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Tauopathy is a neurodegenerative condition associated with oligomeric tau formation through abnormal phosphorylation. We previously showed that tauopathy is involved in death of retinal ganglion cells (RGCs) after optic nerve crush (ONC). It has been proposed that glycogen synthase kinase 3ß (GSK3ß) is involved in the hyperphosphorylation of tau in Alzheimer's disease. To determine the roles of GSK3ß in tauopathy-related death of RGCs, lithium chloride (LiCl), a GSK3ß inhibitor, was injected intravitreally just after ONC. The neuroprotective effects of LiCl were determined by counting Tuj-1-stained RGCs on day 7. Changes of phosphorylated (ser 396) tau in the retina were determined by Simple Western analysis (WES) on day 3. Retinal GSK3ß levels were determined by immunohistochemistry (IHC) and an ELISA. There was a 1.9- and 2.1-fold increase in the levels of phosphorylated tau monomers and dimers on day 3 after ONC. LiCl significantly suppressed the increase in the levels of phosphorylated tau induced by ONC. GSK3ß was mainly present in somas of RGCs, and ELISA showed that retinal levels increased to 2.0-fold on day 7. IHC showed that the GSK3ß expression increased over time and remained in RGCs that were poorly stained by Tuj-1. The GSK3ß and tau expression was colocalized in RGCs. The number of RGCs decreased from 1881 ± 188 (sham control) to 1150 ± 192 cells/mm2 on day 7, and LiCl preserved the levels at 1548 ± 173 cells/mm2. Accordingly, GSK3ß may be a promising target for some optic nerve injuries.
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OBJECTIVES: To evaluate the long-term benefits of tear-exchangeable, limbal-rigid contact lens (CL) wear therapy in patients with Stevens-Johnson syndrome (SJS)-associated ocular sequelae. METHODS: This retrospective study evaluated 50 eyes of 41 SJS patients (15 men and 26 women) who underwent limbal-rigid CL wear therapy for more than 2 years post fitting. Ocular sequelae (i.e., conjunctival hyperemia, corneal neovascularization, and upper tarsus scarring) before fitting and at 3 months, 6 months, 12 months, and annually after initiating CL wear therapy were evaluated and then graded on a severity score (range: 0-3, maximum score: 3). Moreover, visual acuity (VA) at immediately post initiating CL wear therapy was evaluated. RESULTS: The mean follow-up period was 4.3±1.1 years. Compared with before fitting, the mean conjunctival hyperemia score improved from 1.14 to 0.86 at 3 months of CL wear therapy ( P <0.01) and was maintained thereafter; the mean corneal neovascularization score improved from 2.10 to 1.98 at 3 months of CL wear therapy, with no deterioration of the score observed in all cases at the final follow-up examination, and mean VA (log of minimum angle of resolution) improved from 1.60 to 1.04 at immediately post initiating CL wear therapy ( P <0.01). CONCLUSIONS: Limbal-rigid CL wear therapy can provide long-term ocular surface stabilization and improved VA in SJS patients.
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Conjuntivitis , Lentes de Contacto , Enfermedades de la Córnea , Neovascularización de la Córnea , Hiperemia , Síndrome de Stevens-Johnson , Masculino , Humanos , Femenino , Enfermedades de la Córnea/terapia , Enfermedades de la Córnea/complicaciones , Síndrome de Stevens-Johnson/terapia , Síndrome de Stevens-Johnson/complicaciones , Neovascularización de la Córnea/terapia , Neovascularización de la Córnea/complicaciones , Estudios Retrospectivos , Progresión de la EnfermedadRESUMEN
The pathogenesis of both diabetic retinopathy (DR) and rheumatoid arthritis (RA) has recently been considered to involve autoimmunity. Serum and synovial fluid levels of anti-type II collagen antibodies increase early after the onset of RA, thus inducing immune responses and subsequent hydrarthrosis and angiogenesis, which resemble diabetic macular edema and proliferative DR (PDR), respectively. We previously reported that DR is also associated with increased serum levels of anti-type II collagen antibodies. Retinal hypoxia in DR may induce pericytes to express type II collagen, resulting in autoantibody production against type II collagen. As the result of blood-retinal barrier disruption, anti-type II collagen antibodies in the serum come into contact with type II collagen around the retinal vessels. A continued loss of pericytes and type II collagen around the retinal vessels may result in a shift of the immune reaction site from the retina to the vitreous. It has been reported that anti-inflammatory M2 macrophages increased in the vitreous of PDR patients, accompanied by the activation of the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, a key regulator of innate immunity. M2 macrophages promote angiogenesis and fibrosis, which might be exacerbated and prolonged by dysregulated innate immunity.
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Diabetes Mellitus , Retinopatía Diabética , Edema Macular , Humanos , Inmunidad Innata , Inflamasomas , Proteína con Dominio Pirina 3 de la Familia NLRRESUMEN
The purpose of this present study was to investigate the distribution and expression of chymase in the lacrimal glands (LGs) of patients afflicted with IgG4-related ophthalmic disease (IgG4-ROD). LGs from patients with severe canalicular obstruction were considered the control group. Toluidine blue staining confirmed a significant increase in the number of mast cells in the LGs obtained from the IgG4-ROD patients. In addition, immunostaining of serial sections from the LGs showed a significant increase in the number of chymase-positive cells and tryptase-positive cells in the IgG4-ROD LGs compared to the normal control LGs. The mRNA expression of chymase, tryptase, TGF-ß1, and collagen-I tended to increase in the IgG4-ROD LGs. Immunostaining of vimentin and α-smooth muscle actin (α-SMA) showed that myofibroblasts were the main cellular components in severely fibrotic regions of LGs in patients with IgG4-ROD. Linear regression analyses on the number of mast cells, chymase-positive cells, and tryptase-positive cells revealed significant positive correlations between those respective cells. Our findings suggest that chymase may play a role in the fibrotic disorder of IgG4-ROD LGs through the regulation of TGF-ß1 activation and collagen-I deposition, and that it may be a therapeutic target for patients afflicted with IgG4-ROD.
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Enfermedad Relacionada con Inmunoglobulina G4 , Aparato Lagrimal , Quimasas/metabolismo , Colágeno Tipo I/metabolismo , Fibrosis , Humanos , Inmunoglobulina G/metabolismo , Enfermedad Relacionada con Inmunoglobulina G4/patología , Aparato Lagrimal/metabolismo , Mastocitos/metabolismo , Factor de Crecimiento Transformador beta1/genética , Factor de Crecimiento Transformador beta1/metabolismo , Triptasas/metabolismoRESUMEN
PURPOSE: The pathomechanism leading to retinal vein occlusion (RVO) is unclear. Mechanical compression, thrombosis, and functional contractions of veins are discussed as the reasons for the increased resistance of venous outflow. We evaluated changes in the retinal venous pressure (RVP) following intravitreal injection of anti-vascular endothelial growth factor (VEGF) agent to determine the effect on RVO-related macular edema. METHODS: Twenty-six patients with RVO-related macular edema (16 branch RVOs [BRVOs] and 10 central RVOs [CRVOs], age 72.5 ± 8.8 years) who visited our hospital were included in this prospective study. Visual acuity (VA), intraocular pressure (IOP), central retinal thickness (CRT) determined by macular optical coherence tomography, and RVP measured using an ophthalmodynamometer were obtained before intravitreal injection of ranibizumab (IVR) and 1 month later. RESULTS: Comparison of the BRVOs and CRVOs showed that VA was significantly improved by a single injection in BRVOs (P < 0.0001; P = 0.1087 for CRVOs), but CRT and RVP were significantly decreased without significant difference in IOP after the treatment in both groups (P < 0.0001). CONCLUSION: The anti-VEGF treatment resulted in a significant decrease in the RVP, but the RVP remained significantly higher than the IOP. An increased RVP plays a decisive role in the formation of macula edema, and reducing it is desirable.
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Edema Macular , Oclusión de la Vena Retiniana , Anciano , Inhibidores de la Angiogénesis/uso terapéutico , Humanos , Inyecciones Intravítreas , Edema Macular/diagnóstico , Edema Macular/tratamiento farmacológico , Edema Macular/etiología , Estudios Prospectivos , Oclusión de la Vena Retiniana/complicaciones , Oclusión de la Vena Retiniana/diagnóstico , Oclusión de la Vena Retiniana/tratamiento farmacológico , Tomografía de Coherencia Óptica , Resultado del Tratamiento , Factor A de Crecimiento Endotelial Vascular , Presión VenosaRESUMEN
INTRODUCTION: We previously reported that the intravitreal activities of chymase and tryptase were more increased in the patients with macular hole (MH) and epiretinal membrane (ERM) than in those with proliferative diabetic retinopathy (PDR) and that the source of these serine proteases might be mast cells in the bursa premacularis (BPM). The purpose of this study was to compare the density of mast cells in BPM samples obtained from MH, ERM, and PDR patients. METHODS: BPM and vitreous core samples were first collected during vitrectomy from eyes afflicted with vitreoretinal diseases (MH: 6 eyes, ERM: 3 eyes, and PDR: 9 eyes), and then were stained with hematoxylin, toluidine blue, antibodies against chymase and tryptase, and a terminal deoxynucleotidyl transferase dUTP nick end labeling assay kit. RESULTS: Hematoxylin nuclear staining showed fewer positive-staining cells in the BPM samples obtained from PDR patients than in those obtained from MH and ERM patients. Toluidine blue staining of the BPM revealed metachromasia in the mast cells of the patients with MH and ERM, but not those of the patients with PDR. In addition, immunostaining using anti-chymase and anti-tryptase antibodies showed that the BPM samples were more intensely stained than the vitreous core samples from the patients with MH and ERM and that both tissue samples were poorly stained in the patients with PDR. The apoptotic cells were more frequently observed in the BPM samples from patients with MH than in those from patients with PDR. CONCLUSIONS: These findings indicated that lower activities of chymase and tryptase in the vitreous of PDR patients appeared to be attributable to the decreased presence of mast cells in the BPM. The lack of mast cells in the BPM might be related to the pathogenesis of PDR.
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Diabetes Mellitus , Retinopatía Diabética , Perforaciones de la Retina , Quimasas , Membrana Epirretinal , Hematoxilina , Humanos , Mastocitos , Cloruro de Tolonio , TriptasasRESUMEN
Dissociated optic nerve fiber layer (DONFL) appearance is characterized by dimpling of the fundus when observed after vitrectomy with the internal limiting membrane (ILM) peeling in macular diseases. However, the cause of DONFL remains largely unknown. Optical coherence tomography (OCT) findings have indicated that the nerve fiber layer (NFL) and ganglion cells are likely to have been damaged in patients with DONFL appearance. Since DONFL appearance occurs at a certain postoperative period, it is unlikely to be retinal damage directly caused by ILM peeling because apoptosis occurs at a certain period after tissue damage and/or injury. However, it may be due to ILM peeling-induced apoptosis in the retinal tissue. Anoikis is a type of apoptosis that occurs in anchorage-dependent cells upon detachment of those cells from the surrounding extracellular matrix (i.e., the loss of cell anchorage). The anoikis-related proteins ßA3/A1 crystallin and E-cadherin are reportedly expressed in retinal ganglion cells. Thus, we theorize that one possible cause of DONFL appearance is ILM peeling-induced anoikis in retinal ganglion cells.
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Anoicis , Nervio Óptico/patología , Enfermedades de la Retina/cirugía , Células Ganglionares de la Retina/patología , Vitrectomía/efectos adversos , Membrana Basal/diagnóstico por imagen , Membrana Basal/cirugía , Fondo de Ojo , Humanos , Mácula Lútea/citología , Mácula Lútea/patología , Mácula Lútea/cirugía , Fibras Nerviosas/patología , Nervio Óptico/citología , Nervio Óptico/diagnóstico por imagen , Periodo Posoperatorio , Enfermedades de la Retina/patología , Tomografía de Coherencia Óptica , Vitrectomía/métodosRESUMEN
Tauopathies are neurodegenerative diseases characterized by abnormal metabolism of misfolded tau proteins and are progressive. Pathological phosphorylation of tau occurs in the retinal ganglion cells (RGCs) after optic nerve injuries. Cyclin-dependent kinase-5 (Cdk5) causes hyperphosphorylation of tau. To determine the roles played by Cdk5 in retinal degeneration, roscovitine, a Cdk5 inhibitor, was injected intravitreally after optic nerve crush (ONC). The neuroprotective effect of roscovitine was determined by the number of Tuj-1-stained RGCs on day 7. The change in the levels of phosphorylated tau, calpain-1, and cleaved α-fodrin was determined by immunoblots on day 3. The expression of P35/P25, a Cdk5 activator, in the RGCs was determined by immunohistochemistry. The results showed that roscovitine reduced the level of phosphorylated tau by 3.5- to 1.6-fold. Calpain-1 (2.1-fold) and cleaved α-fodrin (1.5-fold) were increased on day 3, suggesting that the calpain signaling pathway was activated. P35/P25 was accumulated in the RGCs that were poorly stained by Tuj-1. Calpain inhibition also reduced the increase in phosphorylated tau. The number of RGCs decreased from 2191 ± 178 (sham) to 1216 ± 122 cells/mm2 on day 7, and roscovitine preserved the level at 1622 ± 130 cells/mm2. We conclude that the calpain-mediated activation of Cdk5 is associated with the pathologic phosphorylation of tau.
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Quinasa 5 Dependiente de la Ciclina/fisiología , Traumatismos del Nervio Óptico , Células Ganglionares de la Retina , Tauopatías , Proteínas tau/metabolismo , Animales , Quinasa 5 Dependiente de la Ciclina/antagonistas & inhibidores , Traumatismos del Nervio Óptico/metabolismo , Traumatismos del Nervio Óptico/patología , Fosforilación , Ratas , Ratas Wistar , Células Ganglionares de la Retina/metabolismo , Células Ganglionares de la Retina/patología , Roscovitina/farmacología , Tauopatías/metabolismo , Tauopatías/patologíaRESUMEN
We previously reported that the bursa premacularis (BPM), a peculiar vitreous structure located above the macula, contains numerous cells expressing markers of lymphatic endothelial cells, such as podoplanin and LYVE-1. Herein, we examined the expression of lymphatic markers in the Berger's space (BS), BPM, and vitreous core (VC). BS, BPM, and VC specimens were selectively collected in macular hole and epiretinal membrane patients during vitrectomy and were then immunostained with antibodies for podoplanin, LYVE-1, and fibrillin-1 and -2. By visualization using triamcinolone acetonide, the BS was recognized as a sac-like structure with a septum located behind the lens as well as BPM. Those tissues adhered to the lens or retina in a circular manner by means of a ligament-like structure. Immunostaining showed intense expression of podoplanin and LYVE-1 in the BS. Both BS and BPM stained strongly positive for fibrillin-1 and -2. The VC was faintly stained with antibodies for those lymph-node markers. Our findings indicate that both BS and BPM possibly belong to the lymphatic system, such as lymph nodes, draining excess fluid and waste products into lymphatic vessels in the dura mater of the optic nerve and the ciliary body, respectively, via intravitreal canals.
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Biomarcadores/metabolismo , Vasos Linfáticos/metabolismo , Cuerpo Vítreo/anatomía & histología , Anciano , Anticuerpos/metabolismo , Femenino , Fibrilinas/metabolismo , Humanos , Masculino , Persona de Mediana EdadRESUMEN
The original publication of this paper contains mistakes.
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PURPOSE: The photopic negative response (PhNR) is a negative wave following the b-wave of the photopic electroretinogram (ERG). The PhNR originates from the retinal ganglion cells (RGCs), and it can be used to assess the function of RGCs noninvasively and objectively. The purpose of this study was to determine whether the relative amplitudes (affected/normal eye) of the PhNR are significantly correlated with the degree of the relative afferent pupillary defect (RAPD) in eyes with unilateral or asymmetrical damage of the optic nerve. METHODS: The PhNRs of the full-field photopic ERGs were measured. In addition, videopupillography and automated perimetry were performed on 27 cases with asymmetrical optic nerve disorders including glaucoma. The differences of these assessments were expressed by the relative amplitudes of the PhNRs of the two eyes, the neutral density (ND) filter required to equate the amplitudes of the pupillary light reflexes between the two eyes, and differences of the mean defects (ΔMDs) of the sensitivities of the Humphrey visual fields. The correlations between these values were determined by linear regression analyses. RESULTS: The relative PhNR amplitudes were significantly and negatively correlated with the ΔMDs (R2 = 0.58, P = 0.0001). In addition, the relative PhNR amplitudes were moderately but significantly and positively correlated with the RAPDs (R2 = 0.36, P = 0.002). CONCLUSION: The relative amplitudes of the PhNR of the affected eyes to the contralateral eyes indicate an asymmetric alteration of the RGCs, and they can be used to monitor the physiology of the RGCs objectively.
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Visión de Colores/fisiología , Electrorretinografía/métodos , Disco Óptico/patología , Enfermedades del Nervio Óptico/fisiopatología , Trastornos de la Pupila/etiología , Células Ganglionares de la Retina/patología , Campos Visuales/fisiología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Enfermedades Asintomáticas , Niño , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Fibras Nerviosas/patología , Enfermedades del Nervio Óptico/complicaciones , Enfermedades del Nervio Óptico/diagnóstico , Estimulación Luminosa , Trastornos de la Pupila/diagnóstico , Trastornos de la Pupila/fisiopatología , Estudios Retrospectivos , Pruebas del Campo Visual , Adulto JovenRESUMEN
BACKGROUND: Here we report a case of traction retinal detachment (TRD) associated with congenital retinal vascular hypoplasia localized in the superotemporal quadrant that was treated with vitrectomy. CASE PRESENTATIONS: A 58 year-old female presented with a gradual decrease of visual acuity (VA) and distorted vision in her left eye. She had a past history of amblyopia in her left eye from early childhood, and a previous examination performed at a nearby hospital revealed that the corrected visual acuity (VA) in that eye was 0.15. Upon initial examination, no abnormal findings were observed in her right eye, yet optic-disc traction and macular rotation with a folded TRD extending superotemporally from the macular region was observed in her left eye. Fluorescein fundus angiography showed a retinal nonperfused area localized in the superotemporal quadrant surrounded by a retinal avascular area. The optic disc in her left eye was smaller than that in her right eye. Vitrectomy was performed to remove the proliferative membrane and created an artificial posterior vitreous detachment (PVD). Following surgery, the patient's corrected VA improved from 0.04 to 0.1. CONCLUSIONS: The present case was likely to be TRD caused by PVD in the presence of localized congenital retinal vascular hypoplasia secondary to optic-disc hypoplasia.
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Oftalmopatías , Disco Óptico , Desprendimiento de Retina , Desprendimiento del Vítreo , Preescolar , Femenino , Angiografía con Fluoresceína , Humanos , Persona de Mediana Edad , Desprendimiento de Retina/diagnóstico , Desprendimiento de Retina/etiología , Desprendimiento de Retina/cirugía , VitrectomíaRESUMEN
BACKGROUND: Valsalva retinopathy is known to occur as a sudden preretinal or sub-internal limiting membrane hemorrhage induced by a rapid rise in venous pressure following increased intrathoracic or intraabdominal pressure. Here we report a case of Valsalva retinopathy that was probably induced by straining that occurred due to following a handstand. CASE PRESENTATION: A 15-year-old boy became aware of decreased visual acuity in his left eye immediately after doing a handstand for approximately 10 s during physical education class, and subsequently visited a local clinic on the same day. Upon examination, a vitreous hemorrhage (VH) in the posterior pole of the fundus was found in his left eye, and he was subsequently referred to our department 7 days later. Upon examination, the VH around the optic nerve head of the left eye appeared to be resolved, and an oval-shaped sub-internal limiting membrane (sub-ILM) hemorrhage was found in the superonasal side of the optic nerve head. No abnormalities were observed in the macular area. Four months later, the sub-ILM hemorrhage was found to have spontaneously resolved. Subsequent fluorescein angiography examinations revealed no abnormal findings at the lesion site. CONCLUSIONS: In this patient, we hypothesize that the Valsalva retinopathy was induced by straining that occurred due to a handstand, and that the resultant sub-ILM hemorrhage progressed to VH.
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Tomografía de Coherencia Óptica , Maniobra de Valsalva , Adolescente , Angiografía con Fluoresceína , Humanos , Masculino , Hemorragia Retiniana/diagnóstico , Hemorragia Retiniana/etiología , Agudeza VisualRESUMEN
BACKGROUND: Here we report two patients who developed an atypical macular hole (MH) during the treatment course for diabetic macular edema (DME). CASE PRESENTATIONS: Patient 1 was a 73-year-old male. Optical coherence tomography (OCT) revealed perifoveal retinoschisis (RS) in addition to cystoid macular edema and serous retinal detachment (SRD) in his left eye, and that an MH had developed during the clinical course. A convex surface was formed at the MH margin toward the vitreous cavity, and granular shadows were observed in the fluid cuff. Intraoperative findings revealed a thin epiretinal macular membrane (ERM) around the MH. Patient 2 was a 79-year-old male. Although the patient underwent pars plana vitrectomy (PPV) for proliferative diabetic retinopathy (PDR) in both eyes, RS and a thin ERM in addition to SRD was observed in his left eye after surgery, and an MH developed during the clinical course. As in Patient 1, a convex surface was formed at the fluid cuff margin toward the vitreous cavity. CONCLUSIONS: Both patients had persistent DME, SRD, RS, and a thin ERM before the development of the MH. OCT revealed the formation of a convex surface at the MH margin toward the vitreous cavity, suggesting that the fragility of the layered structure of the retina combined with tangential retinal traction may have been involved in the atypical MH form.
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Retinopatía Diabética/complicaciones , Edema Macular/complicaciones , Perforaciones de la Retina/etiología , Anciano , Inhibidores de la Angiogénesis/uso terapéutico , Retinopatía Diabética/diagnóstico , Retinopatía Diabética/terapia , Membrana Epirretinal/complicaciones , Membrana Epirretinal/diagnóstico , Membrana Epirretinal/terapia , Humanos , Presión Intraocular , Inyecciones Intravítreas , Edema Macular/diagnóstico , Edema Macular/terapia , Masculino , Receptores de Factores de Crecimiento Endotelial Vascular/uso terapéutico , Proteínas Recombinantes de Fusión/uso terapéutico , Desprendimiento de Retina/complicaciones , Desprendimiento de Retina/diagnóstico , Desprendimiento de Retina/terapia , Perforaciones de la Retina/diagnóstico , Perforaciones de la Retina/terapia , Retinosquisis/complicaciones , Retinosquisis/diagnóstico , Retinosquisis/terapia , Tomografía de Coherencia Óptica , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Agudeza Visual , VitrectomíaRESUMEN
PURPOSE: We investigated the thinning of central choroidal thickness (CCT) following intravitreal injections of anti-vascular endothelial growth factor (anti-VEGF) drugs to treat central retinal vein occlusion (CRVO)-related macular edema in patients with and without systemic hypertension (HT) to assess the influence of repeated anti-VEGF therapy and HT on the choroid in CRVO eyes. METHODS: We conducted a retrospective study involving 27 patients with CRVO-related macular edema from January 2014 to July 2017, with follow-ups exceeding 18 months. Visual acuity (VA), central retinal thickness (CRT), and CCT were evaluated before and after initial anti-VEGF drug treatment during follow-up. RESULTS: The mean follow-up period was 35.2 months. Seventeen (63.0%) patients had HT. At 1 month after treatment, VA had improved in 21 (77.8%) patients, and CRT had decreased in 25 (92.6%). At the final visit, 22 (81.5%) showed improved VA, 19 (70.4%) had resolved macular edema, and the CCT had gradually become thinner with additional drug injections in all the patients. Furthermore, the mean CCT in HT patients (209.0 µm) was significantly lower than in non-HT patients (256.1 µm), and the mean injections were 7.8 and 5.3, respectively (p = 0.2067). CONCLUSION: The CCTs were thinner in eyes with HT than in eyes without HT both before and after the repeated anti-VEGF injections.
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Bevacizumab/administración & dosificación , Coroides/patología , Hipertensión/complicaciones , Edema Macular/tratamiento farmacológico , Oclusión de la Vena Retiniana/complicaciones , Agudeza Visual , Adulto , Anciano , Anciano de 80 o más Años , Inhibidores de la Angiogénesis/administración & dosificación , Femenino , Estudios de Seguimiento , Humanos , Inyecciones Intravítreas , Edema Macular/diagnóstico , Edema Macular/etiología , Masculino , Persona de Mediana Edad , Oclusión de la Vena Retiniana/diagnóstico , Oclusión de la Vena Retiniana/tratamiento farmacológico , Estudios Retrospectivos , Factores de Tiempo , Tomografía de Coherencia Óptica , Resultado del Tratamiento , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidoresRESUMEN
Microvascular changes are the earliest adverse events in diabetic retinopathy, but recent studies have shown that oxidative stress induced by photoreceptors is associated with the development of the retinopathy. The purpose of this study was to determine the roles played by superoxides formed by photoreceptors under hyperglycemic conditions on autophagy. To accomplish this, we cultured 661 W cells, a transformed murine cone cell line, with 5.5 or 25 mM glucose in the presence or absence of 3 methyl adenine (3MA) or rapamycin. The superoxides were determined by flow cytometry using hydroethidine as a fluorescence probe. The autophagy activity was determined by changes in the expression of LC3B2 and P62 by immunoblotting. The degree of mitophagy was determined by the accumulation of mitochondria and lysosomes. Apoptotic changes of 661 W cells were determined by the caspase 3/7 activities. Our results showed higher levels of P62 and superoxides in cells cultured in 25 mM glucose than in 5.5 mM glucose. Addition of 3MA caused a significant increase of P62, superoxides, and caspase 3/7 activities in the 661 W cells cultured in high glucose but not in low glucose. These findings suggest that autophagy is important for the functioning and survival of 661 W cells under hyperglycemic conditions.
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Retinopatía Diabética/metabolismo , Glucosa/efectos adversos , Proteínas Asociadas a Microtúbulos/metabolismo , Células Fotorreceptoras Retinianas Conos/citología , Proteína Sequestosoma-1/metabolismo , Superóxidos/metabolismo , Adenina/análogos & derivados , Adenina/farmacología , Animales , Autofagia/efectos de los fármacos , Línea Celular , Supervivencia Celular/efectos de los fármacos , Retinopatía Diabética/etiología , Relación Dosis-Respuesta a Droga , Regulación de la Expresión Génica/efectos de los fármacos , Ratones , Modelos Biológicos , Estrés Oxidativo/efectos de los fármacos , Células Fotorreceptoras Retinianas Conos/efectos de los fármacos , Células Fotorreceptoras Retinianas Conos/metabolismo , Sirolimus/farmacologíaRESUMEN
PURPOSE: To investigate the effect of a selective aquaporin 4 (AQP4) inhibitor, 2-(nicotinamide)-1,3,4-thiadiazole (TGN-020), on the expression of vascular endothelial growth factor (VEGF) and reactive oxygen species (ROS) production, as well as on the retinal edema in diabetic retina. METHODS: Intravitreal injections of bevacizumab, TGN-020, or phosphate-buffered saline (PBS) were performed on streptozotocin-induced diabetic rats. Retinal sections were immunostained for anti-glial fibrillary acidic protein (GFAP), anti-AQP4, and anti-VEGF. Protein levels of VEGF from collected retinas were determined by Western blot analysis. In addition, retinal vascular leakage of Evans Blue was observed in the flat-mounted retina from the diabetic rats in the presence or absence of TGN-020. Volumetric changes of rat retinal Müller cells (TR-MUL5; transgenic rat Müller cells) and intracellular levels of ROS were determined using flow cytometry analysis of ethidium fluorescence in the presence or absence of TGN-020 or bevacizumab under physiological and high glucose conditions. RESULTS: In the diabetic retina, the immunoreactivity and protein levels of VEGF were suppressed by TGN-020. AQP4 immunoreactivity was higher than in the control retinas and the expressions of AQP4 were co-localized with GFAP. Similarly to VEGF, AQP4 and GFAP were also suppressed by TGN-020. In the Evans Blue assay, TGN-020 decreased leakage in the diabetic retinas. In the cultured Müller cells, the increase in cell volumes and intracellular ROS production under high glucose condition were suppressed by exposure to TGN-020 as much as by exposure to bevacizumab. CONCLUSION: TGN-020 may have an inhibitory effect on diabetic retinal edema.
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Acuaporina 4/efectos de los fármacos , Diabetes Mellitus Experimental/metabolismo , Niacinamida/análogos & derivados , Niacinamida/antagonistas & inhibidores , Retina/metabolismo , Tiadiazoles/antagonistas & inhibidores , Animales , Vasos Sanguíneos/diagnóstico por imagen , Vasos Sanguíneos/metabolismo , Retinopatía Diabética/metabolismo , Células Ependimogliales/metabolismo , Proteína Ácida Fibrilar de la Glía/metabolismo , Masculino , Ratones , Ratas , Ratas Wistar , Retina/diagnóstico por imagen , Factor A de Crecimiento Endotelial Vascular/metabolismo , Factores de Crecimiento Endotelial Vascular/metabolismoRESUMEN
Lattice degeneration involves thinning of the retina that occurs over time. Here we performed an immunohistological study of tissue sections of human peripheral retinal lattice degeneration to investigate if retinal pigment epithelium (RPE) cells are involved in the pathogenesis of this condition. In two cases of retinal detachment with a large tear that underwent vitreous surgery, retinal lattice degeneration tissue specimens were collected during surgery. In the obtained specimens, both whole mounts and horizontal section slices were prepared, and immunostaining was then performed with hematoxylin and antibodies against glial fibrillary acidic protein (GFAP), RPE-specific protein 65 kDa (RPE65), pan-cytokeratin (pan-CK), and CK18. Hematoxylin staining showed no nuclei in the center of the degenerative lesion, thus suggesting the possibility of the occurrence of apoptosis. In the degenerative lesion specimens, GFAP staining was observed in the center, RPE65 staining was observed in the slightly peripheral region, and pan-CK staining was observed in all areas. However, no obvious CK18 staining was observed. In a monkey retina used as the control specimen of a normal healthy retina, no RPE65 or pan-CK staining was observed in the neural retina. Our findings suggest that migration, proliferation, and differentiation of RPE cells might be involved in the repair of retinal lattice degeneration.
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Proteína Ácida Fibrilar de la Glía/genética , Queratina-18/genética , Degeneración Retiniana/genética , cis-trans-Isomerasas/genética , Anciano , Femenino , Regulación de la Expresión Génica/genética , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Retina/metabolismo , Retina/patología , Degeneración Retiniana/patología , Desprendimiento de Retina/genética , Desprendimiento de Retina/patología , Epitelio Pigmentado de la Retina/metabolismo , Epitelio Pigmentado de la Retina/patologíaRESUMEN
PURPOSE: Diabetic retinopathy (DR) involves a proliferation of vascular endothelial cells and loss of pericytes. There is a link among the action of protein kinase C (PKC) and insulin signaling. Thus, we investigated the differences between these cells in insulin receptor (IR) phosphorylation in DR. METHODS: Retinas were removed from streptozotocin-induced diabetic or healthy rats, and IR expression levels were compared by immunoblot and immunohistochemistry. In vitro assays also were performed in order to determine the expressions of phosphorylated IR in both cells cultured under 5.5 or 25 mM glucose by immunoblot. Cell viability was determined in both cells cultured under different concentrations of phorbol myristate acetate (PMA), a PKC activator. To determine the involvement of the PI3 kinase pathway of IR, PMA with or without wortmannin-induced changes in Akt was also analyzed. RESULTS: Immunoreactivity to the IR was decreased in diabetic retina. High glucose (25 mM) increased phosphorylated IR levels in endothelial cells but not in pericytes. PMA (1 nM or higher) induced death of pericytes, while endothelial cells were increased. PMA increased phosphorylated Akt in endothelial cells and decreased in pericytes. Wortmannin suppressed the PMA-induced phosphorylation of Akt in endothelial cells. CONCLUSIONS: The different responses to 25 mM glucose and PMA were observed between retinal endothelial cells and pericytes. Thus, IR phosphorylation is likely important for retinal vascular cells to survive in diabetic retina.
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Diabetes Mellitus Experimental , Retinopatía Diabética/metabolismo , Endotelio Vascular/metabolismo , Proteína Quinasa C/metabolismo , Receptor de Insulina/metabolismo , Vasos Retinianos/metabolismo , Animales , Western Blotting , Proliferación Celular , Células Cultivadas , Retinopatía Diabética/patología , Endotelio Vascular/patología , Masculino , Fosforilación , Fotomicrografía , Ratas , Ratas Wistar , Vasos Retinianos/patologíaRESUMEN
PURPOSE: The purpose of this study was to investigate the thermal injuries caused by ultrasonic pars plana phacoemulsification and aspiration (PPPEA) using pig eyes. METHOD: Using a 20-gauge (G) vitrectomy system (Accurus®, Fragmatome; Alcon Laboratories) in both the 'open-tip' and 'closed-tip' techniques, PPPEA was performed in pig eyes and the subsequent thermal injuries generated around the scleral wound were measured by infrared thermal imaging (thermography). Post surgery, the state of the scleral wound was observed under a microscope, and a tissue slice containing the scleral wound was then prepared and observed under an optical microscope. RESULTS: Thermography measurements revealed a slight temperature rise around the scleral wound in the open-tip case, yet a marked temperature rise in the closed-tip case. The scleral wound incision produced by the open tip was linear, while that produced by the closed tip was expanded. Histological examination revealed mild degeneration of the sclera around the wound in the open-tip case, yet marked tissue degeneration by thermal injuries in the closed-tip case. CONCLUSION: Our findings showed that in PPPEA, the temperature of the tip of a 20G vitrectomy system rapidly increases due to the closed-tip technique, thus producing obvious thermal damage to the scleral wound. In order to prevent thermal injuries to the scleral wound during PPPEA, it is important to shorten the time of ultrasonic oscillation during surgery as much as possible while the tip is occluded with nuclear fragments.