suppresses the senescent cell phenotype and extends life span in diverse species, including mice. Rapamycin decreases senescence-associated phenotypes in retinal pigment epithelial cells in culture. Herein, we investigated the effect of rapamycin on spontaneous retinopathy in senescence-accelerated OXYS rats, an animal model of age-related macular degeneration. Rats were treated with either 0.1 or 0.5 mg/kg rapamycin, which was given orally as a food mixture. In a dose-dependent manner, rapamycin decreased the incidence and severity of retinopathy. Rapamycin improved some (but not all) histological abnormalities associated with retinopathy. Thus, in retinal pigment epithelial cell layers, rapamycin decreased nuclei heterogeneity and normalized intervals between nuclei. In photoreceptor cells, associated neurons, and radial glial cells, rapamycin prevented nuclear and cellular pyknosis. More important, rapamycin prevented destruction of ganglionar neurons in the retina. Rapamycin did not exert any adverse effects on the retina in control disease-free Wistar rats. Taken together, our data suggest the therapeutic potential of rapamycin for treatment and prevention of retinopathy. PMID:22683466
Kolosova, Nataliya G; Muraleva, Natalia A; Zhdankina, Anna A; Stefanova, Natalia A; Fursova, Anzhela Z; Blagosklonny, Mikhail V
... us Macular Degeneration Questions to Discuss with Your Doctor: Have you noticed a change in vision in ... have a family history of macular degeneration? Your Doctor Might Examine the Following Body Structures or Functions: ...
Age-related macular degeneration (AMD) is a major cause of vision loss. It is associated with development of characteristic plaque-like deposits (soft drusen) in Bruch's membrane basal to the retinal pigment epithelium (RPE). A sequence variant (Y402H) in short consensus repeat domain 7 (SCR7) of complement factor H (CFH) is associated with risk for "dry" AMD. We asked whether the eye-targeting of this disease might be related to specific interactions of CFH SCR7 with proteins expressed in the aging human RPE/choroid that could contribute to protein deposition in drusen. Yeast 2-hybrid (Y2H) screens of a retinal pigment epithelium/choroid library derived from aged donors using CFH SCR7 baits detected an interaction with EFEMP1/Fibulin 3 (Fib3), which is the locus for an inherited macular degeneration and also accumulates basal to macular RPE in AMD. The CFH/Fib3 interaction was validated by co-immunoprecipitation of native proteins. Quantitative Y2H and ELISA assays with different recombinant protein constructs both demonstrated higher affinity for Fib3 for the disease-related CFH 402H variant. Immuno-labeling revealed colocalization of CFH and Fib3 in globular deposits within cholesterol-rich domains in soft drusen in two AMD donors homozygous for CFH 402H (H/H). This pattern of labeling was quite distinct from those seen in examples of eyes with Y/Y and H/Y genotypes. The CFH 402H/Fib3 interaction could contribute to the development of pathological aggregates in soft drusen in some patients and as such might provide a target for therapeutic intervention in some forms of AMD. PMID:23840815
Wyatt, M Keith; Tsai, Jen-Yue; Mishra, Sanghamitra; Campos, Maria; Jaworski, Cynthia; Fariss, Robert N; Bernstein, Steven L; Wistow, Graeme
Age-related macular degeneration (AMD) is a major health problem in the developed world accounting for approximately half of all blind registrations. Current treatment options are unsuitable for the majority of patients and therefore the identification of modifiable risk factors that may inform disease prevention programmes is a priority. This review evaluates the long-held belief that blue light exposure has a role in the pathogenesis of AMD. Laboratory evidence has demonstrated that photochemical reactions in the oxygen-rich environment of the outer retina lead to the liberation of cytotoxic reactive oxygen species (ROS). These ROS cause oxidative stress which is known to contribute to the development of AMD. The precise chromopore that may be involved in the pathogenesis of AMD is unclear but the age pigment lipofuscin is a likely candidate. Its aerobic photoreactivity and adverse effects on antioxidant activity combined with its gradual accumulation over time suggests that its in vivo phototoxicity increases with age despite changes in the absorption characteristics of the crystalline lens. Evidence from animal studies confirms blue light's damaging potential but the results are not directly applicable to macular degeneration in humans. Studies of human macular pigment density and the risk of AMD progression following cataract surgery lend further weight to the hypothesis that blue light exposure has a role in the pathogenesis of AMD but the epidemiological evidence is equivocal. On balance the evidences suggests but does not yet confirm that blue light is a risk factor for AMD. Given the socio-economic impact of this disease and urgent need to identify modifiable risk factors, future work should include a large-scale clinical trial to evaluate the effect of blue blocking filters on AMD progression rates. PMID:15302349
Margrain, T H; Boulton, M; Marshall, J; Sliney, D H
Age-related macular degeneration (ARMD) is the leading cause of blindness in the developed world and yet its pathogenesis remains poorly understood. Retina has high levels of polyunsaturated fatty acids (PUFAs) and functions under conditions of oxidative stress. To investigate whether peroxidative products of PUFAs induce apoptosis in retinal pigmented epithelial (RPE) cells and possibly contribute to ARMD, human retinal pigmented epithelial cells (ARPE-19) were exposed to micromolar concentrations of H2O2, 4-hydroxynonenal (HNE) and 4-hydroxyhexenal (HHE). A concentration- and time-dependent increase in H2O2-, HNE-, and HHE-induced apoptosis was observed when monitored by quantifying DNA fragmentation as determined by ELISA, flow cytometry, and Hoechst staining. The broad-spectrum inhibitor of apoptosis Z-VAD inhibited apoptosis. Treatment of RPE cells with a thionein peptide prior to exposure to H2O2 or HNE reduced the formation of protein-HNE adducts as well as alteration in mitochondrial membrane potential and apoptosis. Using 3H-HNE, various metabolic pathways to detoxify HNE by ARPE-19 cells were studied. The metabolites were separated by HPLC and characterized by ElectroSpray Ionization-Mass Spectrometry (ESI-MS) and gas chromatography-MS. Three main metabolic routes of HNE detoxification were detected: (1) conjugation with glutathione (GSH) to form GS-HNE, catalyzed by glutathione-S-transferase (GST), (2) reduction of GS-HNE catalyzed by aldose reductase, and (3) oxidation of HNE catalyzed by aldehyde dehydrogenase (ALDH). Preventing HNE formation by a combined strategy of antioxidants, scavenging HNE by thionein peptide, and inhibiting apoptosis by caspase inhibitors may offer a potential therapy to limit retinal degeneration in ARMD. PMID:15808518
Choudhary, S; Xiao, T; Srivastava, S; Zhang, W; Chan, L L; Vergara, L A; Van Kuijk, F J G M; Ansari, N H
PURPOSE: To describe the incidence and characteristics of iatrogenic retinal breaks in 25-gauge macular surgery. DESIGN: Retrospective, noncomparative, interventional case series. METHODS: We included 177 consecutive operations in 171 patients who underwent 25,gauge vitrectomy for idiopathic macular pucker or idiopathic macular hole. Main outcome measures were the incidence of breaks related to the sclerotomies, the incidence of breaks occurring elsewhere,
H. Stevie Tan; Marco Mura; Marc D. de Smet
A patient underwent successful vitrectomy for macular epiretinal membrane with anatomical and functional improvement. 10 weeks later, there was a recurrence of macular edema with corresponding visual decline. An intravitreal injection of triamcinolone acetonide not only restored the macular anatomy but also improved the visual outcome beyond that achieved after surgery.
We determined whether there is an association between complement factor H (CFH), high-temperature requirement A-1 (HTRA1),\\u000a vascular endothelial growth factor (VEGF), and pigment epithelium-derived factor (PEDF) genotypes and the response to treatment\\u000a with a single intravitreous injection of bevacizumab for age-related macular degeneration (AMD). Eighty-three patients with\\u000a exudative AMD treated by bevacizumab injection were genotyped for three single nucleotide polymorphisms
Daisuke Imai; Keisuke Mori; Kuniko Horie-Inoue; Peter L. Gehlbach; Takuya Awata; Satoshi Inoue; Shin Yoneya
Zinc (Zn) is abundantly enriched in sub-retinal pigment epithelial (RPE) deposits, the hallmarks of age-related macular degeneration (AMD), and is thought to play a role in the formation of these deposits. However, it is not known whether Zn is the only metal relevant for sub-RPE deposit formation. Because of their involvement in the pathogenesis of AMD, we determined the concentration and distribution of calcium (Ca), iron (Fe) and copper (Cu) and compared these with Zn in isolated and sectioned macular (MSD), equatorial (PHD) and far peripheral (FPD) sub-RPE deposits from an 86 year old donor eye with post mortem diagnosis of early AMD. The sections were mounted on Zn free microscopy slides and analyzed by microprobe synchrotron X-ray fluorescence (?SXRF). Metal concentrations were determined using spiked sectioned sheep brain matrix standards, prepared the same way as the samples. The heterogeneity of metal distributions was examined using pixel by pixel comparison. The orders of metal concentrations were Ca ? Zn > Fe in all three types of deposits but Cu levels were not distinguishable from background values. Zinc and Ca were consistently present in all deposits but reached highest concentration in MSD. Iron was present in some but not all deposits and was especially enriched in FPD. Correlation analysis indicated considerable variation in metal distribution within and between sub-RPE deposits. The results suggest that Zn and Ca are the most likely contributors to deposit formation especially in MSD, the characteristic risk factor for the development of AMD in the human eye. PMID:24740686
Flinn, Jane M; Kakalec, Peter; Tappero, Ryan; Jones, Blair; Lengyel, Imre
The largest isoform of the Shc adapter protein, p66Shc, has been implicated in oxidative damage-induced apoptosis in vital organs, because mice deficient in p66Shc have a 30% increase in life span and are resistant to the lethal effects of systemically administered paraquat, a source of severe oxidative damage. In this study, we utilized siRNA directed against the CH2 domain of Shc, to reduce p66Shc, but not p52Shc nor p46Shc in retinal pigmented epithelial (RPE) cells. RPE cells deficient in p66Shc had reduced susceptibility to oxidative stress-induced apoptosis. Compared to control cells, those with reduced p66Shc had increased basal and oxidative stress-induced NF-kappaB transcriptional activity, increased levels of antioxidant enzymes, and less generation of reactive oxygen species when challenged with H(2)O(2). The increase in oxidative stress-induced NF-kappaB activity was mediated by activation of ERK. Compared to eyes injected with GFP siRNA, those injected with p66Shc siRNA showed less loss of retinal function as assessed by electroretinograms from paraquat-induced oxidative stress. These data suggest that p66Shc and molecular signals involved in its regulation provide therapeutic targets for retinal degenerations in which oxidative-damage plays a major role, including age-related macular degeneration and cone cell death in retinitis pigmentosa. PMID:16972253
Wu, Zhihao; Rogers, Brian; Kachi, Shu; Hackett, Sean F; Sick, Anna; Campochiaro, Peter A
Oxidative stress in the retinal pigment epithelium (RPE) is hypothesized to be a major contributor to the development of age-related macular degeneration (AMD). Mitochondrial manganese superoxide dismutase (MnSOD) is a critical antioxidant protein that scavenges the highly reactive superoxide radical. We speculated that specific reduction of MnSOD in the RPE will increase the level of reactive oxygen species in the retina/RPE/choroid complex leading to pathogenesis similar to geographic atrophy. To test this hypothesis, an Sod2-specific hammerhead ribozyme (Rz), delivered by AAV2/1 and driven by the human VMD2 promoter was injected subretinally into C57BL/6J mice. Dark-adapted full field electroretinogram (ERG) detected a decrease in the response to light. We investigated the age-dependent phenotypic and morphological changes of the outer retina using digital fundus imaging and SD-OCT measurement of ONL thickness. Fundus microscopy revealed pigmentary abnormalities in the retina and these corresponded to sub-retinal and sub-RPE deposits seen in SD-OCT B-scans. Light and electron microscopy documented the localization of apical deposits and thickening of the RPE. In RPE flat-mounts we observed abnormally displaced nuclei and regions of apparent fibrosis in the central retina of the oldest mice. This region was surrounded by enlarged and irregular RPE cells that have been observed in eyes donated by AMD patients and in other mouse models of AMD. PMID:22687918
Seo, Soo-jung; Krebs, Mark P; Mao, Haoyu; Jones, Kyle; Conners, Mandy; Lewin, Alfred S
Oxidative stress in the retinal pigment epithelium (RPE) is hypothesized to be a major contributor to the development of age-related macular degeneration (AMD). Mitochondrial manganese superoxide dismutase (MnSOD) is a critical antioxidant protein that scavenges the highly reactive superoxide radical. We speculated that specific reduction of MnSOD in the RPE will increase the level of reactive oxygen species in the retina/RPE/choroid complex leading to pathogenesis similar to geographic atrophy. To test this hypothesis, an Sod2-specific hammerhead ribozyme (Rz), delivered by AAV2/1 and driven by the human VMD2 promoter was injected subretinally into C57BL/6J mice. Dark-adapted full field electroretinogram (ERG) detected a decrease in the response to light. We investigated the age-dependent phenotypic and morphological changes of the outer retina digital fundus imaging and SD-OCT measurement of ONL thickness. Fundus microscopy revealed pigmentary abnormalities in the retina and these corresponded to sub-retinal and sub-RPE deposits seen in SD-OCT B-scans. Light and electron microscopy documented the localization of apical deposits and thickening of the RPE. In RPE flat-mounts we observed abnormally displaced nuclei and regions of apparent fibrosis in the central retina of the oldest mice. This region was surrounded by enlarged and irregular RPE cells that have been observed in eyes donated by AMD patients and in other mouse models of AMD.
Seo, Soo-jung; Krebs, Mark P.; Mao, Haoyu; Jones, Kyle; Conners, Mandy; Lewin, Alfred S.
Purpose. The retinal pigment epithelium (RPE) separates photoreceptors from choroidal capillaries, but in age-related macular degeneration (AMD) capillaries breach the RPE barrier. Little is known about human RPE tight junctions or the effects of serum on the retinal side of the RPE. Methods. Cultured human fetal RPE (hfRPE) was assessed by the transepithelial electrical resistance (TER) and the transepithelial diffusion of methylated polyethylene glycol (mPEG). Claudins and occludin were monitored by quantitative RT-PCR, immunoblotting, and immunofluorescence. Results. Similar to freshly isolated hfRPE, claudin-19 mRNA was 25 times more abundant than claudin-3. Other detectable claudin mRNAs were found in even lesser amounts, as little as 3000 times less abundant than claudin-19. Claudin-1 and claudin-10b were detected only in subpopulations of cells, whereas others were undetectable. Knockdown of claudin-19 by small interfering RNA (siRNA) eliminated the TER. siRNAs for other claudins had minimal effects. Serum affected tight junctions only when presented to the retinal side of the RPE. The TER increased 2 times, and the conductance of K+ relative to Na+ decreased without affecting the permeability of mPEG. These effects correlated with increased steady-state levels of occludin. Conclusions. Fetal human RPE is a claudin-19–dominant epithelium that has regional variations in claudin-expression. Apical serum decreases RPE permeability, which might be a defense mechanism that would retard the spread of edema due to AMD.
Peng, Shaomin; Rao, Veena S.; Adelman, Ron A.
Some forms of blinding macular disease are associated with excessive accumulation of bisretinoid lipofuscin in retinal pigment epithelial (RPE) cells of the eye. This material is refractory to lysosomal enzyme degradation. In addition to gene and drug-based therapies, treatments that reverse the accumulation of bisretinoid would be beneficial. Thus, we have examined the feasibility of degrading the bisretinoids by delivery of exogenous enzyme. As proof of principle we report that horseradish peroxidase (HRP) can cleave the RPE bisretinoid A2E. In both cell-free and cell-based assays, A2E levels were decreased in the presence of HRP. HRP-associated cleavage products were detected by ultraperformance liquid chromatography (UPLC) coupled to electrospray ionization mass spectrometry, and the structures of the aldehyde-bearing cleavage products were elucidated by 18O-labeling and 1H NMR spectroscopy and by recording UV-vis absorbance spectra. These findings indicate that RPE bisretinoids such as A2E can be degraded by appropriate enzyme activities.
Wu, Yalin; Zhou, Jilin; Fishkin, Nathan; Rittmann, Bruce E.; Sparrow, Janet R.
Objective: To determine the percent of cases with all pri- mary forms of exudative age-related macular degenera- tion that are eligible for treatment by the Macular Photo- coagulation Study (MPS) guidelines in a retina clinic serving both as a primary care center and as a referral center. Design: Fluorescein angiograms of patients with age- related macular degeneration examined at the
Joseph Moisseiev; Amir Alhalel; Ronen Masuri; Giora Treister
The many factors involved in the normal pigmentation of human skin are highly complex involving anatomic, biochemical, and genetic aspects of melanocytes in the skin and the influence of UV light and various hormones on the melanocytes. It is probably more than just coincidence that the melanocytes, which are of neurogenic origin, are so responsive to several trophic hormones produced in the brain. Understanding of the various factors involved in the normal pigmentary process is crucial to explaining the many alterations and anomalies in human pigmentation.
The treatment of diabetic macular edema is rapidly evolving. The era of laser therapy is being quickly replaced by an era of pharmacotherapy. Several pharmacotherapies have been recently developed for the treatment of retinal vascular diseases such as diabetic macular edema. Several intravitreal injections or sustained delivery devices have undergone phase 3 testing while others are currently being evaluated. The results of clinical trials have shown the superiority of some of these agents to laser therapy. However, with the availability of several of these newer agents, it may be difficult to individualize treatment options especially those patients respond differently to various therapies. As such, more effort is still needed in order to determine the best treatment regimen for a given patient. In this article, we briefly summarize the major new therapeutic additions for the treatment of diabetic macular edema and allude to some future promising therapies. PMID:24379924
Shamsi, Hanan N Al; Masaud, Jluwi S; Ghazi, Nicola G
AIMS/BACKGROUND--The aim of this study was to evaluate whether grid laser photocoagulation of the macula is beneficial in the treatment of cystoid macular oedema in patients with uveitis. METHODS--Six eyes of five patients with long standing cystoid macular oedema due to chronic uveitis were treated by grid laser photocoagulation of the macula. RESULTS--In the first weeks after treatment a temporary increase of oedema and paracentral scotomas were observed. At the long term follow up of more than 18 months in all patients, macular oedema had been reduced significantly or disappeared in all eyes treated. One eye had a significant increase in Snellen acuity, three eyes more or less stabilised, and two eyes deteriorated. CONCLUSION--The beneficial effect of laser treatment on visual acuity in patients with uveitis might be more favourable if performed at an earlier stage of the disease. Images
Suttorp-Schulten, M S; Feron, E; Postema, F; Kijlstra, A; Rothova, A
The method for extracting and separating hydrophobic photosynthetic pigments proposed by Katayama "et al." ("Japanese Journal of Phycology," 42, 71-77, 1994) has been improved to introduce it to student laboratories at the senior high school level. Silica gel powder was used for removing water from fresh materials prior to extracting pigments by a…
Katayama, Nobuyasu; Kanaizuka, Yasuhiro; Sudarmi, Rini; Yokohama, Yasutsugu
The scanning laser ophthalmoscope provided a high quality television image of the fundus with minimal illumination of the retina. This new device based on a totally new electro-optical principle allowed a detailed exploration of macular function directly under simultaneous fundus control. The focused beam of a yellow krypton laser (568,2 nm) was swept up and down, rights and links across the fundus to form a raster of parallel lines on the retina. The S.L.O. illuminated only a single retinal point at a time and illumination was reduced to less than 70 microw/cm2 versus 100,000 microns/cm2 for indirect ophthalmoscopy and 4,000,000 microw/cm2 for fluorescein angiography. The intensity of the laser beam could be modified with the microcomputer by means of an acousto-optic modulator. It was possible to produce static or dynamic graphic designs that were simultaneously viewed by the patient and observed by the examiner on the patient's fundus on the video monitor. Further computerized analysis of the videotaped scanning laser ophthalmoscopic images gave a functional retinal map with correction for shifts of stimulus position due to fixational saccadic eye movements. The map showed true retinal location of 1. fixation area; 2. scotoma. The clinical evaluation was completed with 3. measurement of visual acuity in any foveal or parafoveal location. The results of scanning laser ophthalmoscopy were illustrated with the report of datas in a patient with diffuse retinal pigment epithelial decompensation. PMID:2258548
Koenig, F; Timberlake, G; Jalkh, A; Trempe, C; van de Velde, F; Coscas, G
Aims: To report the histopathology of two specimens of polypoidal choroidal vasculopathy (PCV) obtained from two eyes of Japanese patients. Methods: Specimens were obtained under direct visualisation during macular translocation surgery with 360 degree retinotomy. The clinical findings were correlated with the light microscopic findings of the two specimens. Results: One specimen from a 77 year old man was the central portion of the lesion that lay under the sensory retina on the retinal pigment epithelium (RPE). The specimen was made up mainly of fibrous tissue with small, thin walled vessels. Indocyanine green angiography after surgery revealed that active leaking polypoidal element remained under the RPE. Another specimen obtained from a 62 year old man was made up of a fibrovascular membrane situated within Bruch's membrane. The part of this specimen inferior to the foveal region included a collection of dilated, thin walled blood vessels without pericytes, surrounded by macrophages that stained positive for CD68. The dilated vessels appeared to be correlated with the orange coloured polyps observed by ophthalmoscopy, the polypoidal structure seen in indocyanine green angiograms, and the pyramidal elevation with intermediate reflectivity by optical coherence tomography. Conclusion: Polypoidal structures are located within Bruch's space. They are composed of clusters of dilated, thin walled blood vessels surrounded by macrophages and fibrin material. The positive immunohistochemical staining for vascular endothelial growth factor in the RPE and the vascular endothelial cells suggests that this fibrovascular complex is a subretinal choroidal neovascularisation.
Terasaki, H; Miyake, Y; Suzuki, T; Nakamura, M; Nagasaka, T
A 37-year-old woman presented with an anterior optic neuropathy related to Bartonella henselae. Twenty-nine days after symptom onset, a partial thickness macular hole developed in the involved eye. Fundus photography and optical coherence tomography confirmed the conversion to a full-thickness macular hole in 2 months. Macular hole as a complication of cat scratch disease is a rare entity, with 2 prior reported cases in children. The development of a macular hole following cat scratch disease can appear without the clinical picture of multiple white chorioretinal lesions, macular star, or vitritis. PMID:23681239
Alterman, Michael Adam; Young, Blair Katherine; Eggenberger, Eric Robert; Kaufman, David Irwin
Age-related macular degeneration (AMD) and artherosclerosis share common characteristics in their pathogenesis. In this study, we investigated the effects of lipoproteins like native (n)-LDL, oxidized (ox)-LDL and high-density lipoprotein (HDL) on advanced senescence, extracellular matrix accumulation, cell loss, and transforming growth factor-beta2 (TGF-?2) expression in cultured human retinal pigment epithelial (RPE) cells. Primary human RPE cells were incubated with 10–100?g\\/ml
Alice L. Yu; Reinhard L. Lorenz; Christos Haritoglou; Anselm Kampik; Ulrich Welge-Lussen
The eggs of the brine shrimp, Artemia salina, vary in colour from pale cream to dark brown. This variation is due to different amounts of haematin in the egg shells. Nauplii of Artemia are bright orange in colour owing to a carotenoid pigment, esterified astaxanthin. The same carotenoid is present in the eggs. Adult Artemia which has been reared on
Barbara M. Gilchrist; J. Green
Pigmented villonodular synovitis (PVS) is an uncommon, usually monoarticular disorder encountered mainly in adults. A boy and a girl, both 7 years old, were referred because of recurrent knee effusions. Both were medically treated for other rheumatic disorders for five years. PVS was diagnosed by arthroscopy and synovectomy was curative in both cases. Images p1449-a
Givon, U; Ganel, A; Heim, M
Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly, and the prevalence of the disease increases exponentially with every decade after age 50 years. It is a multifactorial disease involving a complex interplay of genetic, environmental, metabolic, and functional factors. Besides smoking, hypertension, obesity, and certain dietary habits, a growing body of evidence indicates that inflammation and the immune system may play a key role in the development of the disease. AMD may progress from the early form to the intermediate form and then to the advanced form, where two subtypes exist: the nonneovascular (dry) type and the neovascular (wet) type. The results from the Age-Related Eye Disease Study have shown that for the nonneovascular type of AMD, supplementation with high-dose antioxidants (vitamin C, vitamin E, and ?-carotene) and zinc is recommended for those with the intermediate form of AMD in one or both eyes or with advanced AMD or vision loss due to AMD in one eye. As for the neovascular type of the advanced AMD, the current standard of therapy is intravitreal injections of vascular endothelial growth factor inhibitors. In addition, lifestyle and dietary modifications including improved physical activity, reduced daily sodium intake, and reduced intake of solid fats, added sugars, cholesterol, and refined grain foods are recommended. To date, no study has demonstrated that AMD can be cured or effectively prevented. Clearly, more research is needed to fully understand the pathophysiology as well as to develop prevention and treatment strategies for this devastating disease. PMID:23580402
Cheung, Lily K; Eaton, Angie
Best`s macular dystrophy, also known as vitelliform macular degeneration, is an autosomal dominant, early onset form of macular degeneration. The disease is characterized by a roughly circular deposit of lipofuscin beneath the pigment epithelium of the retinal macula. Linkage studies were performed in two families, one Irish and one German, segregating typical Best`s macular dystrophy. In the Irish family (BTMD1), linkage analysis mapped the disease causing gene to chromosome 11q13, in a 10 cM region between the microsatellite markers PYGM and D11S871. Both markers showed different recombinants with the disease phenotype. This is a region that has previously shown linkage in families affected with Best`s macular dystrophy. Lod scores of 9.63, 9.12, 6.92, and 6.83 at zero recombination, were obtained with markers D11S1344, D11S1361, D11S1357 and D11S903, respectively. This data places the disease locus definitvely within the region between PYGM and D11S871. Linkage has been significantly excluded in this region in the German family (FamE), thereby providing evidence for genetic heterogeneity in this disease. The retinal specific gene, rod outer membrane protein 1 (ROM1), which maps to this region, has been screened for mutations in family BTMD1 by SSCPE analysis and by direct sequencing. Some of the promoter region, the three exons, and both introns have been sequenced; however, no mutations were found. It is likely that a gene other than ROM1 within this region may be responsible for causing the disease phenotype.
Mansergh, F.C.; Kenna, P.F.; Farrar, G.J. [Trinity College, Dublin (United Kingdom)] [and others
The aim of the present study was to investigate the pathomorphological and functional variations of choroidal neovascularization (CNV) in age-related macular degeneration (AMD) in a Chinese population using optical coherence tomography (OCT). This population-based study enrolled 59 patients (age, >45 years; eyes, 70) with early and intermediate-stage AMD from Youyi Road Community, Baoshan District, Shanghai, China. Comprehensive standardized ophthalmic examinations included visual acuity, anterior segment analysis using a slit lamp, dilated fundus evaluation by direct ophthalmoscopy, 90D handheld lens analysis, fundus photography, fundus fluorescein angiography (FFA) and fast optic disk scans using OCT. The macular CNV characteristic profiles in early and intermediate-stage AMD were determined by OCT. Data were obtained on the first visit and the follow-up period ranged between 6 and 24 months, where FFA and OCT outcomes of early and intermediate-stage AMD patients were analyzed. Three profiles of early and intermediate-stage AMD were created from the OCT and FFA results, each with a different prognosis. Firstly, drusens with unclear boundaries and evident pigment proliferation, as well as hypofluorescence around the drusens, was observed via FFA. A slight small arch field located in the retinal pigment epithelium (RPE)/choriocapillary layer (CCL) was shown on OCT scans, indicating exudative AMD. Secondly, RPE detachments of >1 pupillary distance, without CNV in the macular area, indicated geographic chorioretinitis atrophy. Finally, drusens with clear boundaries and few pigment proliferations and no certain surrounding fluorescence was observed via FFA, while a clear RPE/CCL band on the OCT scans indicated slow progress. The results of the present study demonstrated that combined OCT and FFA was the most efficient method for identifying CNV and diagnosing AMD. If the two techniques are not available concurrently, then OCT is a safer and more reliable technique to follow-up early and intermediate-stage AMD patients.
ZHAO, JIE; HU, JUN; LU, HAO; YANG, LEI
Background\\/aimsLong-term data of macular translocation for choroidal neovascularisation (CNV) secondary to age-related macular degeneration is lacking. Therefore, we describe the 3-year acuity outcomes.MethodsThis is a retrospective, interventional case series consisting of 40 consecutive patients who underwent translocation between 2003 and 2008. Best-corrected visual acuity (BCVA) at the most recent follow-up visit was compared to that of the 1 year and
Fred K Chen; Praveen J Patel; Gurmit S Uppal; Adnan Tufail; Peter J Coffey; Lyndon Da Cruz
High myopia can be associated with a range of pathologic changes within the macula that are now easily appreciated with optical coherence tomography. In the setting of high myopia and a macular traction retinal detachment, the expectation is for progressive worsening over time, and surgical intervention is often undertaken early. The authors present a case of spontaneous improvement of myopic macular detachment, which illustrates the potential value of an initial period of observation in this clinical setting. PMID:24044716
Goldman, Darin R; Duker, Jay S
Purpose To report the anatomic and visual results following macular buckling for patients with macular retinoschisis related to high myopia. Methods Thirty-nine highly myopic eyes (mean refractive error ?16.7 D; range, ?9 to ?24 D) of 36 patients (mean age 59 years; range, 35–79 years) presenting with macular retinoschisis associated with a posterior staphyloma, who underwent combined vitrectomy and macular buckling were evaluated. Main outcome measures included best-corrected visual acuity (BCVA) and optical coherence tomography (OCT) findings. Three cases were excluded due to short follow-up (less than 3 months). The mean follow-up was 16 months. Results The mean BCVA increased from 0.76 to 0.43 LogMAR (p = 0.001). Visual acuity improved in 30 eyes (83.3%), remained stable in three eyes (8.3%) and decreased in three eyes (8.3%). OCT showed resolution of foveoschisis with foveal reattachment in all eyes. None of the evaluated patients developed a macular hole during follow-up. Conclusion Macular buckling associated with vitrectomy results in good anatomic and visual outcomes in patients with myopic foveoschisis.
Mateo, Carlos; Gomez-Resa, Maria V.; Bures-Jelstrup, Anniken; Alkabes, Micol
All-trans-retinal is the precursor of A2E, a fluorophore within lipofuscin, which accumulates in human retinal pigment epithelial (hRPE) cells and contributes to age-related macular degeneration. Here we have compared the in vitro dark cytotoxicity and visible-light-mediated photoreactivity of all-trans-retinal and A2E in hRPE cells. All-trans-retinal caused distinct cytotoxicity in hRPE cells measured with MTS and LDH assays. Significant increases in intracellular oxidized glutathione (GSSG), extracellular GSH and GSSG levels and lipid hydroperoxide production were observed in cells incubated in the dark with 25 and 50 ?M all-trans-retinal. Light modified all-trans-retinal's harmful action and decreased extracellular glutathione and hydroperoxide levels. A2E (<25 ?M) did not affect cell metabolism or cytoplasmic membrane integrity in the dark or when irradiated. 25 ?M A2E raised the intracellular GSSG level in hRPE cells to a much smaller extent than 25 ?M all-trans-retinal. A2E did not induce glutathione efflux or hydroperoxide generation in the dark or after irradiation. These studies support our previous conclusions that although A2E may be harmful at high concentrations or when oxidized, its phototoxic properties are insignificant compared to those of all-trans-retinal. The endogenous production of A2E may serve as a protective mechanism to prevent damage to the retina by free all-trans-retinal.
Wielgus, Albert R.; Chignell, Colin F.; Ceger, Patricia; Roberts, Joan E.
Aim To objectively evaluate the postoperative face down posturing in macular hole surgery.Materials and Methods An electronic device called ‘Maculog’ was developed consisting of three basic components, a mercury switch triggered by the angle of tilt placed inside an earpiece, a data-recording device connected to the earpiece with cables and a windows based software program, specially written to analyse the
D Verma; M W Jalabi; W G Watts; G Naylor
This article reviews the research literature on driving and age-related macular degeneration, which is motivated by the link between driving and the quality of life of older adults and their increased collision rate. It addresses the risk of crashes, driving performance, driving difficulty, self-regulation, and interventions to enhance, safety,…
Owsley, Cynthia; McGwin, Gerald, Jr.
Age-related macular degeneration (AMD) is a major cause of disability in the elderly, substantially degrades the quality of their lives, and is a risk factor for depression. Rates of depression in AMD are substantially greater than those found in the general population of older people, and are on par with those of other chronic and disabling…
Casten, Robin; Rovner, Barry
BACKGROUND/AIMS—Most surgeons performing macular hole surgery using long acting gas recommend strict postoperative face down posturing for 10-15 days. Patients with chronic systemic illness such as arthritis may be unable to carry out this postoperative regime. Thus there is a need for alternative techniques that would eliminate such a regime. The authors review a series of patients who underwent macular hole surgery using silicone oil without any postoperative posturing.?METHODS—A retrospective case note review was performed of patients who had undergone macular hole surgery with silicone oil tamponade. The patients were unable to posture due to chronic illness and had stage 2, 3, or 4 full thickness macular holes. Removal of silicone oil performed with or without cataract surgery was arranged 3 months or more after surgery.?RESULTS—10 eyes of 10 patients underwent surgery. Duration of oil tamponade ranged from 3-9 months. Following oil removal the hole was closed in eight eyes (80%), of which only three showed any improvement in visual acuity (38%) even after cataract extraction. All eyes developed cataract to varying degrees and one eye developed raised intraocular pressure which settled after oil removal. A serious complication, endophthalmitis, occurred in one eye following removal of sutures after cataract extraction.?CONCLUSION—The anatomical results (80%) in this series are in keeping with those reported in other studies using gas tamponade. The visual results are disappointing and less rewarding than those obtained after successful surgery using gas tamponade.??
Karia, N; Laidlaw, A; West, J; Ezra, E; Gregor, M
Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly in the developed world. The inability to prevent the development of AMD and its complications stems from our lack of knowledge of the underlying pathological mechanisms. A recent report described a rodent with chemokine deficiencies that developed retinal changes similar to those frequently observed in AMD and
Tongalp H. Tezel; Nalini S. Bora; Henry J. Kaplan
Background Many disabling human retinal disorders involve the central retina, particularly the macula. However, the commonly used rodent models in research, mouse and rat, do not possess a macula. The purpose of this study was to identify small laboratory rodents with a significant central region as potential new models for macular research. Methodology/Principal Findings Gerbillus perpallidus, Meriones unguiculatus and Phodopus campbelli, laboratory rodents less commonly used in retinal research, were subjected to confocal scanning laser ophthalmoscopy (cSLO), fluorescein and indocyanine green angiography, and spectral-domain optical coherence tomography (SD-OCT) using standard equipment (Heidelberg Engineering HRA1 and Spectralis™) adapted to small rodent eyes. The existence of a visual streak-like pattern was assessed on the basis of vascular topography, retinal thickness, and the topography of retinal ganglion cells and cone photoreceptors. All three species examined showed evidence of a significant horizontal streak-like specialization. cSLO angiography and retinal wholemounts revealed that superficial retinal blood vessels typically ramify and narrow into a sparse capillary net at the border of the respective area located dorsal to the optic nerve. Similar to the macular region, there was an absence of larger blood vessels in the streak region. Furthermore, the thickness of the photoreceptor layer and the population density of neurons in the ganglion cell layer were markedly increased in the visual streak region. Conclusions/Significance The retinal specializations of Gerbillus perpallidus, Meriones unguiculatus and Phodopus campbelli resemble features of the primate macula. Hence, the rodents reported here may serve to study aspects of macular development and diseases like age-related macular degeneration and diabetic macular edema, and the preclinical assessment of therapeutic strategies.
Huber, Gesine; Heynen, Severin; Imsand, Coni; vom Hagen, Franziska; Muehlfriedel, Regine; Tanimoto, Naoyuki; Feng, Yuxi; Hammes, Hans-Peter; Grimm, Christian; Peichl, Leo; Seeliger, Mathias W.; Beck, Susanne C.
Pigments such as melanin, scytonemin and carotenoids protect microbial cells against the harmful effects of ultraviolet (UV) radiation. The role in UV protection has never been assigned to the prodigiosin pigment. In this work, we demonstrate that prodigiosin provides a significant level of protection against UV stress in Vibrio sp. DSM 14379. In the absence of pigment production, Vibrio sp. was significantly more susceptible to UV stress, and there was no difference in UV survival between the wild-type strain and non-pigmented mutant. The pigment's protective role was more important at higher doses of UV irradiation and correlated with pigment concentration in the cell. Pigmented cells survived high UV exposure (324 J/m(2)) around 1,000-fold more successfully compared to the non-pigmented mutant cells. Resistance to UV stress was conferred to the non-pigmented mutant by addition of exogenous pigment extract to the growth medium. A level of UV protection equivalent to that exhibited by the wild-type strain was attained by the non-pigmented mutant once the prodigiosin concentration had reached comparable levels to those found in the wild-type strain. In co-culture experiments, prodigiosin acted as a UV screen, protecting both the wild-type and non-pigmented mutants. Our results suggest a new ecophysiological role for prodigiosin. PMID:21547449
Bori?, Maja; Danev?i?, Tjaša; Stopar, David
Ocular diseases affect millions worldwide and dramatically influence the quality of life. Although much is known about ocular biology and disease pathologies, effective treatments are still lacking. The eye is well suited for application of emerging cell-based therapies. This chapter explores the development of stem cell-based treatments for age-related macular degeneration (AMD), a prevalent ocular disease in the elderly. Retinal pigmented epithelium (RPE), a cell type implicated in AMD, has been derived from both induced pluripotent stem cells and embryonic stem cells (ESC). Rapidly advancing research has generated various methods of RPE differentiation and several transplantation strategies. Clinical trials are already underway using suspensions of ESC-derived RPE and others are soon to follow. This chapter will provide an overview of current derivation and transplantation strategies for stem cell-derived RPE for the treatment of AMD and other related ocular diseases. PMID:24732763
Croze, Roxanne H; Clegg, Dennis O
Disorders of skin pigmentation pose significant challenges to both patients and physicians, as they have the unfortunate duality of being both common and difficult to treat conditions. This article reviews the etiology, pathophysiology, clinical presentation, and treatment options for melasma and postinflammatory hyperpigmentation. A thorough understanding of the disease process itself, expected agent efficacy, risks, and benefits of various treatments is crucial while treating these complex conditions. PMID:24488633
Chance, Elizabeth W
Retinal is the light-absorbing biochromophore responsible for the activation of vision pigments and light-driven ion pumps. Nature has evolved molecular tuning mechanisms that significantly shift the optical properties of the retinal pigments to enable their absorption of visible light. Using large-scale quantum chemical calculations at the density functional theory level combined with frozen density embedding theory, we show here how the protein environment of vision pigments tunes the absorption of retinal by electrostatically dominated interactions between the chromophore and the surrounding protein residues. The calculations accurately reproduce the experimental absorption maxima of rhodopsin and the red, green, and blue color pigments. We further identify key interactions responsible for the color-shifting effects by mutating the rhodopsin structure in silico, and we find that deprotonation of the retinyl is likely to be responsible for the blue-shifted absorption in the blue cone vision pigment. PMID:24422511
Zhou, Xiuwen; Sundholm, Dage; Weso?owski, Tomasz A; Kaila, Ville R I
The association of macular detachment with posttraumatic macular hole is a known but rare occurrence. Spontaneously occurring resolution of the detachment and closure of the macular hole has been reported only once in the literature. We describe a similar rare event in a young male, the documentation of which was done serially by microperimetry (MP) and optical coherence tomography (OCT). A 17-year-old male presented with a decrease in vision following a closed globe injury to the left eye. A coexisting macular hole and macular detachment were detected in the affected eye. Serial follow-up with OCT and MP documented complete resolution of the macular hole and the macular detachment within 1 week of presentation. The case highlights that spontaneous resolution of traumatic macular hole and related macular detachment may occur and a waiting period is advisable before undertaking any corrective surgical procedure. The pathophysiologic mechanisms of causation and the resolution of posttraumatic macular hole-related retinal detachment are discussed. PMID:22218253
Aalok, Lalit; Azad, Rajvardhan; Sharma, Yog R; Phuljhele, Swati
Background Alzheimer's disease (AD) and age-related macular degeneration (AMD) share several pathological features including ?-amyloid (A?) peptide accumulation, oxidative damage, and cell death. The causes of AD and AMD are not known but several studies suggest disturbances in cholesterol metabolism as a culprit of these diseases. We have recently shown that the cholesterol oxidation metabolite 27-hydroxycholesterol (27-OHC) causes AD-like pathology in human neuroblastoma SH-SY5Y cells and in organotypic hippocampal slices. However, the extent to which and the mechanisms by which 27-OHC may also cause pathological hallmarks related to AMD are ill-defined. In this study, the effects of 27-OHC on AMD-related pathology were determined in ARPE-19 cells. These cells have structural and functional properties relevant to retinal pigmented epithelial cells, a target in the course of AMD. Methods ARPE-19 cells were treated with 0, 10 or 25 ?M 27-OHC for 24 hours. Levels of A? peptide, mitochondrial and endoplasmic reticulum (ER) stress markers, Ca2+ homeostasis, glutathione depletion, reactive oxygen species (ROS) generation, inflammation and cell death were assessed using ELISA, Western blot, immunocytochemistry, and specific assays. Results 27-OHC dose-dependently increased A? peptide production, increased levels of ER stress specific markers caspase 12 and gadd153 (also called CHOP), reduced mitochondrial membrane potential, triggered Ca2+ dyshomeostasis, increased levels of the nuclear factor ?B (NF?B) and heme-oxygenase 1 (HO-1), two proteins activated by oxidative stress. Additionally, 27-OHC caused glutathione depletion, ROS generation, inflammation and apoptotic-mediated cell death. Conclusions The cholesterol metabolite 27-OHC is toxic to RPE cells. The deleterious effects of this oxysterol ranged from A? accumulation to oxidative cell damage. Our results suggest that high levels of 27-OHC may represent a common pathogenic factor for both AMD and AD.
Autosomal recessive Stargardt macular dystrophy is caused by mutations in the photoreceptor disc rim protein ABCA4/ABCR. Key clinical features of Stargardt disease include relatively mild rod defects such as delayed dark adaptation, coupled with severe cone defects reflected in macular atrophy and central vision loss. In spite of this clinical divergence, there has been no biochemical study of the effects of ABCA4 deficiency on cones vs. rods. Here we utilize the cone-dominant Abca4?/?/Nrl?/? double knockout mouse to study this issue. We show that as early as post-natal day (P) 30, Abca4?/?/Nrl?/? retinas have significantly fewer rosettes than Abca4+/+/Nrl?/? retinas, a phenotype often associated with accelerated degeneration. Abca4-deficient mice in both the wild-type and cone-dominant background accumulate more of the toxic bisretinoid A2E than their ABCA4-competent counterparts, but Abca4?/?/Nrl?/? eyes generate significantly more A2E per mole of 11-cis-retinal (11-cisRAL) than Abca4?/? eyes. At P120, Abca4?/?/Nrl?/? produced 340±121 pmoles A2E/nmol 11-cisRAL while Abca4?/? produced 50.4±8.05 pmoles A2E/nmol 11-cisRAL. Nevertheless, the retinal pigment epithelium (RPE) of Abca4?/?/Nrl?/? eyes exhibits fewer lipofuscin granules than the RPE of Abca4?/? eyes; at P120: Abca4?/?/Nrl?/? exhibit 0.045±0.013 lipofuscin granules/?m2 of RPE vs. Abca4?/? 0.17±0.030 lipofuscin granules/?m2 of RPE. These data indicate that ABCA4-deficient cones simultaneously generate more A2E than rods and are less able to effectively clear it, and suggest that primary cone toxicity may contribute to Stargardt’s-associated macular vision loss in addition to cone death secondary to RPE atrophy.
Conley, Shannon M.; Cai, Xue; Makkia, Rasha; Wu, Yalin; Sparrow, Janet R.; Naash, Muna I.
Purpose Describe qualitative spectral-domain optical coherence tomography (SD-OCT) characteristics of eyes classified as intermediate age-related macular degeneration (nonadvanced AMD) from Age-Related Eye Disease Study 2 (AREDS2) color fundus photography (CFP) grading. Design Prospective cross-sectional study. Participants We included 345 AREDS2 participants from 4 study centers and 122 control participants who lack CFP features of intermediate AMD. Methods Both eyes were imaged with SD-OCT and CFP. The SD-OCT macular volume scans were graded for the presence of 5 retinal, 5 subretinal, and 4 drusen characteristics. In all, 314 AREDS2 participants with ?1 category-3 AMD eye and all controls each had 1 eye entered into SD-OCT analysis, with 63 eyes regraded to test reproducibility. Main Outcome Measures We assessed SD-OCT characteristics at baseline. Results In 98% of AMD eyes, SD-OCT grading of all characteristics was successful, detecting drusen in 99.7%, retinal pigment epithelium (RPE) atrophy/absence in 22.9%, subfoveal geographic atrophy in 2.5%, and fluid in or under the retina in 25.5%. Twenty-eight percent of AMD eyes had characteristics of possible advanced AMD on SD-OCT. Two percent of control eyes had drusen on SD-OCT. Vision loss was not correlated with foveal drusen alone, but with foveal drusen that were associated with other foveal pathology and with overlying focal hyperreflectivity. Focal hyperreflectivity over drusen, drusen cores, and hyper- or hyporeflectivity of drusen were also associated with RPE atrophy. Conclusions Macular pathologies in AMD can be qualitatively and reproducibly evaluated with SD-OCT, identifying pathologic features that are associated with vision loss, RPE atrophy, and even possibly the presence of advanced AMD not apparent on CFP. Qualitative and detailed SD-OCT analysis can contribute to the anatomic characterization of AMD in clinical studies of vision loss and disease progression.
Leuschen, Jessica N.; Schuman, Stefanie G.; Winter, Katrina P.; McCall, Michelle N.; Wong, Wai T.; Chew, Emily Y.; Hwang, Thomas; Srivastava, Sunil; Sarin, Neeru; Clemons, Traci; Harrington, Molly; Toth, Cynthia A.
ABSTRACT Background/Purpose Cumulative sunlight exposure and cataract surgery are reported risk factors for advanced age-related macular degeneration (AMD). Laboratory studies suggest that accumulation and photochemical reactions of A2E (N-retinylidene-N-retinylethanolamine) and its epoxides, components of lipofuscin, are important in AMD. To relate this data to the clinical setting, we modeled the effects of macular irradiance and spectral filtering on production of A2E and reactive oxygen intermediates (ROIs) in pseudophakic eyes with a clear or “yellow” intraocular lens (IOL) and in phakic eyes. Methods We calculated relative changes of macular irradiance as a function of light (390 to 700 nm) intensity, pupil size, age, and lens status, and modeled resulting all-trans-retinal concentration and rates of production of A2E-related photochemicals and photon-induced ROIs in rods and retinal pigment epithelium (RPE). We compared these photoproducts following cataract surgery and IOL implantation with and without spectral sunglasses to normal age-related nuclear sclerotic lens changes. Results Following cataract and IOL surgery, all-trans-retinal and lipofuscin photochemistry would theoretically increase average generation of 1) A2E-related photochemicals, 2) ROI in rods and 3) ROI in RPE, respectively, 2.6-, 15- and 6.6-fold with a clear IOL, and 2.1-, 4.1- and 2.6 fold with a yellow IOL, but decrease approximately 30-, approximately 20-and 4-fold with a vermillion filter sunglass and clear IOL compared to an average 70 year old phakic eye. Conclusion Sunglasses that strongly decrease both deep blue light and rod photobleaching, while preserving photopic sensitivity and color perception, would provide upstream protection from potential photochemical damage in subjects at risk for AMD progression after cataract surgery.
Meyers, Sanford M; Ostrovsky, Mikhail A; Bonner, Robert F
Pigmentation disorders include a large number of heterogeneous conditions that are usually characterized by altered melanocyte density, melanin concentration, or both, and result in altered pigmentation of the skin. Some of these disorders are extremely common (melasma, vitiligo), whereas others are rare. In this contribution, we review the most common pigmentation disorders that appear on the face. These lesions, even though mostly asymptomatic, have a great impact on a patient's quality of life. PMID:24314378
Nicolaidou, Electra; Katsambas, Andreas D
The traditional method for documenting and quantifying geographic atrophy (GA) is color photography. This method has been shown to be reproducible in several clinical trials, including the Age-related Eye Disease Study (AREDS) and the natural progression of GA studies by Sunness et al. (AREDS No. 6, Am J Ophthalmol 132(5):668-681, 2001; Sunness et al., Invest Ophthalmol Vis Sci 40(8):1761-1769, 1999). Nevertheless, it can be difficult to distinguish between dead/nonfunctioning retinal pigment epithelium (RPE), living but depigmented RPE (RPE often release melanin granules upon injury), and yellowish coloration caused by large drusen or calcified regressed drusen. Two imaging technologies that seem promising are fundus autofluorescence (FAF) and spectral domain (high resolution) optical coherence tomography (SDOCT). Here we provide an overview of FAF imaging in the setting of age-related macular degeneration (AMD) and GA. PMID:20238040
Bearelly, Srilaxmi; Cousins, Scott W
Dysfunction and loss of retinal pigment epithelium (RPE) are major pathologic changes observed in various retinal degenerative diseases such as aged-related macular degeneration. RPE generated from human pluripotent stem cells can be a good candidate for RPE replacement therapy. Here, we show the differentiation of human embryonic stem cells (hESCs) toward RPE with the generation of spherical neural masses (SNMs), which are pure masses of hESCs-derived neural precursors. During the early passaging of SNMs, cystic structures arising from opened neural tube-like structures showed pigmented epithelial morphology. These pigmented cells were differentiated into functional RPE by neuroectodermal induction and mechanical purification. Most of the differentiated cells showed typical RPE morphologies, such as a polygonal-shaped epithelial monolayer, and transmission electron microscopy revealed apical microvilli, pigment granules, and tight junctions. These cells also expressed molecular markers of RPE, including Mitf, ZO-1, RPE65, CRALBP, and bestrophin. The generated RPE also showed phagocytosis of isolated bovine photoreceptor outer segment and secreting pigment epithelium-derived factor and vascular endothelial growth factor. Functional RPE could be generated from SNM in our method. Because SNMs have several advantages, including the capability of expansion for long periods without loss of differentiation capability, easy storage and thawing, and no need for feeder cells, our method for RPE differentiation may be used as an efficient strategy for generating functional RPE cells for retinal regeneration therapy. PMID:22683799
Cho, Myung Soo; Kim, Sang Jin; Ku, Seung-Yup; Park, Jung Hyun; Lee, Haksup; Yoo, Dae Hoon; Park, Un Chul; Song, Seul Ae; Choi, Young Min; Yu, Hyeong Gon
We report on a new method for segmenting the retinal pigment epithelium (RPE) in polarization sensitive optical coherence tomography (PS-OCT) images of the human retina. Contrary to previous segmentation algorithms that were based on variations of backscattered intensity between individual layers, our method uses an intrinsic tissue property of the RPE: its depolarizing, or polarization scrambling effect on backscattered light. By using a state of the art spectral domain PS-OCT instrument, we demonstrate the method in healthy eyes and in eyes of patients with age related macular degeneration.
Hitzenberger, Christoph K.; Götzinger, Erich; Pircher, Michael; Baumann, Bernhard; Michels, Stephan; Geitzenauer, Wolfgang; Schmidt-Erfurth, Ursula
Raman spectroscopy is a rapid nondestructive technique providing spectroscopic and structural information on both organic and inorganic molecular compounds. Extensive applications for the method in the characterization of pigments have been found. Due to the high sensitivity of Raman spectroscopy for the detection of chlorophylls, carotenoids, scytonemin, and a range of other pigments found in the microbial world, it is an excellent technique to monitor the presence of such pigments, both in pure cultures and in environmental samples. Miniaturized portable handheld instruments are available; these instruments can be used to detect pigments in microbiological samples of different types and origins under field conditions. PMID:24682303
Jehli?ka, Jan; Edwards, Howell G M; Oren, Aharon
A 21-year-old female presented with progressive bilateral visual loss for the past 8 years. The patient had no history of systemic disease, surgery or medications. Complete ophthalmologic examination and topography were performed. On ophthalmic examination, uncorrected visual acuity was counting fingers at 2.5 m (20/50 with pinhole) in the right and left eyes. Both corneas appeared hazy on gross examination. On slit-lamp biomicroscopy, focal grayish-white opacities with indistinct borders were noted in the superficial and deep corneal stroma of both eyes. Both corneas were thin and bulging. Corneal topography showed a pattern consistent with keratoconus. The patient underwent penetrating keratoplasty (PKP). Histopathologic studies after PKP confirmed the diagnosis of macular corneal dystrophy and keratoconus in the same eye. The patient was clinically diagnosed as a case of concurrent macular dystrophy and keratoconus, which is a very rare presentation.
Mohammad-Rabei, Hossein; Shojaei, Ahmad; Aslani, Mehdi
Acute macular neuroretinopathy (AMNR) is a rare disorder characterised by acute onset of unilateral or bilateral visual impairment associated with reddish-brown wedge-shaped outer macular lesions. It is more frequently reported in young females and though the pathophysiology remains unclear, factors reported in association with its onset include post-viral illness and vasoconstrictor use. We report a case of AMNR in an 18-year old female patient presenting with a 2-day history of acute painless blurring of central vision bilaterally, following 1 month of preceding flu-like illness. For 1 week prior to presentation, the patient had taken large doses of oral preparations containing phenylephrine hydrochloride. In addition to demonstrating characteristic optical coherence tomography findings seen in AMNR, we illustrate some rarely seen acute ophthalmoscopic features. Based on associations from this case, we add further insight into the pathophysiology of this condition which remains poorly understood. PMID:24037593
Garg, Anurag; Shah, Anish N; Richardson, Theresa; O'Sullivan, Eoin; Eleftheriadis, Haralabos
Being the leading cause of blindness in modern world Age Related Macular Degeneration has beneficiated in the last decade of important progress in diagnosis, classification and the discovery of diverse factors who contribute to the etiology of this disease. Treatments have arised who can postpone the irreversible evolution of the disease and thus preserve vision. Recent findings have identified predisposing genetic factors and also inflamatory and imunological parameters that can be modified trough a good and adequate prevention and therapy This articole reviews new aspects of patology of Age Related Macular Degeneration like the role of complement in maintaining inflamation and the role of oxidative stress on different structures of the retina. PMID:22888685
Age-related macular degeneration (AMD) is one of the leading causes of blindness in the developed world. Although effective\\u000a treatment modalities such as anti-VEGF treatment have been developed for neovascular AMD, there is still no effective treatment\\u000a for geographical atrophy, and therefore the most cost-effective management of AMD is to start with prevention. This review\\u000a looks at current evidence on preventive
Ian Yat Hin Wong; Simon Chi Yan Koo; Clement Wai Nang Chan
Pigmented villonodular synovitis (PVNS), also known as tenosynovial giant cell tumour is an articular pathology that occurs predominantly in young adults and is caused by an abnormal proliferation of the synovial membrane. The clinical presentation includes pain and joint swelling. MRI represents the best imaging modality to investigate this disease but the histopathology of synovial tissue provides the definitive diagnosis. The management of PVNS is often difficult due to the high risk of relapse after treatment. The objective of this article is to review the literature regarding the diagnosis and therapy of this poorly understood condition. PMID:24701714
Court, S; Nissen, M J; Gabay, C
Space flight offers the opportunity to study linear bioaccelerometers (vestibular maculas) in the virtual absence of a primary stimulus, gravitational acceleration. Macular research in space is particularly important to NASA because the bioaccelerometers are proving to be weighted neural networks in which information is distributed for parallel processing. Neural networks are plastic and highly adaptive to new environments. Combined morphological-physiological studies of maculas fixed in space and following flight should reveal macular adaptive responses to microgravity, and their time-course. Ground-based research, already begun, using computer-assisted, 3-dimensional reconstruction of macular terminal fields will lead to development of computer models of functioning maculas. This research should continue in conjunction with physiological studies, including work with multichannel electrodes. The results of such a combined effort could usher in a new era in understanding vestibular function on Earth and in space. They can also provide a rational basis for counter-measures to space motion sickness, which may prove troublesome as space voyager encounter new gravitational fields on planets, or must re-adapt to 1 g upon return to earth.
Ross, M. D.; Cutler, L.; Meyer, G.; Vazin, P.; Lam, T.
Background The optical coherence tomography (OCT) and clinical characteristics of traumatic macular holes (TMHs) can be compared to those\\u000a of idiopathic macular holes (IMHs) to gain insights into the pathogenesis of both.\\u000a \\u000a \\u000a \\u000a \\u000a Methods The demographic data and visual acuity of 73 consecutive patients with unilateral, full-thickness TMHs and 182 consecutive\\u000a patients with idiopathic IMHs were recorded. All patients with TMH and 60
Jingjing Huang; Xing Liu; Ziqiang Wu; Srinivas Sadda
Background To report on changes in retinal morphology during the 12 months after macular hole surgery.\\u000a \\u000a \\u000a \\u000a Methods Seventy one eyes of 66 patients after pars plana vitrectomy with ILM peeling and air tamponade were evaluated with spectral\\u000a OCT for 12 months and additionally before surgery. Macular hole size was measured. On consecutive visits, the size of photoreceptor\\u000a layer defects and elevation of the outer
Zofia Michalewska; Janusz Michalewski; Jerzy Nawrocki
The choroid in the eye provides vascular support for the retinal pigment epithelium (RPE) and the photoreceptors. Vascular endothelial growth factor (VEGF) derived from the RPE has been implicated in the physiological regulation of the choroidal vasculature, and overexpression of VEGF in this epithelium has been considered an important factor in the pathogenesis of choroidal neovascularization in age-related macular degeneration. Here, we demonstrate that RPE-derived VEGF is essential for choriocapillaris development. Conditional inactivation of VEGF expression in the RPE (in VEGFrpe?/? mice) results in the absence of choriocapillaris, occurrence of microphthalmia, and the loss of visual function. Severe abnormalities of RPE cells are already observed when VEGF expression in the RPE is only reduced (in VEGFrpe+/? mice), despite the formation of choroidal vessels at these VEGF levels. Finally, using Hif1arpe?/? mice we demonstrate that these roles of VEGF are not dependent on hypoxia-inducible factor-1?-mediated transcriptional regulation of VEGF expression in the RPE. Thus, hypoxia-inducible factor-1?-independent expression of VEGF is essential for choroid development.
Marneros, Alexander G.; Fan, Jie; Yokoyama, Yoshihito; Gerber, Hans Peter; Ferrara, Napoleone; Crouch, Rosalie K.; Olsen, Bjorn R.
Abstract Aims: Age-related macular degeneration (AMD), a major cause of legal blindness in the elderly, is associated with genetic and environmental risk factors, such as cigarette smoking. Recent evidence shows that cigarette smoke (CS) that contains high levels of potent oxidants preferably targets retinal pigment epithelium (RPE) leading to oxidative damage and apoptosis; however, the mechanisms are poorly understood. The present study aimed to investigate the role of endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) in CS-related RPE apoptosis. Results: ER stress and proapoptotic gene C/EBP homologous protein (CHOP) were induced in the RPE/choroid complex from mice exposed to CS for 2 weeks and in human RPE cells treated with hydroquinone, a potent oxidant found at high concentrations in CS. Suppressing ER stress or inhibiting CHOP activation by pharmacological chaperones or genetic approaches attenuated hydroquinone-induced RPE cell apoptosis. In contrast to enhanced CHOP activation, protein level of active X-box binding protein 1 (XBP1), a major regulator of the adaptive UPR, was reduced in hydroquinone-treated cells. Conditional knockout of XBP1 gene in the RPE resulted in caspase-12 activation, increased CHOP expression, and decreased antiapoptotic gene Bcl-2. Furthermore, XBP1-deficient RPE cells are more sensitive to oxidative damage induced by hydroquinone or NaIO3, a CS-unrelated chemical oxidant. Conversely, overexpressing XBP1 protected RPE cells and attenuated oxidative stress-induced RPE apoptosis. Innovation and Conclusion: These findings provide strong evidence suggesting an important role of ER stress and the UPR in CS-related oxidative injury of RPE cells. Thus, the modulation of the UPR signaling may provide a promising target for the treatment of AMD. Antioxid. Redox Signal. 20, 2091–2106.
Chen, Chen; Cano, Marisol; Wang, Joshua J.; Li, Jingming; Huang, Chuangxin; Yu, Qiang; Herbert, Terence P.; Handa, James T.
Lipofuscin accumulates with age in the retinal pigment epithelium (RPE) in discrete granular organelles and may contribute to age-related macular degeneration. Because previous studies suggest that lipofuscin contains protein that may impact pathogenic mechanisms, we pursued proteomics analysis of lipofuscin. The composition of RPE lipofuscin and its mechanisms of pathogenesis are poorly understood in part because of the heterogeneity of isolated preparations. We purified RPE lipofuscin granules by treatment with proteinase K or SDS and showed by light, confocal, and transmission electron microscopy that the purified granules are free of extragranular material and associated membranes. Crude and purified lipofuscin preparations were quantitatively compared by (i) LC MS/MS proteomics analyses, (ii) immunoanalyses of oxidative protein modifications, (iii) amino acid analysis, (iv) HPLC of bisretinoids, and (v) assaying phototoxicity to RPE cells. From crude lipofuscin preparations 186 proteins were identified, many of which appeared to be modified. In contrast, very little protein (?2% (w/w) by amino acid analysis) and no identifiable protein were found in the purified granules, which retained full phototoxicity to cultured RPE cells. Our analyses showed that granules in purified and crude lipofuscin preparations exhibit no statistically significant differences in diameter or circularity or in the content of the bisretinoids A2E, isoA2E, and all-trans-retinal dimer-phosphatidylethanolamine. The finding that the purified granules contain minimal protein yet retain phototoxic activity suggests that RPE lipofuscin pathogenesis is largely independent of associated protein. The purified granules also exhibited oxidative protein modifications, including nitrotyrosine generated from reactive nitrogen oxide species and carboxyethylpyrrole and isolevuglandin E2 adducts generated from reactive lipid fragments. This finding is consistent with previous studies demonstrating RPE lipofuscin to be a potent generator of reactive oxygen species and supports the hypothesis that such species, including reactive fragments from lipids and retinoids, contribute to the mechanisms of RPE lipofuscin pathogenesis.
Ng, Kwok-Peng; Gugiu, Bogdan; Renganathan, Kutralanathan; Davies, Matthew W.; Gu, Xiaorong; Crabb, John S.; Kim, So Ra; Rozanowska, Malgorzata B.; Bonilha, Vera L.; Rayborn, Mary E.; Salomon, Robert G.; Sparrow, Janet R.; Boulton, Michael E.; Hollyfield, Joe G.; Crabb, John W.
Melanocytes are phenotypically prominent but histologically inconspicuous skin cells. They are responsible for the pigmentation of skin and hair, and thereby contribute to the appearance of skin and provide protection from damage by ultraviolet radiation. Pigmentation mutants in various species are highly informative about basic genetic and developmental pathways, and provide important clues to the processes of photoprotection, cancer predisposition
Jennifer Y. Lin; David E. Fisher
The natural range of hair and skin colour is a continuous spectrum, controlled by multiple genes in a complex fashion. Many of these genes are as yet unknown, but several key pigmentation genes have been characterised, in particular the melanocortin 1 receptor gene (MC1R). Here, the function and known mutations of MC1R and other human pigmentation genes including ASIP, MATP,
Lipofuscin accumulation in the retinal pigment epithelium (RPE) is associated with various blinding retinal diseases, including age-related macular degeneration (AMD). The major lipofuscin fluorophor A2-E is thought to play an important pathogenetic role. In previous studies A2-E was shown to severely impair lysosomal function of RPE cells. However, the underlying molecular mechanism remained obscure. Using purified lysosomes from RPE cells
M. Bergmann; F. Schütt; F. G. Holz; J. Kopitz
The objective of this investigation was to evaluate the possibility of substituting Amaranthus pigments for nitrates in the of manufacture pork sausage. Five treatments of pork sausages (5% fat) with two levels of sodium nitrite (0 and 0.015%), or three levels (0.1%, 0.2% and 0.3%) of pigments extracted from red Amaranthus were produced. The addition of Amaranthus pigments resulted in the significant increase of a* values, sensory color, flavor and overall acceptance scores, but the significant reduction of b* values, TBA values and VBN values (p<0.05). Based mainly on the results of overall acceptance during 29 d storage, it could be concluded that Amaranthus pigments showed a potential as nitrite alternative for pork sausage manufacture. PMID:25049507
Zhou, Cunliu; Zhang, Lin; Wang, Hui; Chen, Conggui
The objective of this investigation was to evaluate the possibility of substituting Amaranthus pigments for nitrates in the of manufacture pork sausage. Five treatments of pork sausages (5% fat) with two levels of sodium nitrite (0 and 0.015%), or three levels (0.1%, 0.2% and 0.3%) of pigments extracted from red Amaranthus were produced. The addition of Amaranthus pigments resulted in the significant increase of a* values, sensory color, flavor and overall acceptance scores, but the significant reduction of b* values, TBA values and VBN values (p<0.05). Based mainly on the results of overall acceptance during 29 d storage, it could be concluded that Amaranthus pigments showed a potential as nitrite alternative for pork sausage manufacture.
Zhou, Cunliu; Zhang, Lin; Wang, Hui; Chen, Conggui
Phthalocyanines have been used as a pigment in coatings and related applications for many years. These pigments are some of the most stable organic pigments known. The phthalo blue and green pigments have been known to be ultraviolet (UV) stable and thermally stable to over 400 C. These phthalocyanines are both a semiconductor and photoconductor, exhibiting catalytic activity and photostabilization capability of polymers. Many metal free and metallic phthalocyanine derivatives have been prepared. Development of the new classes of phthalocyanine pigment could be used as coating on NASA spacecraft material such as glass to decrease the optical degradation from UV light, the outside of the space station modules for UV protection, and coating on solar cells to increase lifetime and efficiency.
Trinh, Diep VO
Purpose. The authors showed previously that parafoveal rods, but not cones, decrease during the course of adulthood in donor eyes that were screened to exclude the grossly visible macular drusen and pigmentary disturbances typical of age-related macular degeneration (AMD). Because AMD begins in the parafovea, this selective loss of rods actually may be subclinical AMD not yet visible in the
Christine A. Curcio; Nancy E. Medeiros; C. Leigh Millican
Age-related macular degeneration is the principal cause of registered legal blindness among those aged over 65 in the United States, western Europe, Australia, and Japan. Despite intensive research, the precise etiology of molecular events that underlie age-related macular degeneration is poorly understood. However, investigations on parallel fronts are addressing this prevalent public health problem. Sophisticated biochemical and biophysical techniques have
Jayakrishna Ambati; Balamurali K Ambati; Sonia H Yoo; Sean Ianchulev; Anthony P Adamis
Macular hole is a condition that characterizes older patients, being rare in adolescent patients and exceptionally at children. The etiopathogenic mechanism of most macular holes in children and adolescent is idiopathic. The suggested etiopathogenic mechanism is vitreoretinal traction due to a toxocara granuloma for a 9 years old girl. PMID:17937043
Voinea, Liliana; Podoleanu, Elena; Ion, Daniela; Gr?dinaru, Sînziana; Ungureanu, E; Covaliu, Nicoleta; Tecuceanu, Andreea; Alexandrescu, Cristina; Simionescu, Ruxandra; Popescu, Viorela; Panca, Aida; Dascalu, Ana Maria; Vrapciu, Alexandra; Voicu, M?d?lina
Background: To determine the benefit of vitrectomy on eyes with diabetic macular edema. Methods: A retrospective institutional case series was used including 66 patients (69 eyes) who had undergone pars plana vitrectomy for diabetic macular edema between 1992 and 2000. Prior to surgery, the patients had been treated with laser coagulation as recommended by the Early Treatment Diabetic Retinopathy Study.
Martina T. Kralinger; Markus Pedri; Franz Kralinger; Josef Troger; Gerhard F. Kieselbach
Purpose To evaluate the effect of the recombinant adeno-associated virus (rAAV) vector that expresses human pigment epithelium-derived factor (hPEDF) on reducing blood–retinal barrier (BRB) breakdown in the experimental diabetic rat model. Methods Diabetes was induced by an intraperitoneal (i.p.) injection of streptozotocin (STZ) into 10-week-old male Wister rats. rAAV2-cytomegalovirus (CMV)-hPEDF was delivered into the right eyes by intravitreal injection on the first day after diabetes induction. The contralateral eyes received intravitreal injection of rAAV2-CMV-green fluorescent protein as the paired control. Gene delivery and expression of vascular endothelial growth factor (VEGF), occludin, and intercellular adhesion molecule-1 (ICAM-1) were determined with reverse transciptase PCR or western blotting. BRB breakdown changes were quantified by measuring albumin leakage from retinal blood vessels after an intravenous (i.v.) injection of Evans blue albumin. Results Retinal transfection with the hPEDF gene construct led to sustained hPEDF gene expression for 6 months, significantly suppressing VEGF mRNA expression in the retina after 1, 3, and 6 months of diabetes induced by STZ compared with paired controls. Moreover, hPEDF dramatically reduced the levels of retinal ICAM-1 but increased the expression of occludin. Furthermore, BRB breakdown was much lower in hPEDF-injected diabetic animals in comparison with controls after 6 months. Conclusions A single intravitreal injection of rAAV2-CMV-hPEDF can relieve BRB breakdown in STZ-induced diabetic rats for 6 months. The effect is associated with downregulation of retinal VEGF mRNA and ICAM-1 expression and a reduction in the loss of retinal occludin induced by diabetes. The approach of gene transfer may reduce diabetic macular edema, providing long-term protection for diabetic patients at risk of macular edema.
Yu, Hai; Jiang, Jing
Due to their high prevalence, retinal vascular diseases including age related macular degeneration (AMD), retinal vein occlusions (RVO), diabetic retinopathy (DR) and diabetic macular edema have been major therapeutic targets over the last years. The pathogenesis of these diseases is complex and yet not fully understood. However, increased proliferation, migration and angiogenesis are characteristic cellular features in almost every retinal vascular disease. The introduction of vascular endothelial growth factor (VEGF) binding intravitreal treatment strategies has led to great advances in the therapy of these diseases. While the predominant part of affected patients benefits from the specific binding of VEGF by administering an anti-VEGF antibody into the vitreous cavity, a small number of non-responders exist and alternative or additional therapeutic strategies should therefore be evaluated. The mammalian target of rapamycin (mTOR) is a central signaling pathway that eventually triggers up-regulation of cellular proliferation, migration and survival and has been identified to play a key role in angiogenesis. In the present study we were able to show that both retinal pigment epithelial (RPE) cells as wells as human umbilical vein endothelial cells (HUVEC) are inhibited in proliferating and migrating after treatment with temsirolimus in non-toxic concentrations. Previous studies suggest that the production of VEGF, platelet derived growth factor (PDGF) and other important cytokines is not only triggered by hypoxia but also by mTOR itself. Our results indicate that temsirolimus decreases VEGF and PDGF expression on RNA and protein levels significantly. We therefore believe that the mTOR inhibitor temsirolimus might be a promising drug in the future and it seems worthwhile to evaluate complementary therapeutic effects with anti-VEGF drugs for patients not profiting from mono anti-VEGF therapy alone. PMID:24586308
Liegl, Raffael; Koenig, Susanna; Siedlecki, Jakob; Haritoglou, Christos; Kampik, Anselm; Kernt, Marcus
Age-related macular degeneration (AMD) is the most common reason of visual impairment in the elderly in the Western countries. The degeneration of retinal pigment epithelial cells (RPE) causes secondarily adverse effects on neural retina leading to visual loss. The aging characteristics of the RPE involve lysosomal accumulation of lipofuscin and extracellular protein aggregates called “drusen”. Molecular mechanisms behind protein aggregations are weakly understood. There is intriguing evidence suggesting that protein SQSTM1/p62, together with autophagy, has a role in the pathology of different degenerative diseases. It appears that SQSTM1/p62 is a connecting link between autophagy and proteasome mediated proteolysis, and expressed strongly under the exposure to various oxidative stimuli and proteasomal inhibition. ELAVL1/HuR protein is a post-transcriptional factor, which acts mainly as a positive regulator of gene expression by binding to specific mRNAs whose corresponding proteins are fundamental for key cellular functions. We here show that, under proteasomal inhibitor MG-132, ELAVL1/HuR is up-regulated at both mRNA and protein levels, and that this protein binds and post-transcriptionally regulates SQSTM1/p62 mRNA in ARPE-19 cell line. Furthermore, we observed that proteasomal inhibition caused accumulation of SQSTM1/p62 bound irreversibly to perinuclear protein aggregates. The addition of the AMPK activator AICAR was pro-survival and promoted cleansing by autophagy of the former complex, but not of the ELAVL1/HuR accumulation, indeed suggesting that SQSTM1/p62 is decreased through autophagy-mediated degradation, while ELAVL1/HuR through the proteasomal pathway. Interestingly, when compared to human controls, AMD donor samples show strong SQSTM1/p62 rather than ELAVL1/HuR accumulation in the drusen rich macular area suggesting impaired autophagy in the pathology of AMD.
Marchesi, Nicoletta; Hyttinen, Juha M. T.; Kivinen, Niko; Sironen, Reijo; Rilla, Kirsi; Akhtar, Saeed; Provenzani, Alessandro; D'Agostino, Vito Giuseppe; Govoni, Stefano; Pascale, Alessia; Agostini, Hansjurgen; Petrovski, Goran; Salminen, Antero; Kaarniranta, Kai
Purpose To investigate the incidence of reticular macular disease (RMD), a subphenotype of age-related macular degeneration (AMD), in multilobular geographic atrophy (GA) and its relation to GA progression. Methods 157 eyes of 99 subjects with AMD, primary GA, and good-quality autofluorescence (AF) and/or infrared (IR) images were classified into unilobular GA (1 lesion) or multilobular GA (>= 2 distinct and/or coalescent lesions). 34 subjects (50 eyes) had serial imaging. We determined the spatiotemporal relationships of RMD to GA and GA progression rates in 5 macular fields. Results 144/157 (91.7%) eyes had multilobular GA, 95.8% of which exhibited RMD. In subjects with serial imaging, the mean GA growth rate significantly differed between the unilobular and multilobular groups (0.40 mm2 /yrvs. 1.30 mm2 /yr, p< 0.001). Of the macular fields in these eyes, 77.1% of fields with RMD at baseline showed subsequent GA progression, while 53.4% of fields without RMD showed progression (p <0.001). Percentage of fields with RMD significantly correlated with GA progression rate(p=0.01). Conclusion AF and IR imaging demonstrates that RMD is nearly always present with multilobular GA in AMD. Further, GA lobules frequently develop in areas of RMD, suggesting progression of a single underlying disease process.
Xu, Luna; Blonska, Anna M.; Pumariega, Nicole M.; Bearelly, Srilaxmi; Sohrab, Mahsa A.; Hageman, Gregory S.; Smith, R. Theodore
Since the dawn of mankind, cavemen has expressed himself through art. The earliest known cave paintings date to some 32,000 years ago and used 4 colours derived from the earth. These pigments were iron oxides and known as ochres, blacks and whites. All pigments known by the Egyptians, the Greeks, the Romans and Renaissance man were natural and it was not until the 18th century that synthetic pigments were made and widely used. Until that time all art, be it sacred or secular used only natural pigments, of which the preparation of many have been lost or rarely used because of their tedious preparation. As a geologist, a mineralogist and an artist specializing in iconography, I have been able to rediscover 89 natural pigments extracted from minerals. I use these pigments to paint my icons in the traditional Byzantine manner and also to restore old icons, bringing back their glamour and conserving them for years to come. The use of the natural pigments in its proper way also helps to preserve the traditional skills of the iconographer. In the ancient past, pigments were extremely precious. Many took an exceedingly long journey to reach the artists, and came from remote countries. Research into these pigments is the work of history, geography and anthropology. It is an interesting journey in itself to discover that the blue aquamarines came from Afghanistan, the reds from Spain, the greens Africa, and so on. In this contribution I will be describing the origins, preparation and use of some natural pigments, together with their history and provenance. Additionally, I will show how the natural pigments are used in the creation of an icon. Being a geologist iconographer, for me, is a sacrement that transforms that which is earthly, material and natural into a thing of beauty that is sacred. As bread and wine in the Eucharist, water during baptism and oil in Holy Union transmit sanctification to the beholder, natural pigments do the same when one considers an icon. The iconographer uses earthly creations to create divine images: "Thine own of Thine own we offer unto Thee." (Byzantine Liturgy). Thus, by combining geology with art and religion, I can render homage to God through His creation by using minerals of the Planet Earth, as natural pigments in painting His image.
Kelekian, Lena, ,, Lady
Purpose. Mechanistic studies have shown that inflammation, complement activation, extracellular matrix (ECM) turnover, growth factor imbalance, and oxidative stress are fundamental components of age-related macular degeneration (AMD). Matrix metalloproteinases (MMPs) mediate ECM turnover but also process various bioactive molecules. Here, we tested whether complement attack on RPE monolayers changes MMP secretion and activation, thereby altering the availability of growth factors in the extracellular space. Methods. Human embryonic RPE monolayers with stable transepithelial resistance (TER) were established. Complement activation was induced with H2O2 and normal human serum. MMP-2/9, vascular endothelial growth factor (VEGF) and pigment epithelium-derived factor (PEDF) protein, and mRNA levels were analyzed by Western blotting, ELISA, and real-time PCR; activity of MMP-2/9 by gelatin zymography. Results. Complement activation resulted in a loss of TER, which required transient membrane attack complex formation, activation of the alternative pathway, and VEGF secretion and signaling. Despite the generation of reactive oxygen species, cellular integrity or intracellular adenosine triphosphate (ATP) levels were unaffected. However, expression of MMP-2/9 and their protease activity was elevated. Inhibition of MMP-2/9 activity increased PEDF and decreased VEGF levels in the apical and basal supernatants but had no effect on their expression levels. VEGF levels in the supernatant correlated with the level TER reduction. Conclusions. These studies suggest that complement activation, by altering the expression and activation of MMPs, has the ability to generate a proangiogenic environment by altering the balance between VEGF and PEDF. Our findings link reported results that have been associated with AMD pathogenesis; oxidative stress; complement activation; VEGF/PEDF ratio; and MMP activity.
Bandyopadhyay, Mausumi; Rohrer, Barbel
Inorganic pigments have been utilized by mankind since ancient times, and are still widely used to colour materials exposed to elevated temperatures during processing or application. Indeed, in the case of glasses, glazes and ceramics, there is no alternative to inorganic pigments for colouring. However, most inorganic pigments contain heavy metals or transition metals that can adversely effect the environment and human health if critical levels are exceeded. Cadmium-based pigments in particular are a cause of concern: although the pigments are not toxic due to their very low solubility in water and dilute mineral acids, cadmium itself is toxic and can enter the environment in a bioavailable form through waste-disposal sites and incineration plants. This has led to regulations, based on the precautionary principle, that strongly restrict the use of cadmium pigments. And even though recent assessments have concluded that the risk to humans or the environment might be not as significant as originally feared, a strong demand for inherently safer substitutes remains. Here we demonstrate that solid solutions of the perovskites CaTaO 2N and LaTaON2 constitute promising candidates for such substitutes: their brilliance, tinting strength, opacity, dispersability, light-fastness and heat stability rival that of the cadmium pigments, while their colour can be tuned through the desired range, from yellow through orange to deep red, by simple composition adjustments. Because all the constituent elements are harmless, this perovskite-based inorganic pigment system seems a promising replacement that could eliminate one of the sources for cadmium emissions to the environment and some of the remaining concerns about pigment safety.
Jansen, M.; Letschert, H. P.
The introduction of spectral-domain optical coherence tomography (SD-OCT) has improved the clinical value for assessment of the eyes with macular disease. This article reviews the advances of SD-OCT for the diagnostic of various macular diseases. These include vitreomacular traction syndrome, cystoid macular edema/diabetic macular edema, epiretinal membranes, full-thickness macular holes, lamellar holes, pseudoholes, microholes, and schisis from myopia. Besides offering new insights into the pathogenesis of macular abnormalities, SD-OCT is a valuable tool for monitoring macular disease. PMID:20453539
Wolf, Sebastian; Wolf-Schnurrbusch, Ute
Fluorescent bisretinoids, such as A2E and all-trans-retinal dimer, form as a by-product of vitamin A cycling in retina and accumulate in retinal pigment epithelial (RPE) cells as lipofuscin pigments. These pigments are implicated in pathological mechanisms involved in several vision-threatening diseases including age-related macular degeneration. Efforts to understand damaging events initiated by these bisretinoids have revealed that photoexcitation of A2E by wavelengths in the visible spectrum leads to singlet oxygen production and photooxidation of A2E. Here we have employed liquid chromatography coupled to electrospray ionization mass spectrometry together with tandem mass spectrometry (MS/MS), to demonstrate that A2E also undergoes photooxidation-induced degradation and we have elucidated the structures of some of the aldehyde-bearing cleavage products. Studies in which A2E was incubated with a singlet oxygen generator yielded results consistent with a mechanism involving bisretinoid photocleavage at sites of singlet molecular oxygen addition. We provide evidence that one of the products released by A2E photodegradation is methylglyoxal, a low molecular weight reactive dicarbonyl with the capacity to form advanced glycation end products. Methylglyoxal is already known to be generated by carbohydrate and lipid oxidation; this is the first report of its production via bisretinoid photocleavage. It is significant that AGE-modified proteins are detected in deposits (drusen) that accumulate below RPE cells in vivo; drusen have been linked to age-related macular degeneration pathogenesis. Whereas various processes play a role in drusen formation, these findings are indicative of a contribution from lipofuscin photooxidation in RPE.
Wu, Yalin; Yanase, Emiko; Feng, Xidong; Siegel, Marshall M.; Sparrow, Janet R.
The regulation of water movement is of utmost importance for normal retinal function. Under physiological conditions, water is transported, dependent on the osmotic gradient, through the retinal pigment epithelial cell layer from the subretinal space to the choroid. The osmotic gradient has been found to be modified in eye diseases, thus leading to water accumulation in the subretinal space and the sensory retina, and subsequently contributing to the formation of macular oedema. Understanding the regulation of aquaporin expression is therefore crucial. In this study, we investigated the effects of hyperosmolarity on aquaporin-4 (AQP4) protein expression in the human retinal pigment epithelial cell line, ARPE?19. AQP4 expression was examined by PCR, western blot analysis and immunofluorescence. Ubiquitinylation was examined by immunoprecipitation. The results revealed that hyperosmotic stress rapidly decreased AQP4 expression in the ARPE-19 cells. The effect remained unmodified by lysosomal or mitogen-activated protein kinase inhibitors, but was reversed by proteasome inhibitors. However, no ubiquitinylation of AQP4 was detected. Our results suggest that hyperosmotic stress markedly reduces AQP4 expression possibly through a proteasome ubiquitinylation-independent pathway. This may represent an adaptation to hyperosmotic stress. The results presented in this study contribute to our understanding of the formation of macular oedema. PMID:24888368
Willermain, François; Janssens, Sarah; Arsenijevic, Tatjana; Piens, Isabelle; Bolaky, Nargis; Caspers, Laure; Perret, Jason; Delporte, Christine
The age-dependent accumulation of lipofuscin in the retinal pigment epithelium (RPE) has been associated with the development of retinal diseases, particularly age-related macular degeneration and Stargardt disease. A major component of lipofuscin is the bis-retinoid N-retinylidene-N-retinylethanolamine (A2E). The current model for the formation of A2E requires photoactivation of rhodopsin and subsequent release of all-trans-retinal. To understand the role of light exposure in the accumulation of lipofuscin and A2E, we analyzed RPEs and isolated rod photoreceptors from mice of different ages and strains, reared either in darkness or cyclic light. Lipofuscin levels were determined by fluorescence imaging, whereas A2E levels were quantified by HPLC and UV-visible absorption spectroscopy. The identity of A2E was confirmed by tandem mass spectrometry. Lipofuscin and A2E levels in the RPE increased with age and more so in the Stargardt model Abca4?/? than in the wild type strains 129/sv and C57Bl/6. For each strain, the levels of lipofuscin precursor fluorophores in dark-adapted rods and the levels and rates of increase of RPE lipofuscin and A2E were not different between dark-reared and cyclic light-reared animals. Both 11-cis- and all-trans-retinal generated lipofuscin-like fluorophores when added to metabolically compromised rod outer segments; however, it was only 11-cis-retinal that generated such fluorophores when added to metabolically intact rods. The results suggest that lipofuscin originates from the free 11-cis-retinal that is continuously supplied to the rod for rhodopsin regeneration and outer segment renewal. The physiological role of Abca4 may include the translocation of 11-cis-retinal complexes across the disk membrane.
Boyer, Nicholas P.; Higbee, Daniel; Currin, Mark B.; Blakeley, Lorie R.; Chen, Chunhe; Ablonczy, Zsolt; Crouch, Rosalie K.; Koutalos, Yiannis
We have used a novel human retinal pigmented epithelial (RPE) cell-based model that mimics drusen biogenesis and the pathobiology of age-related macular degeneration to evaluate the efficacy of newly designed peptide inhibitors of the complement system. The peptides belong to the compstatin family and, compared to existing compstatin analogs, have been optimized to promote binding to their target, complement protein C3, and to enhance solubility by improving their polarity/hydrophobicity ratios. Based on analysis of molecular dynamics simulation data of peptide-C3 complexes, novel binding features were designed by introducing intermolecular salt bridge-forming arginines at the N-terminus and at position -1 of N-terminal dipeptide extensions. Our study demonstrates that the RPE cell assay has discriminatory capability for measuring the efficacy and potency of inhibitory peptides in a macular disease environment. PMID:23954241
Gorham, Ronald D; Forest, David L; Tamamis, Phanourios; López de Victoria, Aliana; Kraszni, Márta; Kieslich, Chris A; Banna, Christopher D; Bellows-Peterson, Meghan L; Larive, Cynthia K; Floudas, Christodoulos A; Archontis, Georgios; Johnson, Lincoln V; Morikis, Dimitrios
Persistent spectral hole burning at 4.5 K has been used to investigate the excitonic energy level structure and the excited state dynamics of the recombinant class-IIa water-soluble chlorophyll-binding protein (WSCP) from cauliflower. The hole-burned spectra are composed of four main features: (i) a narrow zero-phonon hole (ZPH) at the burn wavelength, (ii) a number of vibrational ZPHs, (iii) a broad low-energy hole at ~665 and ~683 nm for chlorophyll b- and chlorophyll a-WSCP, respectively, and (iv) a second satellite hole at ~658 and ~673 nm for chlorophyll b- and chlorophyll a-WSCP, respectively. The doublet of broad satellite holes is assigned to an excitonically coupled chlorophyll dimer. The lower-energy holes at ~665 and ~683 nm for chlorophyll b- and chlorophyll a-WSCP, respectively, represent the lower exciton states. Taking into account the parameters of electron-phonon coupling, the lower exciton state can be assigned as the fluorescence origin. The lower exciton state is populated by two processes: (i) exciton relaxation from the higher exciton state and (ii) vibrational relaxation within the lower exciton state. Assuming identical site energies for the two excitonically coupled chlorophyll molecules, the dipole-dipole interaction energy J is directly determined to be 85 and 100 cm(-1) for chlorophyll b- and chlorophyll a-WSCP, respectively, based on the positions of the satellite holes. The Gaussian low-energy absorption band identified by constant fluence hole burning at 4.5 K has a width of ~150 cm(-1) and peaks at 664.9 and 682.7 nm for chlorophyll b- and chlorophyll a-WSCP, respectively. The action spectrum is broader and blue-shifted compared to the fluorescent lower exciton state. This finding can be explained by a slow protein relaxation between energetically inequivalent conformational substates within the lowest exciton state in agreement with the results of Schmitt et al. (J. Phys. Chem. B2008, 112, 13951). PMID:21417356
Pieper, J; Rätsep, M; Trostmann, I; Schmitt, F-J; Theiss, C; Paulsen, H; Eichler, H J; Freiberg, A; Renger, G
The dispersion of pigments in coatings is qualitatively known to affect the appearance and service life of the products. How to characterize pigment dispersion and relate the dispersion with the performance properties still remains challenging. A set of TiO2 pigmented epoxy coatings with different states of pigment dispersion was chosen to investigate the effect of pigment dispersion on surface morphology
Haiqing Hu; Lipiin Sung; Xiaohong Gu; Cyril Clerici; Derek Ho
Selective peptide cleavage has provided a general procedure for the study of the structure, including stereochemistry, of plant bile pigments. The information derived from the synthesis and spectral analysis of a series of 2,3-dihydrodioxobilins allows th...
R. W. Schoenleber
Few anti-pigmenting agents have been designed and developed according to their known hyperpigmentation mechanisms and corresponding intracellular signaling cascades. Most anti-pigmenting agents developed so far are mechanistically involved in the interruption of constitutional melanogenic mechanisms by which skin color is maintained at a normal and unstimulated level. Thus, owing to the difficulty of confining topical application to a specific hyperpigmented skin area, potent anti-pigmenting agents capable of attenuating the natural unstimulated pigmentation process have the risk of leading to hypopigmentation. Since intracellular signaling pathways within melanocytes do not function substantially in maintaining normal skin color and are activated only by environmental stimuli such as UV radiation, specifically down-regulating the activation of melanogenesis to the constitutive level would be an appropriate strategy to develop new potent anti-pigmenting agents with a low risk of hypopigmentation. In this article, we review the hyperpigmentation mechanisms and intracellular signaling pathways that lead to the stimulation of melanogenesis. We also discuss a screening and evaluation system to select candidates for new anti-melanogenic substances by focusing on inhibitors of endothelin-1 or stem cell factor-triggered intracellular signaling cascades. From this viewpoint, we show that extracts of the herbs Withania somnifera and Melia toosendan and the natural chemicals Withaferin A and Astaxanthin are new candidates for potent anti-pigmenting substances that avoid the risk of hypopigmentation. PMID:24823877
Imokawa, Genji; Ishida, Koichi
Few anti-pigmenting agents have been designed and developed according to their known hyperpigmentation mechanisms and corresponding intracellular signaling cascades. Most anti-pigmenting agents developed so far are mechanistically involved in the interruption of constitutional melanogenic mechanisms by which skin color is maintained at a normal and unstimulated level. Thus, owing to the difficulty of confining topical application to a specific hyperpigmented skin area, potent anti-pigmenting agents capable of attenuating the natural unstimulated pigmentation process have the risk of leading to hypopigmentation. Since intracellular signaling pathways within melanocytes do not function substantially in maintaining normal skin color and are activated only by environmental stimuli such as UV radiation, specifically down-regulating the activation of melanogenesis to the constitutive level would be an appropriate strategy to develop new potent anti-pigmenting agents with a low risk of hypopigmentation. In this article, we review the hyperpigmentation mechanisms and intracellular signaling pathways that lead to the stimulation of melanogenesis. We also discuss a screening and evaluation system to select candidates for new anti-melanogenic substances by focusing on inhibitors of endothelin-1 or stem cell factor-triggered intracellular signaling cascades. From this viewpoint, we show that extracts of the herbs Withania somnifera and Melia toosendan and the natural chemicals Withaferin A and Astaxanthin are new candidates for potent anti-pigmenting substances that avoid the risk of hypopigmentation.
Imokawa, Genji; Ishida, Koichi
Human skin pigmentation is the product of two clines produced by natural selection to adjust levels of constitutive pigmentation to levels of UV radiation (UVR). One cline was generated by high UVR near the equator and led to the evolution of dark, photoprotective, eumelanin-rich pigmentation. The other was produced by the requirement for UVB photons to sustain cutaneous photosynthesis of vitamin D3 in low-UVB environments, and resulted in the evolution of depigmented skin. As hominins dispersed outside of the tropics, they experienced different intensities and seasonal mixtures of UVA and UVB. Extreme UVA throughout the year and two equinoctial peaks of UVB prevail within the tropics. Under these conditions, the primary selective pressure was to protect folate by maintaining dark pigmentation. Photolysis of folate and its main serum form of 5-methylhydrofolate is caused by UVR and by reactive oxygen species generated by UVA. Competition for folate between the needs for cell division, DNA repair, and melanogenesis is severe under stressful, high-UVR conditions and is exacerbated by dietary insufficiency. Outside of tropical latitudes, UVB levels are generally low and peak only once during the year. The populations exhibiting maximally depigmented skin are those inhabiting environments with the lowest annual and summer peak levels of UVB. Development of facultative pigmentation (tanning) was important to populations settling between roughly 23° and 46° , where levels of UVB varied strongly according to season. Depigmented and tannable skin evolved numerous times in hominin evolution via independent genetic pathways under positive selection.
Jablonski, Nina G.; Chaplin, George
A 64-year-old man was noted to have a single pigmented lesion in the nostril of his nose. Clinical examination revealed a 5 mm nodular growth and brown lesion. With a presumed clinical diagnosis of malignant skin tumor, a biopsy was performed. The histological examination revealed the unexpected diagnosis of pigmented inverted follicular keratosis. The inverted follicular keratosis is an uncommon benign lesion that is usually diagnosed histologically rather than clinically. It commonly simulates other proliferative skin lesions.
Jaada, Nawel; Zaraa, Ines; Chelly, Ines; Cheikhrouhou, Rym; Trojjet, Sondes; Euch, Dalenda El; Mokni, Mourad; Haouet, Slim; Ben Osman, Amel
A 64-year-old man was noted to have a single pigmented lesion in the nostril of his nose. Clinical examination revealed a 5 mm nodular growth and brown lesion. With a presumed clinical diagnosis of malignant skin tumor, a biopsy was performed. The histological examination revealed the unexpected diagnosis of pigmented inverted follicular keratosis. The inverted follicular keratosis is an uncommon benign lesion that is usually diagnosed histologically rather than clinically. It commonly simulates other proliferative skin lesions. PMID:24396720
Jaada, Nawel; Zaraa, Ines; Chelly, Ines; Cheikhrouhou, Rym; Trojjet, Sondes; Euch, Dalenda El; Mokni, Mourad; Haouet, Slim; Ben Osman, Amel
Purpose The pathogenesis of age-related macular degeneration involves impaired protein degradation in retinal pigment epithelial (RPE) cells. The ubiquitin-proteasome pathway and the lysosomal pathway including autophagy are the major proteolytic systems in eukaryotic cells. Prior to proteolysis, heat shock proteins (HSPs) attempt to refold stress-induced misfolded proteins and thus prevent the accumulation of cytoplasmic protein aggregates. Recently, p62/sequestosome 1 (p62) has been shown to be a key player linking the proteasomal and lysosomal clearance systems. In the present study, the functional roles of p62 and HSP70 were evaluated in conjunction with proteasome inhibitor–induced autophagy in human RPE cells (ARPE-19). Methods The p62, HSP70, and ubiquitin protein levels and localization were analyzed by western blotting and immunofluorescense. Confocal and transmission electron microscopy were used to detect cellular organelles and to evaluate the morphological changes. The p62 and HSP70 levels were modulated using RNA interference and overexpression techniques. Cell viability was measured by colorimetric assay. Results Proteasome inhibition evoked the accumulation of perinuclear aggregates that strongly colocalized with p62 and HSP70. The p62 perinuclear accumulation was time- and concentration-dependent after MG-132 proteasome inhibitor loading. The silencing of p62, rather than Hsp70, evoked suppression of autophagy, when related to decreased LC3-II levels after bafilomycin treatment. In addition, the p62 silencing decreased the ubiquitination level of the perinuclear aggregates. Recently, we showed that hsp70 mRNA depletion increased cell death in ARPE-19 cells. Here, we demonstrate that p62 mRNA silencing has similar effects on cellular viability. Conclusions Our findings open new avenues for understanding the mechanisms of proteolytic processes in retinal cells, and could be useful in the development of novel therapies targeting p62 and HSP70.
Viiri, Johanna; Hyttinen, Juha M. T.; Ryhanen, Tuomas; Rilla, Kirsi; Paimela, Tuomas; Kuusisto, Erkki; Siitonen, Ari; Urtti, Arto; Salminen, Antero
Presentation of a case of crystalline macular distrophy diagnosed in a female patient with Sjögren-Larsson syndrome. The disease consists of clinical findings of spastic diplegia or tetraplegia, mental retardation, and congential ichthyosis. The eyes are affected in up to 100% of cases, and crystalline maculopathy is the main finding as described in this case report. On fundus examination multiple white dots were observed at ophthalmoscopy. The optical coherence tomography has shown not only the hipereflexive intraretinal spots but also macular atrophy with macular thickness reduction. The tomographic findings were first described in our country. PMID:19466337
Isaac, David Leonardo Cruvinel; Queiroz, Gustavo Henrique Medeiros; Feres, Caroline Campelo; Avila, Marcos
Background The association of inflammatory factors and the aqueous flare value with macular edema in branch retinal vein occlusion (BRVO) patients remains unclear. The relationship between the aqueous flare value and the vitreous fluid levels of vascular endothelial growth factor (VEGF), interleukin (IL)-6, monocyte chemotactic protein (MCP)-1, soluble intercellular adhesion molecule 1 (sICAM-1), and soluble VEGF receptor-2 (sVEGFR-2) was evaluated to investigate the role of inflammation in BRVO associated with macular edema. Aqueous flare values and the vitreous levels of VEGF, IL-6, MCP-1, sICAM-1, and sVEGFR-2 were compared between previously untreated patients with BRVO and patients with macular hole (MH). Methods Vitreous samples were obtained from 45 patients during vitreoretinal surgery (28 patients with BRVO and 17 with MH), and the levels of VEGF, IL-6, MCP-1, sICAM-1, and sVEGFR-2 were measured by enzyme-linked immunosorbent assay. Retinal ischemia was evaluated by measuring the area of capillary non-perfusion using fluorescein angiography and the Scion Image program. Aqueous flare values were measured with a laser flare meter and macular edema was examined by optical coherence tomography. Results The median aqueous flare value was significantly higher in the BRVO group (12.1 photon counts/ms) than in the MH group (4.5 photon counts/ms, P?0.001). There were significant correlations between the aqueous flare value and the vitreous levels of VEGF, IL-6, MCP-1, and sICAM-1 in the BRVO group (??=?0.54, P?=?0.005; ??=?0.56, P?=?0.004; ??=?0.52, P?=?0.006; and ??=?0.47, P?=?0.015, respectively). The aqueous flare value was also significantly correlated with the foveal thickness in the BRVO group (??=?0.40, P?=?0.037). Conclusions Inflammation may induce an increase of vascular permeability and disrupt the blood-aqueous barrier via release of inflammatory factors (VEGF, IL-6, MCP-1, and sICAM-1) in BRVO patients with macular edema.
We describe a spectral imaging system for minimally invasive identification, localization and relative quantification of pigments in cells and microbial communities. The modularity of the system allows pigment detection on spatial scales ranging from single-cell level to areas several tens of square-cm. Pigment identification uses in vivo absorption and\\/or auto-fluorescence spectra as the analytical signal. Along with the hardware, which
Lubos Polerecky; Andrew Bissett; Mohammad Al-Najjar; Paul Faerber; Harald Osmers; Peter A. Suci; Paul Stoodley; Dirk de Beer
Visual pigment bleaching desensitizes rod photoreceptors greatly in excess of that due to loss of quantum catch. Whether this phenomenon also occurs in cone photoreceptors was investigated for isolated salamander red-sensitive cones. In parallel experiments, (a) visual pigment depletion by steps of bleaching light was measured by microspectrophotometry, and (b) flash sensitivity was measured by recording light-sensitive membrane current. In isolated cones, visual pigment bleaching permanently reduced flash sensitivity significantly below that due to the reduction in quantum catch, and there was little spontaneous recovery of visual pigment. The "extra" desensitization due to bleaching was most prominent up to bleaches of approximately 80% visual pigment and reached a level approximately 1 log unit beyond that due to loss of quantum catch. At higher bleaches, the effect of loss of quantum catch became more important. Bleaching did not greatly reduce the maximum light-suppressible membrane current. A 99% reduction of the visual pigment permanently reduced the circulating current by only 30%. Visual pigment bleaching speeded up the kinetics of dim flash responses. All electrical effects of bleaching were reversed on exposure to 11-cis retinal, which probably caused visual pigment regeneration. Light adaptation in photopic vision is known to involve significant visual pigment depletion. The present results indicate that cones operate with a maintained circulating current even after a large pigment depletion. It is shown how Weber/Fechner behavior may still be observed in photopic vision when the contributions of bleaching to adaptation are included.
A 65-year-old female presented with visual disturbance in her right eye lasting for over 2 months. Following investigations, she was diagnosed with MacTel type 1 in the right eye. Visual symptoms were refractory to initial treatment with intravitreal bevacizumab and thereafter intravtireal triamicinolone. The patient was then treated with Ozurdex, following which central macular thickness (CMT) decreased (from 397??m to 286??m) and visual acuity deteriorated (from logMAR 0.48 to 0.59). At 14 weeks posttreatment with Ozurdex, a recurrence of cystoid macular oedema (CMO) was observed. Following a second Ozurdex, visual acuity improved (from logMAR 0.7 to 0.64) and CMT decreased (from 349??m to 279??m). An additional recurrence of CMO was observed at eighteen weeks following the second Ozurdex. Following a third Ozurdex injection visual acuity deteriorated (from logMAR 0.74 to 0.78) and CMT decreased (from 332??m to 279??m). Conclusion. Treatment of macular oedema secondary to MacTel with Ozurdex demonstrated promising anatomical outcomes. However, visual outcomes continued to gradually deteriorate.
Age-related macular degeneration (AMD) is the most common cause of blindness among the elderly. AMD patients have elevated levels of membrane attack complex (MAC) in their choroidal blood vessels and retinal pigment epithelium (RPE). MAC forms pores in cell membranes. Low levels of MAC result in an elevation of cytokine release such as vascular endothelial growth factor (VEGF) that promotes the formation of choroidal neovascularization (CNV). High levels of MAC result in cell lysis and RPE degeneration is a hallmark of advanced AMD. The current standard of care for CNV associated with wet AMD is intravitreal injection of anti-VEGF molecules every 4 to 12 weeks. Such injections have significant side effects. Recently, it has been found that membrane pore-forming proteins such as ?-haemolysin can mediate their toxic effects through auto- and paracrine signaling and that complement-induced lysis is amplified through ATP release followed by P2X receptor activation. We hypothesized that attenuation of P2X receptor activation may lead to a reduction in MAC deposition and consequent formation of CNV. Hence, in this study we investigated topical application of the purinergic P2X antagonist Pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid (PPADS) as a potential treatment for AMD. We found that 4.17 µM PPADS inhibited formation of HUVEC master junctions and master segments by 74.7%. In a human complement mediated cell lysis assay, 104 µM PPADS enabled almost complete protection of Hepa1c1c7 cells from 1% normal human serum mediated cell lysis. Daily topical application of 4.17 mM PPADS for 3 days attenuated the progression of laser induced CNV in mice by 41.8% and attenuated the deposition of MAC at the site of the laser injury by 19.7%. Our data have implications for the future treatment of AMD and potentially other ocular disorders involving CNV such as angioid streaks, choroidal rupture and high myopia.
Birke, Kerstin; Lipo, Erion; Birke, Marco T.; Kumar-Singh, Rajendra
The effectiveness of latent fingerprint development techniques is heavily influenced by the physical and chemical properties of the deposition surface. The use of powder suspensions is increasing for development of prints on a range of surfaces. We demonstrate that carbon powder suspension development on polymers is detrimentally affected by the presence of common white pigment, titanium dioxide. Scanning electron microscopy demonstrates that patches of the compound are clearly associated with increased levels of powder adhesion. Substrates with nonlocalized titanium dioxide content also exhibit increased levels of carbon powder staining on a surface-wide basis. Secondary ion mass spectrometry and complementary techniques demonstrate the importance of levels of the pigment within the top 30 nm. The association is independent of fingermark deposition and may be related to surface energy variation. The detrimental effect of the pigment is not observed with small-particle reagent (MoS2 SPR) or cyanoacrylate (superglue) fuming techniques that exploit different development mechanisms. PMID:23822671
Bacon, Simon R; Ojeda, Jesus J; Downham, Rory; Sears, Vaughn G; Jones, Benjamin J
SD-OCT has become an essential tool for evaluating macular pathology; however several aspects of data collection and analysis affect the accuracy of retinal thickness measurements. Here we evaluated sampling density, scan centering, and axial length compensation as factors affecting the accuracy of macular thickness maps. Forty-three patients with various retinal pathologies and 113 normal subjects were imaged using Cirrus HD-OCT. Reduced B-scan density was associated with increased interpolation error in ETDRS macular thickness plots. Correcting for individual differences in axial length revealed modest errors in retinal thickness maps, while more pronounced errors were observed when the ETDRS plot was not positioned at the center of the fovea (which can occur as a result of errant fixation). Cumulative error can exceed hundreds of microns, even under “ideal observer” conditions. This preventable error is particularly relevant when attempting to compare macular thickness maps to normative databases or measuring the area or volume of retinal features.
Odell, Daniel; Dubis, Adam M.; Lever, Jackson F.; Stepien, Kimberly E.; Carroll, Joseph
Post traumatic macular holes have shown successful anatomic outcomes with vitrectomy with internal limiting membrane (ILM) peeling and gas injection. Intraocular use of triamcinolone acetonide (TA) crystals is gaining popularity in patients for visualization of the vitreous cortex, posterior vitreous detachment induction and ILM peeling during macular hole surgery. However, the possibility of residual steroid crystals clogging the hole at the conclusion of surgery exists. In our case, residual TA was observed biomicroscopically in the fovea on the seventh day after surgery, Optical Coherence Tomography (OCT) image of the eye showed a hyper reflective mass corresponding to the TA. However, a repeat OCT carried out four weeks after surgery showed recovery of the foveal morphologic features to an almost normal depression, with closure of the hole. Residual TA crystals in the macular hole post vitreous surgery may not interfere with ultimate macular hole closure or visual improvement. PMID:20413928
Kumar, Atul; Sinha, Subijay; Gupta, Anoop
Dobesilate is an anti-inflammatory and antipermeability agent. Intravitreal administration of this compound is a therapeutically beneficial agent in the treatment of chronic cystoid macular oedema. PMID:22778475
Cuevas, Pedro; Outeirińo, Luis A; Angulo, Javier; Giménez-Gallego, Guillermo
The authors present the main modifiable risk factors that may trigger and/or worsen age-related macular degeneration. Mechanisms of action related to these factors as well as preventive measures and intervention effectiveness are discussed. PMID:19668979
Torres, Rogil José de Almeida; Maia, Maurício; Muccioli, Cristina; Winter, Guilherme; Souza, Greyce Kelly de; Pasqualotto, Luca Rodrigo; Luchini, Andréa; Précoma, Dalton Bertolim
Rhodopsin and related opsin-based pigments, which are photosensitive membrane proteins, have been extensively studied using a wide variety of techniques, with rhodopsin being the most understood G protein-coupled receptor (GPCR). Animals use various opsin-based pigments for vision and a wide variety of non-visual functions. Many functionally varied pigments are roughly divided into two kinds, based on their photoreaction: bistable and monostable pigments. Bistable pigments are thermally stable before and after photo-activation, but monostable pigments are stable only before activation. Here, we review the diversity of bistable pigments and their molecular characteristics. We also discuss the mechanisms underlying different molecular characteristics of bistable and monostable pigments. In addition, the potential of bistable pigments as a GPCR model is proposed. PMID:20852774
Tsukamoto, Hisao; Terakita, Akihisa
There is an increasing body of evidence as to the risk factors for age-related macular degeneration. Age and genetic make-up are the most important risk factors identified to date. Over the next decade, the different genes that are involved in the development of age-related macular degeneration will be identified. There is reasonably consistent evidence that smoking cigarettes results in increased
Jennifer R. Evans
Breakdown of the inner endothelial blood-retinal barrier (BRB), as occurs in diabetic retinopathy, age-related macular degeneration, retinal vein occlusions, uveitis and other chronic retinal diseases, results in vasogenic edema and neural tissue damage, causing loss of vision. The central mechanism of altered BRB function is a change in the permeability characteristics of retinal endothelial cells caused by elevated levels of growth factors, cytokines, advanced glycation end products, inflammation, hyperglycemia and loss of pericytes. Subsequently, paracellular but also transcellular transport across the retinal vascular wall increases via opening of endothelial intercellular junctions and qualitative and quantitative changes in endothelial caveolar transcellular transport, respectively. Functional changes in pericytes and astrocytes, as well as structural changes in the composition of the endothelial glycocalyx and the basal lamina around BRB endothelium further facilitate BRB leakage. As Starling's rules apply, active transcellular transport of plasma proteins by the BRB endothelial cells causing increased interstitial osmotic pressure is probably the main factor in the formation of macular edema. The understanding of the complex cellular and molecular processes involved in BRB leakage has grown rapidly in recent years. Although appropriate animal models for human conditions like diabetic macular edema are lacking, these insights have provided tools for rational design of drugs aimed at restoring the BRB as well as for design of effective transport of drugs across the BRB, to treat the chronic retinal diseases such as diabetic macular edema that affect the quality-of-life of millions of patients. PMID:23416119
Klaassen, Ingeborg; Van Noorden, Cornelis J F; Schlingemann, Reinier O
Macular oedema (ME) occurs in a wide variety of pathological conditions and accounts for different degrees of vision loss. Early detection of ME is therefore critical for diagnosis and therapeutic management. Optical coherence tomography (OCT) is a non-contact, diagnostic method that uses infrared light, which allows the analysis of the retinal structure by means of high-resolution tomographic cross sections. The identification, localisation, quantification and long-term follow-up of fluid collections are the most important capabilities of OCT. Since the introduction of OCT in clinical practice, it has become an invaluable diagnostic tool and different patterns of ME have been reported. The purpose of this manuscript is to review OCT profiles of ME according to the aetiology and describe what has been reported regarding intraretinal features in vivo. PMID:24934220
Trichonas, George; Kaiser, Peter K
Age-related macular degeneration (AMD) is one of the leading causes of blindness in the developed world. Although effective treatment modalities such as anti-VEGF treatment have been developed for neovascular AMD, there is still no effective treatment for geographical atrophy, and therefore the most cost-effective management of AMD is to start with prevention. This review looks at current evidence on preventive measures targeted at AMD. Modalities reviewed include (1) nutritional supplements such as the Age-Related Eye Disease Study (AREDS) formula, lutein and zeaxanthin, omega-3 fatty acid, and berry extracts, (2) lifestyle modifications, including smoking and body-mass-index, and (3) filtering sunlight, i.e. sunglasses and blue-blocking intraocular lenses. In summary, the only proven effective preventive measures are stopping smoking and the AREDS formula.
Koo, Simon Chi Yan; Chan, Clement Wai Nang
Age-related macular degeneration (AMD) is one of the leading causes of blindness in the developed world. Although effective treatment modalities such as anti-VEGF treatment have been developed for neovascular AMD, there is still no effective treatment for geographical atrophy, and therefore the most cost-effective management of AMD is to start with prevention. This review looks at current evidence on preventive measures targeted at AMD. Modalities reviewed include (1) nutritional supplements such as the Age-Related Eye Disease Study (AREDS) formula, lutein and zeaxanthin, omega-3 fatty acid, and berry extracts, (2) lifestyle modifications, including smoking and body-mass-index, and (3) filtering sunlight, i.e. sunglasses and blue-blocking intraocular lenses. In summary, the only proven effective preventive measures are stopping smoking and the AREDS formula. PMID:20862519
Wong, Ian Yat Hin; Koo, Simon Chi Yan; Chan, Clement Wai Nang
Background Age-related macular degeneration (AMD) is a degenerative process that leads to severe vision loss. Wet AMD is defined by choroidal neovascularisation, leading to the accumulation of subretinal fluid (SRF), macular oedema (ME), and pigment epithelium detachments (PED). Purpose To evaluate the initial clinical experience of conversion from bevacizumab or ranibizumab to aflibercept in wet AMD patients. Methods Records of 250 consecutive wet AMD patients were retrospectively reviewed. Of 250 patients, 29 were naive (with no previous treatment), and 221 were previously treated with bevacizumab (1/3) or ranibizumab (2/3). On average, converted patients received 14 injections every 6?weeks on a treat-and-extend regimen with Avastin or Lucentis before being converted to aflibercept every 7?weeks on average (no loading dose) for three doses. For the purposes of this study, we concentrated on the patients converted to aflibercept since the number of naive patients was too small to draw any conclusion from. Snellen (as logMar) visual acuities, and optical coherence tomography (OCT) were compared predrug and postdrug conversion. Results Converted patients did not show a significant difference in visual acuity or average OCT thickness from preconversion values; however, small improvements in ME (p=0.0001), SRF (p=0.0001), and PED (p=0.008) grading were noted on average after conversion to aflibercept. Conclusions No significant difference in visual outcome or average OCT thickness was observed when switched from bevacizumab or ranibizumab q6?week to aflibercept 7-week dosing, on average. Mild anatomic improvements did occur in converted patients with regard to ME, SRF and PED improvement, on average, after conversion to aflibercept, and aflibercept was injected less frequently. No serious adverse reactions, including ocular infections or inflammation, as well as ocular and systemic effects were noted.
Ferrone, Philip J; Anwar, Farihah; Naysan, Jonathan; Chaudhary, Khurram; Fastenberg, David; Graham, Kenneth; Deramo, Vincent
Background There have been reports that by compensating for the ocular aberrations using adaptive optical systems it may be possible to improve the resolution of clinical retinal imaging systems beyond what is now possible. In order to develop such system to observe eyes with retinal disease, understanding of the ocular wavefront aberrations in individuals with retinal disease is required. Methods 82 eyes of 66 patients with macular disease (epiretinal membrane, macular edema, macular hole etc.) and 85 eyes of 51 patients without retinal disease were studied. Using a ray-tracing wavefront device, each eye was scanned at both small and large pupil apertures and Zernike coefficients up to 6th order were acquired. Results In phakic eyes, 3rd order root mean square errors (RMS) in macular disease group were statistically greater than control, an average of 12% for 5mm and 31% for 3mm scan diameters (p<0.021). In pseudophakic eyes, there also was an elevation of 3rd order RMS, on average 57% for 5mm and 51% for 3mm scan diameters (p<0.031). Conclusion Higher order wavefront aberrations in eyes with macular disease were greater than in control eyes without disease. Our study suggests that such aberrations may result from irregular or multiple reflecting retinal surfaces. Modifications in wavefront sensor technology will be needed to accurately determine wavefront aberration and allow correction using adaptive optics in eyes with macular irregularities.
Bessho, Kenichiro; Bartsch, Dirk-Uwe G.; Gomez, Laura; Cheng, Lingyun; Koh, Hyoung Jun; Freeman, William R.
Age-related macular degeneration (AMD) is the leading cause of vision loss in the elderly throughout the industrialized world. Its most prominent pathologic features are lesions involving the retinal pigment epithelium (RPE) the Bruch's membrane, the degeneration of photoreceptors, and, in the most aggressive cases, choroidal neovascularization. Genetic associations between the risk of developing AMD and polymorphism within components of the complement system, as well as chemokine receptors expressed on microglial cells and macrophages, have linked retinal degeneration and choroidal neovascularization to innate immunity (inflammation). In addition to inflammation, players of the adaptive immunity including cytokines, chemokines, antibodies, and T cells have been detected in animal models of AMD and in patients suffering from this pathology. These observations suggest that adaptive immunity might play a role in different processes associated with AMD such as RPE atrophy, neovascularization, and retinal degeneration. To this date however, the exact roles (if any) of autoantibodies and T cells in AMD remain unknown. In this review we discuss the potential effects of adaptive immune responses in AMD pathogenesis.
PurposeTo report the results of a prospective clinical series to evaluate the management of both torsion and diplopia in a large group of patients after full macular translocation (FMT) and extraocular muscle surgery.
Sharon F Freedman; Sandra Holgado; Laura B Enyedi; Cynthia A Toth
Purpose Age-related macular degeneration (AMD) is a major cause of blindness in developed countries. The molecular pathogenesis of early events in AMD is poorly understood. We investigated differential gene expression in samples of human retinal pigment epithelium (RPE) and choroid from early AMD and control maculas with exon-based arrays. Methods Gene expression levels in nine human donor eyes with early AMD and nine control human donor eyes were assessed using Affymetrix Human Exon ST 1.0 arrays. Two controls did not pass quality control and were removed. Differentially expressed genes were annotated using the Database for Annotation, Visualization and Integrated Discovery (DAVID), and gene set enrichment analysis (GSEA) was performed on RPE-specific and endothelium-associated gene sets. The complement factor H (CFH) genotype was also assessed, and differential expression was analyzed regarding high AMD risk (YH/HH) and low AMD risk (YY) genotypes. Results Seventy-five genes were identified as differentially expressed (raw p value <0.01; ?50% fold change, mean log2 expression level in AMD or control ? median of all average gene expression values); however, no genes were significant (adj. p value <0.01) after correction for multiple hypothesis testing. Of 52 genes with decreased expression in AMD (fold change <0.5; raw p value <0.01), 18 genes were identified by DAVID analysis as associated with vision or neurologic processes. The GSEA of the RPE-associated and endothelium-associated genes revealed a significant decrease in genes typically expressed by endothelial cells in the early AMD group compared to controls, consistent with previous histologic and proteomic studies. Analysis of the CFH genotype indicated decreased expression of ADAMTS9 in eyes with high-risk genotypes (fold change = –2.61; raw p value=0.0008). Conclusions GSEA results suggest that RPE transcripts are preserved or elevated in early AMD, concomitant with loss of endothelial cell marker expression. These results are consistent with the notion that choroidal endothelial cell dropout or dedifferentiation occurs early in the pathogenesis of AMD.
Whitmore, S. Scott; Braun, Terry A.; Skeie, Jessica M.; Haas, Christine M.; Sohn, Elliott H.; Stone, Edwin M.; Scheetz, Todd E.
Aim: Selective retinal pigment epithelium (RPE) laser treatment is a new technique which selectively damages the RPE while sparing the neural retina. One difficulty is the inability to visualise the laser lesions. The aim of the study was to investigate whether fundus autofluorescence (AF) is changed because of the RPE damage, and thus might be used for treatment control. Additionally, the clinical course of patients with various macular diseases was evaluated. Methods: 26 patients with macular diseases (diabetic maculopathy (DMP), soft drusen maculopathy (AMD), and central serous retinopathy (CSR)) were treated and followed up for at least 6 months. Treatment was performed with a train of repetitive short laser pulses (800 ns) of a frequency doubled Nd:YAG laser (parameters: 532 nm, 50 and 500 pulses at 100 and 500 Hz, retinal spot diameter 200 ?m, pulse energies 75–175 ?J). AF was excited by 488 nm and detected by a barrier filter at 500 nm (HRA, Heidelberg Engineering, Germany). Patients were examined by ophthalmoscopy, fluorescein angiography, and autofluorescence measurements at various times after treatment (10 minutes, 1 hour, 1 and 6 weeks, 3, 6, and 12 months). Results: Fluorescein angiography showed leakage from the irradiated areas for about 1 week after treatment. None of the laser lesions was ophthalmoscopically visible during treatment. Identification of the lesions was possible by AF imaging showing an intensity decay in the irradiated area in 22 out of 26 patients, predominantly in patients with CSR and AMD. Lesions could be identified 10 minutes after treatment as hypoautofluorescent spots, which were more pronounced 1 hour later. During follow up the laser spots became hyperautofluorescent. In patients with DMP some AF images were less helpful because of diffuse oedema and larger retinal thickness. In these cases ICG angiography was able to confirm therapeutic success very well. Most of the patients have had benefit from the treatment, with best results obtained for CSR patients. Conclusion: Imaging of non-visible selective RPE laser effects can be achieved by AF measurements predominantly in patients without retinal oedema. Therefore, AF may replace invasive fluorescein angiography in many cases to verify therapeutic laser success. Selective laser treatment has the potential to improve the prognosis of macular diseases without the risk of laser scotomas.
Framme, C; Brinkmann, R; Birngruber, R; Roider, J
We present polarization-sensitive optical coherence tomography (PS-OCT) for quantitative assessment of retinal pathologies in age-related macular degeneration (AMD). On the basis of the polarization scrambling characteristics of the retinal pigment epithelium, novel segmentation algorithms were developed that allow one to segment pathologic features such as drusen and atrophic zones in dry AMD as well as to determine their dimensions. Results from measurements in the eyes of AMD patients prove the ability of PS-OCT for quantitative imaging based on the retinal features polarizing properties. Repeatability measurements were performed in retinas diagnosed with drusen and geographic atrophy in order to evaluate the performance of the described methods. PS-OCT appears as a promising imaging modality for three-dimensional retinal imaging and ranging with additional contrast based on the structures' tissue-inherent polarization properties.
Baumann, Bernhard; Götzinger, Erich; Pircher, Michael; Sattmann, Harald; Schütze, Christopher; Schlanitz, Ferdinand; Ahlers, Christian; Schmidt-Erfurth, Ursula; Hitzenberger, Christoph K.
We present polarization-sensitive optical coherence tomography (PS-OCT) for quantitative assessment of retinal pathologies in age-related macular degeneration (AMD). On the basis of the polarization scrambling characteristics of the retinal pigment epithelium, novel segmentation algorithms were developed that allow one to segment pathologic features such as drusen and atrophic zones in dry AMD as well as to determine their dimensions. Results from measurements in the eyes of AMD patients prove the ability of PS-OCT for quantitative imaging based on the retinal features polarizing properties. Repeatability measurements were performed in retinas diagnosed with drusen and geographic atrophy in order to evaluate the performance of the described methods. PS-OCT appears as a promising imaging modality for three-dimensional retinal imaging and ranging with additional contrast based on the structures’ tissue-inherent polarization properties.
Baumann, Bernhard; Gotzinger, Erich; Pircher, Michael; Sattmann, Harald; Schutze, Christopher; Schlanitz, Ferdinand; Ahlers, Christian; Schmidt-Erfurth, Ursula; Hitzenberger, Christoph K.
Students perform DNA forensics using food coloring to enhance their understanding of DNA fingerprinting, restriction enzymes, genotyping and DNA gel electrophoresis. They place small drops of different food coloring ("water-based paint") on strips of filter paper and then place one paper strip end in water. As water travels along the paper strips, students observe the pigments that compose the paint decompose into their color components. This is an example of the chromatography concept applied to DNA forensics, with the pigments in the paint that define the color being analogous to DNA fragments of different lengths.
University Of Houston
Pigmented paravenous retinochoroidal atrophy (PPRCA) is an uncommon disease characterized by perivenous aggregations of pigment clumps associated with peripapillary and radial zones of retinochoroidal atrophy that are distributed along the retinal veins. Patients are usually asymptomatic and the disease process is non-progressive or slow and subtly progressive. It is commonly bilateral and symmetric. The cause of the condition may be unknown or idiopathic, although a dysgenetic, degenerative, hereditary etiology or even an inflammatory cause has been hypothesized. A non-inflammatory cause is referred to as primary, while inflammation-associated PPRCA is referred to as secondary or pseudo PPRCA. The present study reviewed and summarized the features of PPRCA.
HUANG, HOU-BIN; ZHANG, YI-XIN
Over a million people in US alone are visually impaired due to the neovascular form of age-related macular degeneration (AMD). The current treatment is monthly intravitreal injections of a protein which inhibits Vascular Endothelial Growth Factor, thereby slowing progression of the disease. The immense financial and logistical burden of millions of intravitreal injections signifies an urgent need to develop more long-lasting and cost-effective treatments for this and other retinal diseases. Viral transfection of ocular cells allows creation of a "biofactory" that secretes therapeutic proteins. This technique has been proven successful in non-human primates, and is now being evaluated in clinical trials for wet AMD. However, there is a critical need to down-regulate gene expression in the case of total resolution of retinal condition, or if patient has adverse reaction to the trans-gene products. The site for genetic therapy of AMD and many other retinal diseases is the retinal pigment epithelium (RPE). We developed and tested in pigmented rabbits, an optical method to down-regulate transgene expression in RPE following vector delivery, without retinal damage. Microsecond exposures produced by a rapidly scanning laser vaporize melanosomes and destroy a predetermined fraction of the RPE cells selectively. RPE continuity is restored within days by migration and proliferation of adjacent RPE, but since the transgene is not integrated into the nucleus it is not replicated. Thus, the decrease in transgene expression can be precisely determined by the laser pattern density and further reduced by repeated treatment without affecting retinal structure and function.
Palanker, D.; Lavinsky, D.; Chalberg, T.; Mandel, Y.; Huie, P.; Dalal, R.; Marmor, M.
The abstract is concerned with the pigments found in photosynthetic microorganisms, with the function of these pigments in photosynthesis, with the electron spin resonance signals induced by illumination of photosynthetic organisms, and with the isolation...
M. B. Allen
We study excitation energy transfer in a simple model of a photosynthetic complex. The model, described by the Lindblad equation, consists of pigments interacting via dipole-dipole interaction. The overlapping of pigments induces an on-site energy disorder, providing a mechanism for blocking the excitation transfer. Based on the average efficiency as well as the robustness of random configurations of pigments, we calculate the optimal number of pigments that should be enclosed in a pigment-protein complex of a given size. The results suggest that a large fraction of pigment configurations are efficient as well as robust if the number of pigments is properly chosen. We compare the optimal results of the model to the structure of pigment-protein complexes as found in nature, finding good agreement.
Jesenko, Simon; Žnidari?, Marko
Intravitreal injections of anti-vascular endothelial growth factor agents, such as ranibizumab, have significantly improved the management of neovascular age-related macular degeneration. This study used patient-level simulation modelling to estimate the number of individuals in Australia who would have been likely to avoid legal blindness or visual impairment due to neovascular age-related macular degeneration over a 2-year period as a result of intravitreal ranibizumab injections. The modelling approach used existing data for the incidence of neovascular age-related macular degeneration in Australia and outcomes from ranibizumab trials. Blindness and visual impairment were defined as visual acuity in the better-seeing eye of worse than 6/60 or 6/12, respectively. In 2010, 14 634 individuals in Australia were estimated to develop neovascular age-related macular degeneration who would be eligible for ranibizumab therapy. Without treatment, 2246 individuals would become legally blind over 2 years. Monthly 0.5 mg intravitreal ranibizumab would reduce incident blindness by 72% (95% simulation interval, 70–74%). Ranibizumab given as needed would reduce incident blindness by 68% (64–71%). Without treatment, 4846 individuals would become visually impaired over 2 years; this proportion would be reduced by 37% (34–39%) with monthly intravitreal ranibizumab, and by 28% (23–33%) with ranibizumab given as needed. These data suggest that intravitreal injections of ranibizumab, given either monthly or as needed, can substantially lower the number of cases of blindness and visual impairment over 2 years after the diagnosis of neovascular age-related macular degeneration.
Mitchell, Paul; Bressler, Neil; Doan, Quan V.; Dolan, Chantal; Ferreira, Alberto; Osborne, Aaron; Rochtchina, Elena; Danese, Mark; Colman, Shoshana; Wong, Tien Y.
Ultraviolet (UV) cone pigments can provide insights into the molecular evolution of vertebrate vision since they are nearer to ancestral pigments than the dim-light rod photoreceptor rhodopsin. While visible-absorbing pigments contain an 11-cis retinyl chromophore with a protonated Schiff-base (PSB11), UV pigments uniquely contain an unprotonated Schiff-base (USB11). Upon F86Y mutation in model UV pigments, both the USB11 and PSB11 forms of the chromophore are found to coexist at physiological pH. The origin of this intriguing equilibrium remains to be understood at the molecular level. Here, we address this phenomenon and the role of the USB11 environment in spectral tuning by combining mutagenesis studies with spectroscopic (UV-vis) and theoretical [DFT-QM/MM (SORCI+Q//B3LYP/6-31G(d): Amber96)] analysis. We compare structural models of the wild-type (WT), F86Y, S90A and S90C mutants of Siberian hamster ultraviolet (SHUV) cone pigment to explore structural rearrangements that stabilize USB11 over PSB11. We find that the PSB11 forms upon F86Y mutation and is stabilized by an "inter-helical lock" (IHL) established by hydrogen-bonding networks between transmembrane (TM) helices TM6, TM2, and TM3 (including water w2c and amino acid residues Y265, F86Y, G117, S118, A114, and E113). The findings implicate the involvement of the IHL in constraining the displacement of TM6, an essential component of the activation of rhodopsin, in the spectral tuning of UV pigments. PMID:24295328
Sekharan, Sivakumar; Mooney, Victoria L; Rivalta, Ivan; Kazmi, Manija A; Neitz, Maureen; Neitz, Jay; Sakmar, Thomas P; Yan, Elsa C Y; Batista, Victor S
Indocyanine Green Angiography (or ICGA) is a technique performed by ophthalmologists to diagnose abnormalities of the choroidal and retinal vasculature of various eye diseases such as age-related macular degeneration (AMD). ICGA is especially useful to image the posterior choroidal vasculature of the eye due to its capability of penetrating through the pigmented layer with its infrared spectrum. ICGA time course can be divided into early, middle, and late phases. The three phases provide valuable information on the pathology of eye problems. Although time-course ICGA by intravenous (IV) injection is widely used in the clinic for the diagnosis and management of choroid problems, ICGA by intraperitoneal injection (IP) is commonly used in animal research. Here we demonstrated the technique to obtain high-resolution ICGA timecourse images in mice by tail-vein injection and confocal scanning laser ophthalmoscopy. We used this technique to image the choroidal lesions in a mouse model of age-related macular degeneration. Although it is much easier to introduce ICG to the mouse vasculature by IP, our data indicate that it is difficult to obtain reproducible ICGA time course images by IP-ICGA. In contrast, ICGA via tail vein injection provides high quality ICGA time-course images comparable to human studies. In addition, we showed that ICGA performed on albino mice gives clearer pictures of choroidal vessels than that performed on pigmented mice. We suggest that time-course IV-ICGA should become a standard practice in AMD research based on animal models.
Kumar, Sandeep; Berriochoa, Zachary; Jones, Alex D.; Fu, Yingbin
Chronic exposure to oxidative stress causes damage to retinal pigment epithelial cells which may lead to the development of age-related macular degeneration, the major cause of vision loss in humans. Anti-oxidants provide a natural defense against retinal cell damage. The present study was designed to evaluate the potential anti-oxidant activity and protective effect of two diarylheptanoids isolated from a medicinal
Thunchnok Jitsanong; Kornnika Khanobdee; Pawinee Piyachaturawat; Kanokpan Wongprasert
The Macular Photocoagulation Study (MPS) is a set of randomized, controlled clinical trials designed to evaluate the effectiveness of laser photocoagulation of neovascular lesions, secondary to age-related (senile) macular degeneration (AMD or SMD), ocula...
Zinc-ferrite pigment was prepared by solid-state reaction. A mixture of ?-Fe2O3 and ZnO in a molar ratio of 1:1 was fired at 1,200°C. X-ray diffraction measurements proved that the reacted material crystallized into a spinal structure. Measurement of the pigment specification and properties were carried out according to standard international methods. The pigment extract and the extract of the pigment-linseed
Y. M. Abu Ayana; S. M. El-Sawy; S. H. Salah
The chicken retina contains rhodopsin (a rod visual pigment) and four kinds of cone visual pigments. The primary structures of chicken red (iodopsin) and rhodopsin have been determined previously. Here we report isolation of three cDNA clones encoding additional pigments from a chicken retinal cDNA library. Based on the partial amino acid sequences of the purified chicken visual pigments together
Toshiyuki Okano; Daisuke Kojima; Yoshitaka Fukada; Yoshinori Shichida; Toru Yoshizawa
The Monascus species has been used in foods for thousands of years in China. In this study, 10 azaphilone pigments, including four yellow and six orange pigments, were isolated from the fermented rice and dioscorea of Monascus purpureus NTU 568. By employing lipopolysaccharide (LPS)-stimulated murine macrophage RAW 264.7 cells, we determined the inhibitory activities of these pigments on nitric oxide (NO) production. As a result, four orange pigments, monaphilols A-D, showed the highest activities (IC50 = 1.0-3.8 ?M), compared with the other two orange pigments, monascorubrin (IC50 > 40 ?M) and rubropunctatin (IC50 = 21.2 ?M), and the four yellow pigments ankaflavin (IC50 = 21.8 ?M), monascin (IC50 = 29.1 ?M), monaphilone A (IC50 = 19.3 ?M), and monaphilone B (IC50 = 22.6 ?M). Using Western blot and ELISA kits, we found that treatments with 30 ?M of the yellow pigments and 5 ?M of the orange pigments could down-regulate the protein expression of inducible nitric oxide synthase (iNOS) and suppress the production of tumor necrosis factor-? (TNF-?), interleukin-1? (IL-1?), and interleukin-6 (IL-6). We also used two animal experiments to evaluate the anti-inflammatory effects of these pigments. In a 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced ear edema model, eight of these pigments (0.5 mg/ear) could prevent ear edema against TPA administrations on the ears of BALB/c mice. In an LPS-injection mice model, several of these pigments (10 mg/kg) could inhibit the NO, TNF-?, IL-1?, and IL-6 levels in the plasma of BALB/c mice. As concluded from the in vitro and in vivo studies, six azaphilonoid pigments, namely, ankaflavin, monaphilone A, and monaphilols A-D, showed high potential to be developed into chemopreventive foods or drugs against inflammation-associated diseases. PMID:23458314
Hsu, Li-Chuan; Liang, Yu-Han; Hsu, Ya-Wen; Kuo, Yao-Haur; Pan, Tzu-Ming
Retinal pigment epithelial (RPE) cell transplantation represents potential treatment for age-related macular degeneration (AMD). Because delivery of isolated cells can cause serious complications, it is necessary to develop a suitable transplant membrane that could support an intact functioning RPE monolayer. Polydimethylsiloxane (PDMS) possesses the physical properties required for a transplanting device and is widely used clinically. We have investigated the use of PDMS as a potential surface for the growth of healthy RPE monolayers. PDMS discs were surface modified by air and ammonia gas plasma treatments. Dynamic contact angles were measured to determine the changes in wettability. Human ARPE-19 cells were seeded onto untreated and treated samples. Cell number, morphology and monolayer formation, cytotoxicity, and phagocytosis of photoreceptor outer segments (POS) were assessed at set time-points. Air plasma treatment increased the wettability of PDMS. This significantly enhanced cell growth, reaching confluence by day 7. Immunofluorescence revealed well-defined actin staining, monolayer formation, and high cell viability on air plasma treated and untreated surfaces, and to a lesser extent, on ammonia plasma treated. Furthermore, RPE monolayers were able to demonstrate phagocytosis of POS in a time-dependent manner similar to control. PDMS can support an intact functional monolayer of healthy differentiated RPE cells. PMID:17058209
Krishna, Yamini; Sheridan, Carl M; Kent, David L; Grierson, Ian; Williams, Rachel L
Lipofuscin is a deposit that is formed over time by aggregation and clustering of incompletely degraded membrane material in various types of cells. Lipofuscin is made of free-radical-damaged protein and fat and is known to be present in age- related macular dgeneration (AMD), Alzheimer disease, and Parkinson disease. AMD is the leading cause of blindness in adults. The degradation of retinal pigment epithelium cells (RPE) through accumulation of lipsofuscin is considered a significant pathogenic factor in the development of AMD. We will present the results of a study of the kinetics of lipofuscin growth in RPE cells using Kinetic Monte Carlo simulations and scaling theory on a cluster aggregation model. The model captures the essential physics of lipofuscin growth in the cells. A remarkable feature is that small particles may be removed from the cells while the larger ones become fixed and grow by aggregation. We compare our results with the number of lipofuscin granules in eyes with early age-related degeneration.
Family, Fereydoon; Mazzitello, K. I.; Arizmendi, C. M.; Grossniklaus, Hans E.
The visual pigments of vertebrates evolved about 500 million years ago, before the major evolutionary step of the development of jaws. Four spectrally distinct classes of cone opsin evolved through gene duplication, followed by the rod opsin class that arose from the duplication of the middle-wave-sensitive cone opsin. All four cone classes are present in many extant teleost fish, reptiles
James K. Bowmaker
Background: Diagnosis of longitudinal melanonychia is usually difficult, and neither a single clinical criterion nor a combination of symptoms currently can be used to clearly distinguish malignant from benign bandlike pig- mented nail lesions. Biopsy is painful and often leaves definitive dystrophic scars. Objectives: To describe and evaluate dermoscopic pat- terns associated with longitudinal nail pigmentation. Patients and Methods: A
Sandra Ronger; Sandrine Touzet; Claire Ligeron; Brigitte Balme; Anne Marie Viallard; Daniele Barrut; Cyrille Colin; Luc Thomas
By comparing the published DNA sequences for (a) the genes encoding the human visual color pigments (red, green, and blue) with (b) the genes encoding human, bovine, and Drosophila rhodopsins, a phylogenetic tree for the mammalian pigment genes has been constructed. This evolutionary tree shows that the common ancestor of the visual color pigment genes diverged first from that of
Shozo Yokoyama; Ruth Yokoyama
Objective To describe the relationship of systemic inflammatory disease, complement factor H (CFH) Y402H (1277T?C) genotype status and age-related macular degeneration (AMD) prevalence in a multiethnic population of whites, blacks, Hispanics, and Chinese. Design Population-based, cross-sectional study. Participants We included 5887 persons aged 45 to 84 years with gradable AMD. Methods Digital fundus photographs were used to measure AMD. Two years earlier, biomarkers of inflammation were measured and history of inflammatory disease and use of antiinflammatory agents obtained. Main Outcome Measure Prevalence of AMD. Results While controlling for age, gender, race/ethnicity, and study site, there were no associations between systemic inflammatory factors and AMD severity. Higher levels of high-sensitivity C-reactive protein (odds ratio [OR] per standard deviation [SD] increase in natural log [ln] units, 2.34; 95% confidence interval [CI], 1.33–4.13) and interleukin-6 (OR per SD in ln, 2.06; 95% CI, 1.21–3.49) were associated with geographic atrophy but not other AMD end points. History of periodontal disease (OR, 1.68; 95% CI, 1.14–2.47) was related to increased retinal pigment. A history of arthritis was associated with soft distinct drusen (OR, 1.24; 95% CI, 1.06–1.46). A history of oral steroid use was related to large drusen (OR, 2.13; 95% CI, 1.14–3.97) and soft distinct drusen (OR, 1.76; 95% CI, 1.00–3.10) and history of cyclooxygenase 2 inhibitor use were associated with large drusen (OR, 1.50; 95% CI, 1.10–2.04), soft indistinct drusen (OR, 1.84; 95% CI, 1.09–3.10), and large drusen area (OR, 1.66; 95% CI, 1.02–2.71). Whites, blacks, and Hispanics with CFH Y402H CC variant genotype had the highest frequency of early AMD compared with those with wild TT genotype. The frequency of CFH did explain some of the difference in AMD prevalence between Chinese and Hispanics compared with whites, but did not explain the difference in prevalence between whites and blacks. Conclusions This study confirmed associations of the Y402H CFH gene variant with AMD in nonwhite populations, but neither explained the lack of association between inflammatory factors and AMD in the cohort nor the basis for the observed differences in AMD prevalence across ethnic groups.
Klein, Ronald; Knudtson, Michael D.; Klein, Barbara E. K.; Wong, Tien Y.; Cotch, Mary Frances; Liu, Kiang; Cheng, Ching Y.; Burke, Gregory L.; Saad, Mohammed F.; Jacobs, David R.; Sharrett, A. Richey
The purpose of this study is to report a case of cystoid macular edema (CME) as a rare first manifestation of ocular sarcoidosis after cataract surgery. A 60-year-old male developed a CME following uneventful phacoemulsification cataract extraction on his left eye. It resolved with conventional medical therapy. One year later the patient was diagnosed with bilateral CME. Oral corticosteroid therapy produced a significant regression. His medical and ocular histories were unremarkable and all tests for etiological diagnosis were negative. There were inflammation recurrences in his left eye, which were also treated with steroids. Optical coherence tomography showed complete resolution of foveal thickening without improvement in vision. Four years later, the patient presented with CME in both eyes. The laboratory tests included high angiotensin-converting enzyme levels and a gallium scan which were also consistent with sarcoidosis. Azathioprine was needed for management of ocular involvement, but it was withheld due to side-effects. At the present time, the CME is controlled with low-dose corticoids. Ocular involvement in sarcoidosis occurs in 20-50 % of patients. CME is not often the initial manifestation of the disease, but ocular sarcoidosis may present with a wide variety of ocular symptoms in all parts of the eye. Therefore, sarcoidosis should be kept in mind when evaluating a patient with ocular inflammation. PMID:24322273
Cabrillo-Estevez, Lucia; Juan-Marcos, Lourdes de; Kyriakou, Danai; Hernández-Galilea, Emiliano
Age-related macular degeneration (AMD) is a leading cause of irreversible loss of central vision in developing countries. Study of risk factors seems to be more significant because of the lack of effective treatment. Exact recognition especially of modifiable risk factors of AMD development could increase prevention and decrease development and progression. The aim of our study was to evaluate selected modifiable and non-modifiable risk factors of AMD. The examination included 44 AMD patients and 30 healthy subjects in control group. In both groups age, sex, eye color, smoking, UV exposition, blood pressure, cholesterol level, type of diet, family history of AMD and cataract surgeries in anamnesis, were defined. The most significant risk factors of AMD development, in presented study were female gender and UV exposition. They increased a risk accordingly 1.55 and 3 times. Iris color and low vitamin and high fat intake in diet were also essential. There was no dependence on approved risk factor such smoking and AMD appearance. PMID:17725268
Bia?ek-Szyma?ska, Anna; Misiuk-Hoj?o, Marta; Witkowska, Kamila
The development of a low-cost, simple colorimetric sensor array capable of detection and identification of toxic gases is reported. This technology uses a disposable printed array of porous pigments in which metalloporphyrins and chemically responsive dyes are immobilized in a porous matrix of organically modified siloxanes (ormosils) and printed on a porous membrane. The printing of the ormosil into the membrane is highly uniform and does not lessen the porosity of the membrane, as shown by scanning electron microscopy. When exposed to an analyte, these pigments undergo reactions that result in well-defined color changes due to strong chemical interactions: ligation to metal ions, Lewis or Bronsted acid-base interactions, hydrogen bonding, etc. Striking visual identification of 3 toxic gases has been shown at the IDLH (immediately dangerous to life and health), at the PEL (permissible exposure level), and at a level well below the PEL. Identification and quantification of analytes were achieved using the color change profiles, which were readily distinguishable in a hierarchical clustering analysis (HCA) dendrogram, with no misclassifications in 50 trials.
Lim, Sung H.; Kemling, Jonathan W.; Feng, Liang
The development of a low-cost, simple colorimetric sensor array capable of the detection and identification of toxic gases is reported. This technology uses a disposable printed array of porous pigments in which metalloporphyrins and chemically-responsive dyes are immobilized in a porous matrix of organically modified siloxanes (ormosils) and printed on a porous membrane. The printing of the ormosil into the membrane is highly uniform and does not lessen the porosity of the membrane, as shown by scanning electron microscopy. When exposed to an analyte, these pigments undergo reactions that result in well-defined color changes due to strong chemical interactions: ligation to metal ions, Lewis or Brřnsted acid-base interactions, hydrogen bonding, etc. Striking visual identification of 3 toxic gases has been shown at the IDLH (immediately dangerous to life and health) concentration, at the PEL (permissible exposure level), and at a level well below the PEL. Identification and quantification of analytes were achieved using the color change profiles, which were readily distinguishable in a hierarchical clustering analysis (HCA) dendrogram, with no misclassifications in 50 trials. PMID:19918616
Lim, Sung H; Kemling, Jonathan W; Feng, Liang; Suslick, Kenneth S
An eyelid with freshly applied black eyeliner pigment was examined histologically. X-ray microanalysis of the pigment suspension from the manufacturer's vial indicated that its composition was 98% iron and 2% titanium. Transmission electron microscopic examination disclosed that particles were in the extracellular matrix; intracellular particles were not seen. By light microscopy, implant material was detected in various levels of the dermis and was found in dermal lymphatics as well as within and surrounding a hair follicle. This study suggests that systemic exposure to the implant material is possible and offers explanations for permanent eyelash loss, which the authors have seen following this procedure.
Tse, D.T.; Folberg, R.; Moore, K.
PURPOSE: To evaluate the role of vitrectomy in eyes with diffuse diabetic macular edema associated with a taut posterior hyaloid.METHODS: Records of 55 eyes of 50 patients with diabetic retinopathy and diffuse clinically significant diabetic macular edema who underwent vitrectomy with stripping of the premacular posterior hyaloid were reviewed. In all 55 eyes, diffuse diabetic macular edema was present on
Scott D Pendergast; Tarek S Hassan; George A Williams; Morton S Cox; Raymond R Margherio; Philip J Ferrone; Bruce R Garretson; Michael T Trese
Background It is unclear how retinal ischemia influences the changes of visual acuity, macular sensitivity, macular thickness, and macular volume after the performance of pars plana vitrectomy (PPV) for macular edema in patients with central retinal vein occlusion (CRVO). Methods Ten patients (10 eyes) with CRVO and macular edema underwent PPV. Retinal ischemia was evaluated from the area of capillary nonperfusion on fluorescein angiography, and the patients were classified into ischemic or nonischemic groups. Microperimetry was performed with a Micro Perimeter 1. Macular thickness and volume were measured by optical coherence tomography. Results In both groups, the mean macular thickness within the central 4°, 10°, and 20° fields decreased significantly from baseline to 3 and 6 months after PPV (all P?0.05). In the ischemic group, the mean macular sensitivity within the central 4°, 10°, and 20° fields increased from baseline to 3 and 6 months after PPV, but no significant difference was observed. Conclusions These results suggest that PPV may be effective for improving macular thickness, volume, and sensitivity in patients with macular edema secondary to ischemic CRVO, although there was no significant difference.
In diabetic retinopathy, vision loss is usually secondary to macular edema, which is thought to depend on the functional integrity of the blood-retina barrier. The levels of advanced glycation end products in the vitreous correlate with the progression of diabetic retinopathy. Natriuretic peptides (NP) are expressed in the eye and their receptors are present in the retinal pigment epithelium (RPE). Here, we investigated the effect of glycated-albumin (Glyc-alb), an advanced glycation end product model, on RPE-barrier function and the ability of NP to suppress this response. Transepithelial electrical resistance (TEER) measurements were used to assess the barrier function of ARPE-19 and human fetal RPE (hfRPE) monolayers. The monolayers were treated with 0.1-100 ?g/ml Glyc-alb in the absence or presence of 1 pM to 100 nM apical atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), or C-type natriuretic peptide (CNP). Glyc-alb induced a significant reduction in TEER within 2 hours. This response was concentration-dependent (EC(50)= 2.3 ?g/ml) with a maximal reduction of 40 ± 2% for ARPE-19 and 27 ± 7% for hfRPE at 100 ?g/ml 6 hours post-treatment. One hour pretreatment with ANP, BNP, or CNP blocked the reduction in TEER induced by Glyc-alb (100 ?g/ml). The suppression of the Glyc-alb response by NP was dependent on the generation of cyclic guanosine monophosphate and exhibited a rank order of agonist potency consistent with the activation of natriuretic-peptide-receptor-2 (NPR2) subtype (CNP > BNP ? ANP). Our data demonstrate that Glyc-alb is effective in reducing RPE-barrier function, and this response is suppressed by NP. Moreover, these studies support the idea that NPR2 agonists can be potential candidates for treating retinal edema in diabetic patients. PMID:23086231
Dahrouj, Mohammad; Alsarraf, Oday; Liu, Yueying; Crosson, Craig E; Ablonczy, Zsolt
Aging of retinal pigment epithelial (RPE) cells of the eye is marked by accumulations of bisretinoid fluorophores; two of the compounds within this lipofuscin mixture are A2E and all-trans-retinal dimer. These pigments are implicated in pathological mechanisms involved in some vision-threatening disorders including age-related macular degeneration (AMD). Studies have shown that bisretinoids are photosensitive compounds that undergo photooxidation and photodegradation when irradiated with short wavelength visible light. Utilizing ultra performance liquid chromatography (UPLC) with electrospray ionization mass spectrometry (ESI-MS) we demonstrate that photodegradation of A2E and all-trans-retinal dimer generates the dicarbonyls glyoxal (GO) and methylglyoxal (MG), that are known to modify proteins by advanced glycation endproduct (AGE) formation. By extracellular trapping with aminoguanidine, we established that these oxo-aldehydes are released from irradiated A2E-containing RPE cells. Enzyme-linked immunosorbant assays (ELISA) revealed that the substrate underlying A2E-containing RPE was AGE-modified after irradiation. This AGE deposition was suppressed by prior treatment of the cells with aminoguanidine. AGE-modification causes structural and functional impairment of proteins. In chronic diseases such as diabetes and atherosclerosis, MG and GO modify proteins by non-enzymatic glycation and oxidation reactions. AGE-modified proteins are also components of drusen, the sub-RPE deposits that confer increased risk of AMD onset. These results indicate that photodegraded RPE bisretinoid is likely to be a previously unknown source of MG and GO in the eye.
Yoon, Kee Dong; Yamamoto, Kazunori; Ueda, Keiko; Zhou, Jilin; Sparrow, Janet R.
Aim Our aim is to use ultrasound to non-invasively detect differences in choroidal microarchitecture possibly related to ischaemia among normal eyes and those with wet and dry age-related macular degeneration (AMD). Design Prospective case series of subjects with dry AMD, wet AMD and age-matched controls. Methods Digitised 20?MHz B-scan radiofrequency ultrasound data of the region of the macula were segmented to extract the signal from the retina and choroid. This signal was processed by a wavelet transform, and statistical modelling was applied to the wavelet coefficients to examine differences among dry, wet and non-AMD eyes. Receiver operating characteristic (ROC) analysis was used to evaluate a multivariate classifier. Results In the 69 eyes of 52 patients, 18 did not have AMD, 23 had dry AMD and 28 had wet AMD. Multivariate models showed statistically significant differences between groups. Multiclass ROC analysis of the best model showed an excellent volume-under-curve of 0.892±0.17. The classifier is consistent with ischaemia in dry AMD. Conclusions Wavelet augmented ultrasound is sensitive to the organisational elements of choroidal microarchitecture relating to scatter and fluid tissue boundaries such as seen in ischaemia and inflammation, allowing statistically significant differentiation of dry, wet and non-AMD eyes. This study further supports the association of ischaemia with dry AMD and provides a rationale for treating dry AMD with pharmacological agents to increase choroidal perfusion. ClinicalTrials.gov registration NCT00277784.
Coleman, D Jackson; Silverman, Ronald H; Rondeau, Mark J; Lloyd, Harriet O; Khanifar, Aziz A; Chan, R V Paul
In the aging human eye, oxidative damage and accumulation of pro-oxidant lysosomal lipofuscin cause functional decline of the retinal pigment epithelium (RPE), which contributes to age-related macular degeneration. In mice with an RPE-specific phagocytosis defect due to lack of ?v?5 integrin receptors, RPE accumulation of lipofuscin suggests that the age-related blindness we previously described in this model may also result from oxidative stress. Cellular and molecular targets of oxidative stress in the eye remain poorly understood. Here we identify actin among 4-hydroxynonenal (HNE) adducts formed specifically in ?5(-/-) RPE but not in neural retina with age. HNE modification directly correlated with loss of resistance of actin to detergent extraction, suggesting cytoskeletal damage in aging RPE. Dietary enrichment with natural antioxidants, grapes or marigold extract containing macular pigments lutein/zeaxanthin, was sufficient to prevent HNE-adduct formation, actin solubility, lipofuscin accumulation, and age-related cone and rod photoreceptor dysfunction in ?5(-/-) mice. Acute generation of HNE adducts directly destabilized actin but not tubulin cytoskeletal elements of RPE cells. These findings identify destabilization of the actin cytoskeleton as a consequence of a physiological, sublethal oxidative burden of RPE cells in vivo that is associated with age-related blindness and that can be prevented by consuming an antioxidant-rich diet. PMID:22178979
Yu, Chia-Chia; Nandrot, Emeline F; Dun, Ying; Finnemann, Silvia C
In the aging human eye, oxidative damage and accumulation of pro-oxidant lysosomal lipofuscin cause functional decline of the retinal pigment epithelium (RPE), which contributes to age-related macular degeneration. In mice with an RPE-specific phagocytosis defect due to lack of ?v?5 integrin receptors, RPE accumulation of lipofuscin suggests that the age-related blindness we previously described in this model may also result from oxidative stress. Cellular and molecular targets of oxidative stress in the eye remain poorly understood. Here we identify actin among 4-hydroxynonenal (HNE) adducts formed specifically in ?5?/? RPE but not neural retina with age. HNE modification directly correlated with loss of resistance of actin to detergent extraction, suggesting cytoskeletal damage in aging RPE. Dietary enrichment with natural antioxidants grapes or marigold extract containing macular pigments lutein/zeaxanthin was sufficient to prevent HNE-adduct formation, actin solubility, lipofuscin accumulation, and age-related cone and rod photoreceptor dysfunction in ?5?/? mice. Acute generation of HNE-adducts directly destabilized actin but not tubulin cytoskeletal elements of RPE cells. These findings identify destabilization of the actin cytoskeleton as a consequence of physiological, sublethal oxidative burden of RPE cells in vivo that is associated with age-related blindness and that can be prevented by consuming an antioxidant-rich diet.
Yu, Chia-Chia; Nandrot, Emeline F.; Dun, Ying; Finnemann, Silvia C.
Satellite data from the Coastal Zone Colour Scanner (CZCS) and Advanced Very High Resolution Radiometer were examined to determine the relationship between the phytoplankton pigment distribution and sea surface temperature (SST) in the Subtropical Convergence (STC) region south of Africa. The structure of the temperature fronts and their role in phytoplankton pigment distribution was explored. The multichannel sea surface temperature (MCSST) data for 1981-1986 showed considerable interannual variability in both the position of the Agulhas retroflection and the extent of the Rossby wave in the Agulhas Return Current. Pronounced interannual variation in pigment levels was found in the CZCS data for early 1979, 1982 and 1983, with highest pigment levels in early 1982. These greater pigment levels were shown to be a function of increased frontal intensity of the STC front rather than of the Agulhas front, or of SST per se. The principal interannual differences were found in the region where a strong Agulhas front occurred to the north of the STC front. The Agulhas front appeared to play a role in limiting the spatial distribution of phytoplankton pigment. Time series of level-2 CZCS data supported the scenario of upstream Agulhas retroflection resulting in a pronounced Rossby wave in the Agulhas Return Current, and increased phytoplankton pigment levels in the STC region.
Weeks, Scarla J.; Shillington, Frank A.