RESUMO
PURPOSE: To evaluate visual and anatomic outcomes following pars plana vitrectomy and intravitreal or subretinal tissue plasminogen activator for submacular hemorrhage in patients with age-related macular degeneration. METHODS: This was a retrospective study on patients with a minimum follow-up of 12 months undertaken at a tertiary referral center. Data collected include demographic details, visual and optical coherence tomography changes, surgical details, and complications. Surgical results were compared with patients who were age and lesion size matched and treated with anti-vascular endothelial growth factor injections alone. RESULTS: There were 36 patients in surgical and 18 patients in control group. Patients in surgical arm had pars plana vitrectomy, intravitreal tissue plasminogen activator with air 24 (67%), 6 (16%) with C3F8 gas, 1 (3%) with SF6 gas, 4 (11%) subretinal tissue plasminogen activator with air, and 1 (3%) with C2F6 as post-operative tamponade. Mean LogMAR in tissue plasminogen activator group at baseline was 1.56, and it was improved at all time points 1.06 at 1 month (p < 0.05), 0.91 at 6 months (p < 0.05), and 1.07 at 1 year (p < 0.05). Mean best corrected visual acuity in control group at baseline was 1.22LogMAR with no significant improvement at any time points: 1 month (1.27), 6 months (1.35), and 12 months (1.36). Complications included retinal detachment 5%, vitreous hemorrhage 7.5%, and cataract 19%. CONCLUSION: Pars plana vitrectomy with intravitreal (or subretinal) tissue plasminogen activator and pneumatic displacement can offer better outcome in comparison to anti-vascular endothelial growth factor alone in patients with submacular hemorrhage secondary to age-related macular degeneration.
Assuntos
Degeneração Macular/complicações , Hemorragia Retiniana/tratamento farmacológico , Ativador de Plasminogênio Tecidual/uso terapêutico , Acuidade Visual , Idoso , Idoso de 80 Anos ou mais , Feminino , Fibrinolíticos/uso terapêutico , Humanos , Degeneração Macular/tratamento farmacológico , Degeneração Macular/metabolismo , Masculino , Pessoa de Meia-Idade , Decúbito Ventral , Hemorragia Retiniana/etiologia , Hemorragia Retiniana/metabolismo , Estudos Retrospectivos , Tomografia de Coerência ÓpticaRESUMO
Glaucoma is a multifactorial optic neuropathy, possibly involving vascular dysfunction, leading to the death of retinal ganglion cells and their axons. Disc hemorrhage (DH) is known to be closely associated with the widening of retinal nerve fiber layer defect (NFLD); however, it has not been well elucidated how DH affects retinal microvasculature. We aimed to investigate the association between DH history and longitudinal changes in superficial retinal microvasculature in NFLD. We enrolled 15 glaucoma patients with DH history (32 glaucomatous NFLD locations, with or without DH history). NFLD-angle, superficial retinal vessel density (VD), and decreased superficial retinal microvasculature (deMv)-angle were assessed using optical coherence tomography angiography for at least three times over time. The mean follow-up period and OCT/OCTA scan interval were 21.3 ± 5.4 months (range, 12-28) and 6.8 ± 0.4 months (range, 2-18), respectively. Linear mixed-effects models showed that the presence of DH history was significantly associated with an additional NFLD-angle widening of 2.19 degree/year (P = 0.030), VD decrease of 1.88%/year (P = 0.015), and deMv-angle widening of 3.78 degree/year (P < 0.001). These changes were significantly correlated with each other (P < 0.001). Thus, the widening of NFLD was closely associated with deMv, and DH was associated with a subsequent decrease in superficial retinal microvasculature in NFLD.
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Glaucoma , Disco Óptico , Células Ganglionares da Retina , Hemorragia Retiniana , Vasos Retinianos , Adulto , Idoso , Feminino , Seguimentos , Glaucoma/metabolismo , Glaucoma/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Disco Óptico/metabolismo , Disco Óptico/patologia , Células Ganglionares da Retina/metabolismo , Células Ganglionares da Retina/patologia , Hemorragia Retiniana/metabolismo , Hemorragia Retiniana/patologia , Vasos Retinianos/metabolismo , Vasos Retinianos/patologiaRESUMO
Retinal injury is the most common ocular impairment associated with shaken baby syndrome (SBS), which could lead to vision loss and blindness. However, a woodpecker does not develop retinal hemorrhages or detachment even at a high acceleration of 1,000×g during pecking. To understand the mechanism of retinal injury and its resistance strategy, we put insight into the special ability of the woodpecker to protect the retina against damage under acceleration-deceleration impact. In this study, the structural and mechanical differences on the eyes of the woodpecker and human were analyzed quantitatively based on anatomical observation. We developed finite element eye models of the woodpecker and human to evaluate the dynamic response of the retina to the shaking load obtained from experimental data. Moreover, several structural parameters and mechanical conditions were exchanged between the woodpecker and human to evaluate their effects on retinal injury in SBS. The simulation results indicated that scleral ossification, lack of vitreoretinal attachment, and rotational acceleration-deceleration impact loading in a woodpecker contribute to the resistance to retinal injuries during pecking. The above mentioned special physical structures and mechanical behavior can distribute the high strain in the posterior segment of the woodpecker's retina, which decrease the risk of retinal injury to SBS.
Assuntos
Doenças Retinianas/metabolismo , Hemorragia Retiniana/metabolismo , Síndrome do Bebê Sacudido/metabolismo , Animais , Fenômenos Biomecânicos , Aves , Encéfalo , Simulação por Computador , Olho , Análise de Elementos Finitos , Humanos , Retina/metabolismo , Hemorragia Retiniana/complicações , Síndrome do Bebê Sacudido/complicações , Fatores de TempoRESUMO
INTRODUCTION: Haemorrhage confined to the sub-internal limiting membrane (ILM) space can be associated with good visual recovery. There is controversy as to the best management of purely sub-ILM haemorrhage, which ranges from observation to immediate surgical intervention. METHODS: We studied a retrospective case series of patients with sub-ILM haemorrhage who underwent vitrectomy with subsequent histological analysis of the removed ILM. RESULTS: Sixteen patients underwent vitrectomy for sub-ILM haemorrhage. Five patients had underlying Terson syndrome, 6 had ruptured macro-aneurysms, and 5 had Valsalva retinopathy. Seven patients demonstrated cellular proliferation on the retinal surface of the ILM with staining for glial fibrillary acidic protein and cytokeratin 7, as well as CD68pg and Prussian blue. All but 1 of these cases were isolated from patients undergoing surgery >4 weeks following initial symptoms, the other presented at >2 weeks. Serial optical coherence tomography (OCT) was available in 8 patients; serial OCT in patients with delayed intervention demonstrated persistent inner retinal layer hyper-reflectance. Fourteen of 15 patients demonstrated symptomatic recovery and showed visual improvement with acuity ranging from -0.1 to 1.8 (mean 0.43) within 3 months of intervention (1 was lost to follow-up). The post-operative vision was 0.11 logMAR (mean; range -0.1 to 0.4) at 3 months in the group with intervention within 2 weeks of symptoms, and 0.9 logMAR (mean; range 0.0 to HM) in the group with delayed surgery. CONCLUSIONS: Early surgical intervention for sub-ILM haemorrhage resulted in good visual outcomes; delayed surgery may lead to proliferative vitreoretinopathy-like changes on the inner retinal surface of the ILM, and untreated cases may demonstrate persistent inner retinal changes potentially limiting visual prognosis despite subsequent surgical intervention.
Assuntos
Membrana Basal/patologia , Membrana Epirretiniana/patologia , Hemorragia Retiniana/patologia , Vitrectomia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Membrana Basal/diagnóstico por imagem , Membrana Basal/metabolismo , Membrana Basal/cirurgia , Membrana Epirretiniana/diagnóstico por imagem , Membrana Epirretiniana/metabolismo , Membrana Epirretiniana/cirurgia , Feminino , Proteína Glial Fibrilar Ácida/metabolismo , Humanos , Queratina-7/metabolismo , Masculino , Pessoa de Meia-Idade , Hemorragia Retiniana/diagnóstico por imagem , Hemorragia Retiniana/metabolismo , Hemorragia Retiniana/cirurgia , Estudos Retrospectivos , Tomografia de Coerência Óptica , Acuidade Visual/fisiologia , Adulto JovemRESUMO
Naturally occurring cell death is a fundamental developmental mechanism for regulating cell numbers and sculpting developing organs. This is particularly true in the nervous system, where large numbers of neurons and oligodendrocytes are eliminated via apoptosis during normal development. Given the profound impact of death upon these two major cell populations, it is surprising that developmental death of another major cell type-the astrocyte-has rarely been studied. It is presently unclear whether astrocytes are subject to significant developmental death, and if so, how it occurs. Here, we address these questions using mouse retinal astrocytes as our model system. We show that the total number of retinal astrocytes declines by over 3-fold during a death period spanning postnatal days 5-14. Surprisingly, these astrocytes do not die by apoptosis, the canonical mechanism underlying the vast majority of developmental cell death. Instead, we find that microglia engulf astrocytes during the death period to promote their developmental removal. Genetic ablation of microglia inhibits astrocyte death, leading to a larger astrocyte population size at the end of the death period. However, astrocyte death is not completely blocked in the absence of microglia, apparently due to the ability of astrocytes to engulf each other. Nevertheless, mice lacking microglia showed significant anatomical changes to the retinal astrocyte network, with functional consequences for the astrocyte-associated vasculature leading to retinal hemorrhage. These results establish a novel modality for naturally occurring cell death and demonstrate its importance for the formation and integrity of the retinal gliovascular network.
Assuntos
Astrócitos/citologia , Morte Celular/genética , Microglia/citologia , Retina/citologia , Animais , Animais Recém-Nascidos , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Vasos Sanguíneos/metabolismo , Vasos Sanguíneos/fisiopatologia , Comunicação Celular , Contagem de Células , Toxina Diftérica/toxicidade , Regulação da Expressão Gênica no Desenvolvimento , Genes Reporter , Proteína Glial Fibrilar Ácida/genética , Proteína Glial Fibrilar Ácida/metabolismo , Proteínas Luminescentes/genética , Proteínas Luminescentes/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microglia/efeitos dos fármacos , Microglia/metabolismo , Fator de Transcrição PAX2/genética , Fator de Transcrição PAX2/metabolismo , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Retina/efeitos dos fármacos , Retina/metabolismo , Hemorragia Retiniana/genética , Hemorragia Retiniana/metabolismo , Hemorragia Retiniana/fisiopatologia , Fatores de Transcrição SOX9/genética , Fatores de Transcrição SOX9/metabolismo , Transdução de Sinais , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
Purpose: To determine the effects of aldosterone exposure on retinal edema and retinopathy in a mouse model of retinal vein occlusion (RVO). Methods: RVO was induced immediately following intravenous injection of Rose bengal (66 mg/kg) using a 532-nm wavelength laser to place three to seven applications at 80 mW and 50-µm spot size directed at the superior retinal vein one disc diameter away from the nerve. Negative control consisted of placing an equal number of laser spots without targeting the vein. Male and female C57BL/6J mice aged 7 to 9 months with confirmed absence of Crb1rd8 were used. Aldosterone pellets releasing a daily dose of 0.83 µg/day were implanted subcutaneously 4 weeks prior to RVO. Retinal imaging by optical coherence tomography (OCT) was performed using a Micron IV rodent imaging system. Retinas were analyzed by immunohistochemistry using standard techniques. Retinal imaging and tissue analysis were performed 2, 4, and 7 days following RVO. Comparisons were made using Student's t-test, ANOVA, and Pearson's χ2. Results: RVO caused retinal edema in the form of cystic spaces and retinal thickening detectable by both OCT and histology. RVO also caused Müller glia (MG) dysfunction manifest as upregulated glial fibrillary acidic protein (GFAP) and altered localization of aquaporin 4 (AQP4) and Kir4.1. Treatment with aldosterone caused a significant increase in retinal edema and more severe retinopathy manifest as retinal whitening and extensive intraretinal hemorrhage. MG dysfunction was more severe and persistent in aldosterone-treated mice. Finally, aldosterone greatly increased the number of infiltrating mononuclear phagocytes following RVO. Conclusions: Systemic aldosterone exposure causes a more severe RVO phenotype manifest as increased severity and duration of retinal edema and more severe retinopathy. The effects of aldosterone may be mediated by MG dysfunction and increased infiltration of mononuclear phagocytes. This suggests that small increases in aldosterone levels may be a risk factor for severe RVO.
Assuntos
Aldosterona/efeitos adversos , Modelos Animais de Doenças , Fotocoagulação a Laser/efeitos adversos , Edema Macular/induzido quimicamente , Hemorragia Retiniana/induzido quimicamente , Oclusão da Veia Retiniana/etiologia , Aldosterona/administração & dosagem , Animais , Biomarcadores/metabolismo , Western Blotting , Implantes de Medicamento , Feminino , Corantes Fluorescentes , Edema Macular/metabolismo , Edema Macular/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microscopia de Fluorescência , Hemorragia Retiniana/metabolismo , Hemorragia Retiniana/fisiopatologia , Oclusão da Veia Retiniana/metabolismo , Oclusão da Veia Retiniana/fisiopatologia , Rosa Bengala , Tomografia de Coerência ÓpticaRESUMO
PURPOSE: Abnormal retinal angiogenesis leads to visual impairment and blindness. Understanding how retinal vessels develop normally has dramatically improved treatments for people with retinal vasculopathies, but additional information about development is required. Abnormal neuron patterning in the outer retina has been shown to result in abnormal vessel development and blindness, for example, in people and mouse models with Crumbs homologue 1 (CRB1) mutations. In this study, we report and characterize a mouse model of inner retinal lamination disruption and bleeding, the Down syndrome cell adhesion molecule (Dscam) mutant, and test how neuron-neurite placement within the inner retina guides development of intraretinal vessels. METHODS: Bax mutant mice (increased neuron cell number), Dscam mutant mice (increased neuron cell number, disorganized lamination), Fat3 mutant mice (disorganized neuron lamination), and Dscam gain-of-function mice (Dscam(GOF)) (decreased neuron cell number) were used to manipulate neuron placement and number. Immunohistochemistry was used to assay organization of blood vessels, glia, and neurons. In situ hybridization was used to map the expression of angiogenic factors. RESULTS: Significant changes in the organization of vessels within mutant retinas were found. Displaced neurons and microglia were associated with the attraction of vessels. Using Fat3 mutant and Dscam(GOF) retinas, we provide experimental evidence that vessel branching is induced at the neuron-neurite interface, but that other factors are required for full plexus layer formation. We further demonstrate that the displacement of neurons results in the mislocalization of angiogenic factors. CONCLUSIONS: Inner retina neuron lamination is required for development of intraretinal vessels.
Assuntos
Modelos Animais de Doenças , Retina/anormalidades , Hemorragia Retiniana/etiologia , Neovascularização Retiniana/etiologia , Neurônios Retinianos/patologia , Animais , Western Blotting , Caderinas/genética , Moléculas de Adesão Celular/genética , Contagem de Células , Proteínas do Citoesqueleto , Glicoproteínas/metabolismo , Hibridização In Situ , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Mutantes , Microscopia Confocal , Hemorragia Retiniana/metabolismo , Hemorragia Retiniana/patologia , Neovascularização Retiniana/metabolismo , Neovascularização Retiniana/patologia , Vasos Retinianos/patologia , Semaforinas/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Proteína X Associada a bcl-2/genéticaRESUMO
PURPOSE: To investigate ß-amyloid precursor protein (ß-APP), ubiquitin, and glial fibrillary acid protein (GFAP) immunostaining as a diagnostic tool to aid in the discrimination between abusive head trauma and nonabusive head trauma in postmortem ocular histopathologic investigation. DESIGN: Retrospective cross-sectional study. METHODS: Seventy-four eyes of 37 infants were studied for hemorrhage and immunohistochemical expression of ß-APP, ubiquitin, and GFAP in the retina and optic nerve. Infants were assigned to abusive head trauma or control groups, according to published criteria. RESULTS: In the abusive head trauma group, positive ß-APP and ubiquitin immunostaining of the retina was significantly more likely to be found than in the control group, odds ratio (OR) 11.4, confidence interval (CI) 2.9-44.3; P < .001 and OR 8.8, CI 2.2-34.5; P = .002, respectively. Positive correlations were found between retinal expression of ß-APP and ubiquitin immunostaining and retinal hemorrhage. Vitreal hemorrhages, orbital fat hemorrhages, and macular folds could only be identified in abusive head trauma cases. Retinal hemorrhages were significantly more severe, occupied a larger proportion of the retina, and involved more retinal layers in abusive head trauma compared to controls (OR 2.7, CI 1.7-4.4; P < .001). CONCLUSIONS: This study shows correlations between positive retinal ß-APP and ubiquitin immunostaining as a sign of axonal injury in abusive head trauma. Axonal injury is a useful pathologic feature that can be demonstrated in postmortem ocular investigation of deceased children using immunohistochemical staining for ß-APP and ubiquitin with a high OR for abusive head trauma when compared to controls.
Assuntos
Precursor de Proteína beta-Amiloide/análise , Maus-Tratos Infantis , Traumatismos Craniocerebrais/complicações , Imuno-Histoquímica/métodos , Hemorragia Retiniana/diagnóstico , Ubiquitina/análise , Autopsia , Traumatismos Craniocerebrais/diagnóstico , Estudos Transversais , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Hemorragia Retiniana/etiologia , Hemorragia Retiniana/metabolismo , Estudos RetrospectivosRESUMO
IMPORTANCE: Retinal hemorrhages are an important sequela of fatal head trauma. The accurate pathologic diagnosis of retinal hemorrhages has critical implications for determination of the manner of death. OBSERVATIONS: We describe an autolytic postmortem histologic artifact of eosinophilic Müller cell foot process swelling that mimics a nerve fiber layer hemorrhage. From April 24, 2012, through November 11, 2014, we conducted postmortem examination of the eyes of 23 infants and children who were referred to our institution for possible nonaccidental head trauma. A focal artifact of Müller cell foot process swelling was identified in most patients (16 of 23) up to 4 years of age. Three infants, all of whom were younger than 3 months, demonstrated diffusely swollen Müller cell foot processes with intensely eosinophilic cytoplasm that mimicked erythrocytes of nerve fiber layer hemorrhages. The difference in the mean age between patients with diffuse eosinophilic artifacts (1.7 months) and patients with only a multifocal, focal, or absent artifact (13.3 months) was 11.6 months (95% CI, 6.5-16.7 months). Glycophorin C immunohistochemical analysis was useful to differentiate this artifact from nerve fiber layer hemorrhage. CONCLUSIONS AND RELEVANCE: Our case review demonstrates an artifact of eosinophilic Müller cell foot processes swelling in postmortem examination of young infant eyes, a potential pitfall in the diagnosis of retinal hemorrhages. Our findings have important implications for the diagnosis of retinal hemorrhages in potential cases of nonaccidental head injury.
Assuntos
Artefatos , Autopsia , Células Ependimogliais/patologia , Hemorragia Retiniana/diagnóstico , Autólise , Síndrome da Criança Espancada/diagnóstico , Pré-Escolar , Traumatismos Craniocerebrais/diagnóstico , Células Ependimogliais/metabolismo , Feminino , Glicoforinas/metabolismo , Humanos , Imuno-Histoquímica , Lactente , Masculino , Hemorragia Retiniana/metabolismoRESUMO
PURPOSE: To evaluate treatment outcomes of intravitreal vascular endothelial growth factor (VEGF) in eyes with polypoidal choroidal vasculopathy (PCV) that exhibited poor baseline visual acuity. METHODS: This retrospective, observational study included 47 eyes with treatment-naïve PCV with baseline visual acuity of 20/200 or worse treated with intravitreal anti-VEGF. Eyes were divided into 2 groups according to the presence of submacular hemorrhage (hemorrhage and no-hemorrhage groups). The best-corrected visual acuity (BCVA) at baseline was compared with that measured at 3 and 6 months after treatment. RESULTS: A mean of 3.3±0.9 intravitreal anti-VEGF injections were performed during the 6-month follow-up period. In the hemorrhage group (n=23), 6 patients additionally underwent pneumatic displacement with or without intravitreal tissue plasminogen activator. The logarithm of minimal angle of resolution BCVA at diagnosis, 3, and 6 months was 1.47±0.49, 0.91±0.79, and 0.81±0.83, respectively. Compared with baseline, BCVA was significantly better at 3 and 6 months (P=0.007 and P=0.001, respectively). In the no-hemorrhage group (n=24), the BCVA at defined time points was 1.23±0.32, 1.06±0.33, and 1.02±0.35, respectively. BCVA was significantly better at 3 and 6 months compared with baseline (P=0.006 and P=0.025, respectively). CONCLUSIONS: Intravitreal anti-VEGF was found to be beneficial in PCV eyes with poor baseline visual acuity, regardless of the presence of submacular hemorrhage. The magnitude of visual improvement was relatively greater in eyes with submacular hemorrhage.
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Inibidores da Angiogênese/administração & dosagem , Doenças da Coroide/tratamento farmacológico , Corioide/irrigação sanguínea , Neovascularização de Coroide/tratamento farmacológico , Ranibizumab/administração & dosagem , Acuidade Visual/efeitos dos fármacos , Idoso , Corioide/efeitos dos fármacos , Corioide/metabolismo , Corioide/patologia , Doenças da Coroide/metabolismo , Doenças da Coroide/patologia , Neovascularização de Coroide/metabolismo , Neovascularização de Coroide/patologia , Feminino , Fibrinolíticos/administração & dosagem , Angiofluoresceinografia/métodos , Seguimentos , Humanos , Verde de Indocianina , Injeções Intravítreas , Masculino , Pessoa de Meia-Idade , Hemorragia Retiniana/metabolismo , Hemorragia Retiniana/patologia , Estudos Retrospectivos , Ativador de Plasminogênio Tecidual/administração & dosagem , Resultado do Tratamento , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
BACKGROUND: Neonatal intermittent hyperoxia-hypoxia (IHH) is involved in the pathogenesis of retinopathy of prematurity. Whether similar oxygen fluctuations will create pathological changes in the grey and white matter of the brain is unknown. METHODS: From birth until postnatal day 14 (P14), two litters (total n = 22) were reared in IHH: hyperoxia (50% O2) interrupted by three consecutive two-minute episodes of hypoxia (12% O2) every sixth hour. Controls (n = 8) were reared in room-air (20.9% O2). Longitudinal MRI (Diffusion Tensor Imaging and T2-mapping) was performed on P14 and P28 and retinal and brain tissue were examined for histopathological changes. Long-term neurodevelopment was assessed on P20 and P27. RESULTS: Mean, radial and axial diffusivity were higher in white matter of IHH versus controls at P14 (p < 0.04), while fractional anisotropy (FA) was lower in the hippocampal fimbria and tended to be lower in corpus callosum (p = 0.08) and external capsule (p = 0.05). White matter diffusivity in IHH was similar to controls at P28. Higher cortical vessel density (p = 0.005) was observed at P14. Cortical and thalamic T2-relaxation time and mean diffusivity were higher in the IHH group at P14 (p ≤ 0.03), and albumin leakage was present at P28. Rats in the IHH group ran for a longer time on a Rotarod than the control group (p ≤ 0.005). Pups with lower bodyweight had more severe MRI alterations and albumin leakage. CONCLUSION: IHH led to subtle reversible changes in brain white matter diffusivity, grey matter water content and vascular density. However, alterations in blood-brain barrier permeability may point to long-term effects. The changes seen after IHH exposure were more severe in animals with lower bodyweight and future studies should aim at exploring possible interactions between IHH and growth restriction.
Assuntos
Encéfalo/metabolismo , Hiperóxia/metabolismo , Hipóxia/metabolismo , Imageamento por Ressonância Magnética , Animais , Animais Recém-Nascidos , Peso Corporal , Encéfalo/patologia , Imuno-Histoquímica , Tamanho do Órgão , Ratos , Retina/metabolismo , Retina/patologia , Hemorragia Retiniana/metabolismo , Hemorragia Retiniana/patologia , Teste de Desempenho do Rota-RodRESUMO
The familial transthyretin (TTR) amyloidosis (FTA) demonstrates variable penetrance of clinical features associated with mutations in the plasma thyroid hormone-binding protein TTR gene. The purpose of this study was to assess the ocular features, to analyze vitreous and serum vascular endothelial growth factor (VEGF) levels, and to identify the genetic defect in a Chinese family with TTR FTA. The pedigree of interest was a three-generation family with eleven members. The primary ocular signs were vitreous opacities, beginning from the third or fourth decade, accompanied by retinal vasculitis, hemorrhages, and widespread pinpoint deposits in the peripheral retina. Two patients underwent vitrectomy with marked improvement of visual acuity postoperatively. Vitreous and serum samples for VEGF were analyzed with an enzyme-linked immunosorbent assay (ELISA). Forty-eight healthy adult volunteers were enrolled as a control group for the analysis of serum VEGF. Eight subjects who underwent vitrectomy for a macular epiretinal membrane or macular hole were enrolled as control for the analysis of vitreous VEGF. Both serum and vitreous VEGF levels of patients were raised compared to that of controls. Venous blood was collected from family members and the genomic DNA was extracted. All exons and exon-intron boundaries of the TTR gene were sequenced. A previously-described pathogenic transversion in exon 2 (c.G106C, p.Ala36Pro) was identified. Within this family eight individuals were confirmed as affected. In conclusion, a Chinese family with TTR Ala36Pro associated FTA is characterized by early ocular involvement. Widespread pinpoint lesions indicate RPE lesions caused by TTR deposition. FTA is associated with increased VEGF levels, both in serum and vitreous.
Assuntos
Neuropatias Amiloides Familiares/genética , Povo Asiático/genética , Mutação Puntual , Pré-Albumina/genética , Fator A de Crescimento do Endotélio Vascular/sangue , Corpo Vítreo/metabolismo , Adulto , Idoso , Neuropatias Amiloides Familiares/diagnóstico , Neuropatias Amiloides Familiares/metabolismo , Análise Mutacional de DNA , Eletroculografia , Eletrorretinografia , Ensaio de Imunoadsorção Enzimática , Oftalmopatias/diagnóstico , Oftalmopatias/genética , Oftalmopatias/metabolismo , Feminino , Angiofluoresceinografia , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Reação em Cadeia da Polimerase , Hemorragia Retiniana/diagnóstico , Hemorragia Retiniana/genética , Hemorragia Retiniana/metabolismo , Vasculite Retiniana/diagnóstico , Vasculite Retiniana/genética , Vasculite Retiniana/metabolismo , Tomografia de Coerência Óptica , Acuidade Visual/fisiologia , Vitrectomia , Corpo Vítreo/patologia , Adulto JovemRESUMO
PURPOSE: Retinal hemorrhages occur in a variety of sight-threatening conditions including ocular trauma, high altitude retinopathy, and chronic diseases such as diabetic and hypertensive retinopathies. The goal of this study is to investigate the effects of blood in the vitreous on retinal vascular function in rats. METHODS: Intravitreal injections of autologous blood, plasma kallikrein (PK), bradykinin, and collagenase were performed in Sprague-Dawley and Long-Evans rats. Retinal vascular permeability was measured using vitreous fluorophotometry and Evans blue dye permeation. Leukostasis was measured by fluorescein isothiocyanate-coupled concanavalin A lectin and acridine orange labeling. Retinal hemorrhage was examined on retinal flatmounts. Primary cultures of bovine retinal pericytes were cultured in the presence of 25 nM PK for 24 hours. The pericyte-conditioned medium was collected and the collagen proteome was analyzed by tandem mass spectrometry. RESULTS: Intravitreal injection of autologous blood induced retinal vascular permeability and retinal leukostasis, and these responses were ameliorated by PK inhibition. Intravitreal injections of exogenous PK induced retinal vascular permeability, leukostasis, and retinal hemorrhage. Proteomic analyses showed that PK increased collagen degradation in pericyte-conditioned medium and purified type IV collagen. Intravitreal injection of collagenase mimicked PK's effect on retinal hemorrhage. CONCLUSIONS: Intraocular hemorrhage increases retinal vascular permeability and leukostasis, and these responses are mediated, in part, via PK. Intravitreal injections of either PK or collagenase, but not bradykinin, induce retinal hemorrhage in rats. PK exerts collagenase-like activity that may contribute to blood-retinal barrier dysfunction.
Assuntos
Calicreína Plasmática/metabolismo , Doenças Retinianas/etiologia , Hemorragia Retiniana/complicações , Vasos Retinianos/patologia , Animais , Sangue , Barreira Hematorretiniana/efeitos dos fármacos , Bradicinina/farmacologia , Permeabilidade Capilar , Bovinos , Células Cultivadas , Colagenases/farmacologia , Concanavalina A/metabolismo , Azul Evans/metabolismo , Fluoresceína-5-Isotiocianato/análogos & derivados , Fluoresceína-5-Isotiocianato/metabolismo , Fluorofotometria , Injeções Intravítreas , Leucostasia/etiologia , Masculino , Pericitos/efeitos dos fármacos , Pericitos/metabolismo , Calicreína Plasmática/farmacologia , Ratos , Ratos Long-Evans , Ratos Sprague-Dawley , Doenças Retinianas/metabolismo , Hemorragia Retiniana/metabolismo , Vasos Retinianos/metabolismo , Espectrometria de Massas em Tandem , Corpo Vítreo/efeitos dos fármacos , Corpo Vítreo/metabolismoRESUMO
Photoreceptor degeneration is the most critical cause of visual impairment in age-related macular degeneration (AMD). In neovascular form of AMD, severe photoreceptor loss develops with subretinal hemorrhage due to choroidal neovascularization (CNV), growth of abnormal blood vessels from choroidal circulation. However, the detailed mechanisms of this process remain elusive. Here we demonstrate that neovascular AMD with subretinal hemorrhage accompanies a significant increase in extracellular ATP, and that extracellular ATP initiates neurodegenerative processes through specific ligation of Purinergic receptor P2X, ligand-gated ion channel, 7 (P2RX7; P2X7 receptor). Increased extracellular ATP levels were found in the vitreous samples of AMD patients with subretinal hemorrhage compared to control vitreous samples. Extravascular blood induced a massive release of ATP and photoreceptor cell apoptosis in co-culture with primary retinal cells. Photoreceptor cell apoptosis accompanied mitochondrial apoptotic pathways, namely activation of caspase-9 and translocation of apoptosis-inducing factor (AIF) from mitochondria to nuclei, as well as TUNEL-detectable DNA fragmentation. These hallmarks of photoreceptor cell apoptosis were prevented by brilliant blue G (BBG), a selective P2RX7 antagonist, which is an approved adjuvant in ocular surgery. Finally, in a mouse model of subretinal hemorrhage, photoreceptor cells degenerated through BBG-inhibitable apoptosis, suggesting that ligation of P2RX7 by extracellular ATP may accelerate photoreceptor cell apoptosis in AMD with subretinal hemorrhage. Our results indicate a novel mechanism that could involve neuronal cell death not only in AMD but also in hemorrhagic disorders in the CNS and encourage the potential application of BBG as a neuroprotective therapy.
Assuntos
Trifosfato de Adenosina/farmacologia , Degeneração Macular/metabolismo , Células Fotorreceptoras/efeitos dos fármacos , Receptores Purinérgicos P2X7/metabolismo , Hemorragia Retiniana/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Apoptose/efeitos dos fármacos , Fator de Indução de Apoptose/genética , Fator de Indução de Apoptose/metabolismo , Caspase 9/genética , Caspase 9/metabolismo , Corioide/irrigação sanguínea , Corioide/metabolismo , Corioide/patologia , Neovascularização de Coroide , Técnicas de Cocultura , Fragmentação do DNA/efeitos dos fármacos , Humanos , Degeneração Macular/patologia , Masculino , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Células Fotorreceptoras/metabolismo , Células Fotorreceptoras/patologia , Cultura Primária de Células , Antagonistas do Receptor Purinérgico P2X/farmacologia , Receptores Purinérgicos P2X7/genética , Hemorragia Retiniana/patologia , Epitélio Pigmentado da Retina , Corantes de Rosanilina/farmacologia , Corpo Vítreo/irrigação sanguínea , Corpo Vítreo/metabolismo , Corpo Vítreo/patologiaRESUMO
OBJECTIVE: To investigate the compatibility of recombinant tissue plasminogen activator (rtPA) and bevacizumab in vitro because during surgery, rtPA or rtPA-induced plasmin may cleave and inactivate bevacizumab. METHODS: To simulate the intraoperative range of mixing ratios of rtPA, bevacizumab, and subretinal blood, we calculated the volumes of 12 submacular hemorrhages (SHs) with a spherical cap formula using measurements derived from fundus photographs and spectral-domain optical coherence tomographic images. Bevacizumab was incubated with rtPA or plasmin before gel electrophoresis with Coomassie blue and silver staining. The anti-angiogenetic activity of bevacizumab in the presence of rtPA with or without clotted human blood or of plasmin was quantified by vascular endothelial growth factorenzyme-linked immunosorbent assay after incubation with the supernatant of porcine retinal pigment epithelium cell cultures. RESULTS: The mean (SD) volume of SH was 28.6 (24.7) mm3 (range, 6.2-94.6 mm3). In sodium dodecyl sulfatepolyacrylamid electrophoresis with Coomassie blue or silver staining, bevacizumab displayed characteristic patterns of protein bands. No additional fragments were detected in co-application of bevacizumab with either rtPA or plasmin. The anti-angiogenetic activity of bevacizumab remained unchanged in co-application with rtPA with or without blood or plasmin. CONCLUSIONS: We demonstrated the absence of cleavage or functional inactivation of bevacizumab by rtPA in an in-vitro model of their intraoperative co-application as a treatment of SH. CLINICAL RELEVANCE: In clinical practice, rtPA and bevacizumab can be co-applied as a treatment for neovascular age-related macular degeneration with SH to simultaneously clear SH and reduce choroidal new vessel activity.
Assuntos
Inibidores da Angiogênese/farmacologia , Anticorpos Monoclonais Humanizados/farmacologia , Fibrinolíticos/farmacologia , Hemorragia Retiniana/tratamento farmacológico , Ativador de Plasminogênio Tecidual/farmacologia , Degeneração Macular Exsudativa/tratamento farmacológico , Animais , Bevacizumab , Células Cultivadas , Interações Medicamentosas , Quimioterapia Combinada , Eletroforese em Gel de Poliacrilamida , Ensaio de Imunoadsorção Enzimática , Fibrinolisina/farmacologia , Humanos , Proteínas Recombinantes/farmacologia , Hemorragia Retiniana/metabolismo , Epitélio Pigmentado da Retina/efeitos dos fármacos , Epitélio Pigmentado da Retina/metabolismo , Suínos , Tomografia de Coerência Óptica , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Degeneração Macular Exsudativa/metabolismoRESUMO
PURPOSE: To examine the evolution and complications of preretinal hemorrhage under silicone oil after diabetic vitrectomy. METHODS: A total of 44 cases of primary diabetic vitrectomy with silicone oil infusion were reviewed in a 3-year period. Intravitreal bevacizumab was used preoperatively for cases with active proliferation, and in all cases at the end of surgery. Intraoperative bleeding, postoperative extent of preretinal hemorrhage, blood reabsorption time, and reproliferation and treatment results were assessed. RESULTS: Maximal blood distributed in thin and scattered patterns (23 cases), thick and localized patterns (10 cases), or thick and scattered patterns (10 cases) developed within 1 week after surgery, and was largely reabsorbed within a month with improved postoperative vision. Confluent blood extending to the midperiphery (one case) resulted in severe fibrosis and detachment. Complications included fibrotic plaque (two cases), and fibrous band and thick membrane (seven cases). Six cases underwent preretinal tissue removal. Vision improvement ≥ 3 lines was noted in three cases. CONCLUSION: Most of the rebleeding occurred within the first post-op week, with gradual reabsorption in the posterior pole within 4 weeks; widespread confluent bleeding might result in severe reproliferation and detachment. A major complication of preretinal bleeding was the formation of preretinal fibrosis. Re-operation achieved a mild VA improvement.
Assuntos
Retinopatia Diabética/cirurgia , Hemorragia Retiniana/metabolismo , Óleos de Silicone/administração & dosagem , Vitrectomia/métodos , Absorção , Idoso , Inibidores da Angiogênese/administração & dosagem , Anticorpos Monoclonais Humanizados/administração & dosagem , Bevacizumab , Retinopatia Diabética/tratamento farmacológico , Feminino , Humanos , Complicações Intraoperatórias , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias , Análise de Regressão , Hemorragia Retiniana/complicações , Hemorragia Retiniana/patologia , Estudos Retrospectivos , Óleos de Silicone/efeitos adversos , Vitrectomia/efeitos adversosRESUMO
BACKGROUND: Eales' disease (ED) is an idiopathic obliterative vasculopathy that usually affects the peripheral retina of young adults. The aim of this study is to investigate Th1/Th2 serum cytokine profiling in patients with ED. METHODS: This study included 30 male patients with ED and 10 healthy controls. The ED patients were divided into two subgroups: the vitreous haemorrhage (VH) group (n = 18) and non-vitreous haemorrhage (NVH) group (n = 12). Sixteen patients (six from the VH group and 10 from the NVH group) received glucocorticoid treatment for three months and were followed for six months. Levels of six cytokines including interferon-gamma (IFN-gamma), tumour necrosis factor-alpha (TNF-alpha) and four interleukins (IL-2, IL-4, IL-5 and IL-10) in the serum samples were determined by Luminex assays. RESULTS: Compared to controls, ED patients showed significantly higher levels of IL-10 and TNF-alpha, increased IFN-gamma/IL-4 (Th1/Th2) ratio, and lower levels of IL-4 (p < 0.05). Glucocorticoid treatment caused a restoration in the cytokine levels and the IFN-gamma/IL-4 ratio. Multivariate analysis revealed that reduced IL-4 (less than 4 pg/ml) and elevated IL-10 (greater than 4 pg/ml) levels were independent predictors of ED with odds ratios of 0.024 (95% CI, 0.002-0.255; p = 0.002) and 12.108 (95% CI, 1.045-140.233; p = 0.046), respectively. CONCLUSION: The findings demonstrate for the first time that there is an imbalance of Th1/Th2 cytokines in ED patients, which can be reversed by glucocorticoid treatment. Additionally, both IL-4 and IL-10 might represent potential diagnostic markers for the disease.
Assuntos
Interferon gama/sangue , Interleucina-4/sangue , Hemorragia Retiniana/sangue , Hemorragia Retiniana/diagnóstico , Hemorragia Vítrea/sangue , Hemorragia Vítrea/diagnóstico , Adulto , Citocinas/sangue , Citocinas/metabolismo , Glucocorticoides/uso terapêutico , Humanos , Interleucina-10/sangue , Masculino , Razão de Chances , Valor Preditivo dos Testes , Hemorragia Retiniana/tratamento farmacológico , Hemorragia Retiniana/metabolismo , Células Th1/metabolismo , Células Th2/metabolismo , Resultado do Tratamento , Fator de Necrose Tumoral alfa/sangue , Hemorragia Vítrea/tratamento farmacológico , Hemorragia Vítrea/metabolismoRESUMO
PURPOSE: To investigate the vitreous levels of bevacizumab and vascular endothelial growth factor-A (VEGF-A) after intravitreal injection of the drug in patients with choroidal neovascularization (CNV). DESIGN: Interventional case series. PARTICIPANTS: Eleven eyes of 11 patients with submacular hemorrhage and CNV due to age-related macular degeneration (n = 10) or angioid streaks (n = 1). METHODS: All patients were treatment naïve except for a single dose of intravitreal injection of bevacizumab (1.25 mg/50 muL dose) and subsequent vitrectomy after various intervals (1-101 days) because of active and progressive lesion. Intravitreal free bevacizumab and VEGF-A levels were measured using enzyme-linked immunosorbent assay and microsphere-based immunoassay, respectively. Vitreous VEGF-A isoforms were analyzed by sodium dodecyl sulfate polyacrylamide gel electrophoresis and Western blotting. MAIN OUTCOME MEASURES: Intravitreal bevacizumab and VEGF-A levels were measured and pharmacokinetic parameters were calculated. RESULTS: Pharmacokinetics of intravitreal bevacizumab followed a 2-compartment model with initial and terminal half-lives of 0.5 and 6.7 days, respectively. Bevacizumab could be detected in all cases, ranging from 2.63 ng/ml to 165 microg/ml. The peak concentration was observed on the second day after intravitreal bevacizumab injection. Vitreous free VEGF-A levels ranged from 0.2 to 33.9 pg/ml and showed a negative correlation with the bevacizumab concentration (P<0.001; r = -0.955) and a positive correlation with time (P<0.001; r = 0.964). However, the percentage expression of VEGF-A(165) exhibited a positive correlation with the bevacizumab concentration (P = 0.032, r = 0.645) and a negative correlation with time (P = 0.007, r = -0.755). A time-dependent increase was found for the percentage expression of VEGF-A(189) (P = 0.023, r = 0.673). Neither bevacizumab- nor time-related alterations were found for VEGF-A(121). CONCLUSIONS: Based on pharmacokinetics, the interval of 6-7 weeks would be appropriate for efficacy, although clinical trials should guide dosing recommendations. Vitreous levels of free VEGF-A showed a negative correlation with the bevacizumab concentration, which confirmed the in vivo binding affinity of bevacizumab to VEGF-A. The analysis of the VEGF-A isoforms suggests differences of interaction between bevacizumab and individual VEGF-A isoforms.
Assuntos
Inibidores da Angiogênese/farmacocinética , Anticorpos Monoclonais/farmacocinética , Neovascularização de Coroide/metabolismo , Fator A de Crescimento do Endotélio Vascular/farmacocinética , Corpo Vítreo/metabolismo , Idoso , Idoso de 80 Anos ou mais , Estrias Angioides/complicações , Estrias Angioides/metabolismo , Anticorpos Monoclonais Humanizados , Bevacizumab , Western Blotting , Neovascularização de Coroide/tratamento farmacológico , Neovascularização de Coroide/etiologia , Eletroforese em Gel de Poliacrilamida , Ensaio de Imunoadsorção Enzimática , Feminino , Meia-Vida , Humanos , Injeções , Degeneração Macular/complicações , Degeneração Macular/metabolismo , Masculino , Pessoa de Meia-Idade , Hemorragia Retiniana/etiologia , Hemorragia Retiniana/metabolismo , VitrectomiaRESUMO
PURPOSE: A patient with subretinal and preretinal hemorrhage after secondary systemic amyloidosis due to familial Mediterranean fever is presented. METHODS: Case presentation. RESULTS: A 30-year-old woman with secondary systemic amyloidosis secondary to familial Mediterranean fever presented with painless visual loss in the right eye. The examination demonstrated multiple subretinal and preretinal hemorrhages, massive deposits which may represent amyloid material at the left macular region. After 6 months, the hemorrhages disappeared, but deposits persisted. CONCLUSIONS: The macular deposition and hemorrhage is an uncommon manifestation of secondary systemic amyloidosis secondary to familial Mediterranean fever. Further evidence is necessary to understand the nature of these deposits and their relevance to secondary systemic amyloidosis and/or familial Mediterranean fever.