Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 3.930
Filtrar
2.
Int J Mol Sci ; 21(14)2020 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-32674481

RESUMO

Effective treatment of retinal diseases with adeno-associated virus (AAV)-mediated gene therapy is highly dependent on the proportion of successfully transduced cells. However, due to inflammatory reactions at high vector doses, adjunctive treatment may be necessary to enhance the therapeutic outcome. Hydroxychloroquine and chloroquine are anti-malarial drugs that have been successfully used in the treatment of autoimmune diseases. Evidence suggests that at high concentrations, hydroxychloroquine and chloroquine can impact viral infection and replication by increasing endosomal and lysosomal pH. This effect has led to investigations into the potential benefits of these drugs in the treatment of viral infections, including human immunodeficiency virus and severe acute respiratory syndrome coronavirus-2. However, at lower concentrations, hydroxychloroquine and chloroquine appear to exert immunomodulatory effects by inhibiting nucleic acid sensors, including toll-like receptor 9 and cyclic GMP-AMP synthase. This dose-dependent effect on their mechanism of action supports observations of increased viral infections associated with lower drug doses. In this review, we explore the immunomodulatory activity of hydroxychloroquine and chloroquine, their impact on viral infections, and their potential to improve the efficacy and safety of retinal gene therapy by reducing AAV-induced immune responses. The safety and practicalities of delivering hydroxychloroquine into the retina will also be discussed.


Assuntos
Cloroquina/uso terapêutico , Terapia Genética , Hidroxicloroquina/uso terapêutico , Doenças Retinianas/terapia , Viroses/tratamento farmacológico , Animais , Betacoronavirus/efeitos dos fármacos , Cloroquina/farmacologia , Dependovirus/genética , Humanos , Hidroxicloroquina/farmacologia , Imunomodulação/efeitos dos fármacos , Doenças Retinianas/patologia
3.
Proc Natl Acad Sci U S A ; 117(31): 18780-18787, 2020 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-32699144

RESUMO

Macular telangiectasia type 2 (MacTel), a late-onset macular degeneration, has been linked to a loss in the retina of Müller glial cells and the amino acid serine, synthesized by the Müller cells. The disease is confined mainly to a central retinal region called the MacTel zone. We have used electron microscopic connectomics techniques, optimized for disease analysis, to study the retina from a 48-y-old woman suffering from MacTel. The major observations made were specific changes in mitochondrial structure within and outside the MacTel zone that were present in all retinal cell types. We also identified an abrupt boundary of the MacTel zone that coincides with the loss of Müller cells and macular pigment. Since Müller cells synthesize retinal serine, we propose that a deficiency of serine, required for mitochondrial maintenance, causes mitochondrial changes that underlie MacTel development.


Assuntos
Conectoma/métodos , Retina , Doenças Retinianas , Feminino , Humanos , Degeneração Macular/diagnóstico por imagem , Degeneração Macular/patologia , Microscopia Eletrônica , Pessoa de Meia-Idade , Retina/citologia , Retina/diagnóstico por imagem , Retina/patologia , Doenças Retinianas/diagnóstico por imagem , Doenças Retinianas/patologia
4.
Med Sci (Paris) ; 36(6-7): 626-632, 2020.
Artigo em Francês | MEDLINE | ID: mdl-32614314

RESUMO

Generation of retinal organoids from pluripotent stem cells represents an important advance in the study of retinal development and offer new perspectives for the study of retinal diseases missing suitable animal models. Understanding the key stages of retinal development in vertebrates enabled to design protocols to generate self-organized three-dimensional structures derived from pluripotent stem cells and containing all retinal cell types. In addition to their application in basic research, such as the characterization of molecular and cellular mechanisms in retinal pathophysiology, these miniature organs also open up encouraging prospects in the field of cell therapy or the screening of therapeutic molecules, although some obstacles remain to be overcome.


Assuntos
Organoides/citologia , Retina/citologia , Doenças Retinianas/etiologia , Doenças Retinianas/patologia , Doenças Retinianas/terapia , Animais , Células Cultivadas , Humanos , Modelos Biológicos , Organoides/fisiologia , Retina/patologia , Retina/fisiologia , Terapias em Estudo/métodos , Terapias em Estudo/tendências , Técnicas de Cultura de Tecidos/métodos , Técnicas de Cultura de Tecidos/tendências
6.
PLoS One ; 15(6): e0234151, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32520956

RESUMO

OBJECTIVES: To examine interocular asymmetry of foveal avascular zone (FAZ) and parafoveal capillary density metrics in sickle cell retinopathy (SCR) using optical coherence tomography angiography (OCT-A). METHODS: This cross-sectional, retrospective study evaluated SCR patients and unaffected controls who underwent 3x3mm macular OCT-A imaging using a spectral domain-OCT system. FAZ (area, perimeter, and acircularity index) and parafoveal capillary density metrics were computed for both eyes of each participant. In unaffected controls, interocular difference in FAZ and parafoveal capillary density metrics were evaluated using Bland-Altman plots. SCR patients with interocular difference outside the upper 97.5% and lower 2.5% limits of agreement from controls were defined as having interocular asymmetry. Area under receiver operating characteristic curve (AROC) was also performed to determine the ability of the absolute interocular difference to differentiate between subjects with SCR-including non-proliferative SCR (NP-SCR) and proliferative SCR (P-SCR)-and unaffected controls. RESULTS: Thirty-one patients with SCR (21 NP-SCR and 10 P-SCR) and 14 race-matched and age-matched controls were included for analysis. Interocular asymmetry was seen for all FAZ and parafoveal capillary density metrics in NP-SCR and P-SCR subjects. SCR subjects showed greater disease severity in the left-eye for FAZ and parafoveal capillary density metrics. CONCLUSIONS: NP-SCR and P-SCR patients demonstrated quantifiable interocular asymmetry in FAZ and parafoveal capillary density metrics compared to unaffected subjects, with left-eye predominance in disease severity.


Assuntos
Anemia Falciforme/patologia , Capilares/fisiologia , Fóvea Central/fisiologia , Doenças Retinianas/patologia , Adulto , Anemia Falciforme/complicações , Área Sob a Curva , Estudos de Casos e Controles , Estudos Transversais , Olho/diagnóstico por imagem , Feminino , Fóvea Central/irrigação sanguínea , Humanos , Masculino , Pessoa de Meia-Idade , Curva ROC , Doenças Retinianas/etiologia , Estudos Retrospectivos , Índice de Gravidade de Doença , Tomografia de Coerência Óptica , Adulto Jovem
7.
Am J Pathol ; 190(8): 1723-1734, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32389572

RESUMO

Retinal ischemic events, which result from occlusion of the ocular vasculature share similar causes as those for central nervous system stroke and are among the most common cause of acute and irreversible vision loss in elderly patients. Currently, there is no established treatment, and the condition often leaves patients with seriously impaired vision or blindness. The immune system, particularly T-cell-mediated responses, is thought to be intricately involved, but the exact roles remain elusive. We found that acute ischemia-reperfusion injury to the retina induced a prolonged phase of retinal ganglion cell loss that continued to progress during 8 weeks after the procedure. This phase was accompanied by microglial activation and CD4+ T-cell infiltration into the retina. Adoptive transfer of CD4+ T cells isolated from diseased mice exacerbated retinal ganglion cell loss in mice with retinal reperfusion damage. On the other hand, T-cell deficiency or administration of T-cell or interferon-γ-neutralizing antibody attenuated retinal ganglion cell degeneration and retinal function loss after injury. These findings demonstrate a crucial role for T-cell-mediated responses in the pathogenesis of neural ischemia. These findings point to novel therapeutic targets of limiting or preventing neuron and function loss for currently untreatable conditions of optic neuropathy and/or central nervous system ischemic stroke.


Assuntos
Linfócitos T CD4-Positivos/patologia , Isquemia/patologia , Retina/patologia , Degeneração Retiniana/patologia , Doenças Retinianas/patologia , Vasos Retinianos/patologia , Transferência Adotiva , Animais , Modelos Animais de Doenças , Progressão da Doença , Camundongos , Células Ganglionares da Retina/patologia
8.
Proc Natl Acad Sci U S A ; 117(16): 9001-9012, 2020 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-32265282

RESUMO

The interplay of transcription factors and cis-regulatory elements (CREs) orchestrates the dynamic and diverse genetic programs that assemble the human central nervous system (CNS) during development and maintain its function throughout life. Genetic variation within CREs plays a central role in phenotypic variation in complex traits including the risk of developing disease. We took advantage of the retina, a well-characterized region of the CNS known to be affected by pathogenic variants in CREs, to establish a roadmap for characterizing regulatory variation in the human CNS. This comprehensive analysis of tissue-specific regulatory elements, transcription factor binding, and gene expression programs in three regions of the human visual system (retina, macula, and retinal pigment epithelium/choroid) reveals features of regulatory element evolution that shape tissue-specific gene expression programs and defines regulatory elements with the potential to contribute to Mendelian and complex disorders of human vision.


Assuntos
Evolução Molecular , Regulação da Expressão Gênica no Desenvolvimento , Sequências Reguladoras de Ácido Nucleico/genética , Retina/patologia , Doenças Retinianas/genética , Adulto , Animais , Análise Mutacional de DNA , Epigenômica , Feminino , Variação Genética , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Mutação , RNA-Seq , Retina/crescimento & desenvolvimento , Doenças Retinianas/patologia , Especificidade da Espécie
10.
Zhonghua Yan Ke Za Zhi ; 56(4): 258-265, 2020 Apr 11.
Artigo em Chinês | MEDLINE | ID: mdl-32306617

RESUMO

Objective: To investigate the characteristics of retinal nerve fiber layer (RNFL) thickness in AIDS patients with normal fundus, HIV-related microvascular retinopathy (MVR), and cytomegalovirus retinitis (CMVR). Methods: In this cross-sectional study, 111 patients were diagnosed with AIDS from 2012 to 2017 by infectious disease physicians in Beijing You'an Hospital. There were 105 males and 6 females, aged 20-65 years. According to the results of ophthalmic examination, the patients were divided into three groups: 31 patients in the active-stage CMVR group, 47 patients in the MVR group, and 33 patients with normal fundus in the control group. RNFL thickness was measured by optical coherence tomography in all patients. At the same time, visual acuity, intraocular pressure, and fundus were examined, and AIDS-related systemic examination (CD4(+) T lymphocyte count, HAART treatment status, and blood cytomegalovirus DNA level) was performed. The measurement data were compared by t-test, variance analysis or rank sum test. The counting data were compared by chi square test or Fisher exact probability method. Results: In the control group, the thickness of RNFL in the superior quadrant in the left and right eyes was 145 (79, 231) µm and 142 (46, 179) µm, respectively; the difference was statistically significant (Z=-2.481, P=0.013). The RNFL thickness of the diseased and healthy eyes in the MVR group was 116 (91, 138) µm and 122 (82, 192) µm, respectively, with no significant difference (Z=-0.861, P=0.389); the best corrected visual acuity was 0.0 (0.0, 0.2) and 0.0 (0.0, 0.2), respectively, with no significant difference (Z=-0.378, P=0.705). In the CMVR group, the best corrected visual acuity of the diseased and healthy eyes was (0.23±0.48) and (0.02±0.82), respectively, and the difference was statistically significant (t=-2.944, P=0.003); the RNFL thickness was 133 (61, 219) µm and 121 (69, 146), respectively, in the whole optic disc, with statistically significant difference (Z=-2.385, P=0.017), 104 (41, 374) µm and 82 (55, 121) µm, respectively, in the nasal quadrant, and 99 (14, 173) µm and 72 (36, 111) µm, respectively, in the temporal quadrant, with statistically significant difference (Z=-2.045, -2.543; P=0.041, 0.011). The RNFL thickness in the CMVR group, the MVR group, and the control group was 149 (61, 350) µm, 126 (71, 304) µm, and 113 (87, 149) µm, respectively, with statistically significant difference (H=20.908, P=0.000). Conclusions: The fundus of AIDS patients had different characteristics on optical coherence tomography. In active CMVR patients, the thickness of RNFL was generally thickened. In MVR patients, the average thickness of RNFL was thicker than that in the normal control group.(Chin J Ophthalmol, 2020, 56:258-265).


Assuntos
Síndrome de Imunodeficiência Adquirida/complicações , Retinite por Citomegalovirus/patologia , Fibras Nervosas/patologia , Disco Óptico , Doenças Retinianas/patologia , Adulto , Idoso , Estudos Transversais , Retinite por Citomegalovirus/complicações , Feminino , Fundo de Olho , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Retinianas/complicações , Tomografia de Coerência Óptica , Adulto Jovem
11.
Medicine (Baltimore) ; 99(15): e19794, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32282743

RESUMO

RATIONALE: Multiple evanescent white dot syndrome (MEWDS) is a self-limited multifocal chorioretinopathy that typically affects otherwise healthy young females in the second to fourth decades of life. Current understanding of the pathophysiology of MEWDS is still limited. One of the possible underlying causes is an infectious etiology. PATIENT CONCERNS: A 24-year-old female with recurrent episodes of typical MEWDS ocular manifestation was observed over 2 years. Viral-specific antibody serologic tests showed evidence of exposure to the Herpesviridae family during the acute stage of MEWDS in the first and recurrent episodes. DIAGNOSES: MEWDS was diagnosed by the clinical findings and ancillary testing results of fundus photography, optical coherence tomography, fluorescein angiography, indocyanine green angiography and electroretinogram. The laboratory serology data was positive for varicella-zoster virus (VZV) immunoglobulin M (IgM) in the first episode and exhibited high Epstein-Barr virus (EBV) elevated immunoglobulin G (IgG) titer in the recurrent episode. INTERVENTIONS: Due to the self-limited nature of MEWDS, we observed the clinical course without intervention. OUTCOMES: During acute onset of MEWDS, serologic data for VZV IgM antibody was positive in the first episode. Two years later, the patient had recurrent episodes of MEWDS in the contralateral eye. Serologic study showed highly elevated IgG titer (1:160) of Epstein-Barr virus capsid antigen (EB-VCA) in the acute stage. The follow-up paired serum virus serology test showed that the prior EB-VCA IgG titer decreased fourfold to 1:40 in the recovery stage. LESSONS: Recurrence of MEWDS may be associated with acute systemic infection of the Herpesviridae family or virus-induced autoimmune inflammatory reaction.


Assuntos
Infecções por Herpesviridae/complicações , Herpesviridae/imunologia , Doenças Retinianas/virologia , Síndromes do Ponto Branco/virologia , Angiografia/métodos , Antígenos Virais/imunologia , Grupo com Ancestrais do Continente Asiático/etnologia , Proteínas do Capsídeo/imunologia , Eletrorretinografia/métodos , Feminino , Angiofluoresceinografia/métodos , Fundo de Olho , Infecções por Herpesviridae/virologia , Herpesvirus Humano 3/imunologia , Herpesvirus Humano 4/imunologia , Humanos , Imunoglobulina G/imunologia , Imunoglobulina M/imunologia , Verde de Indocianina/administração & dosagem , Recidiva , Doenças Retinianas/diagnóstico por imagem , Doenças Retinianas/patologia , Tomografia de Coerência Óptica/métodos , Síndromes do Ponto Branco/diagnóstico por imagem , Síndromes do Ponto Branco/etiologia , Adulto Jovem
12.
Medicine (Baltimore) ; 99(16): e19875, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32312013

RESUMO

INTRODUCTION: Systemic lupus erythematosus (SLE) is a multisystem, chronic, autoimmune disease which can affect any organ system including the eye. About one-third of the patients can be diagnosed with SLE-related eye involvement which is usually indicative of disease activity. Retinopathy is one of the most vision-threatening complications that can be associated with the disease. PATIENT CONCERNS: An 11-year-old girl was hospitalized with complains of repeated swelling and pain in her extremities for 1 month, chest pain for 24 days, rash for 5 days and proteinuria for 1 day. On the morning of her fourth day in hospital, she suddenly complained of sudden, painless vision loss in the left eye. The ophthalmologist found that she had obstruction of central retinal vein and artery with diffuse retinal hemorrhages and macular edema. DIAGNOSIS: The patient was diagnosed with systemic lupus erythematosus, lupus nephritis, and lupus retinopathy through her clinical manifestations and laboratory tests. INTERVENTIONS: After diagnosis, she received steroid therapy, retinal laser photocoagulation, and intravitreal injection of dexamethasone (OZURDEX, Allergan Pharmaceuticals, Dublin, Ireland) early in her course. OUTCOMES: At the latest follow-up, her vision improved partially. However, she still has the possibility of subsequent neovascular glaucoma and bleeding in the future. CONCLUSIONS: An early diagnosis and the prompt therapeutic measures are necessary to prevent sight-threatening consequences, especially in pediatric patients with SLE.


Assuntos
Lúpus Eritematoso Sistêmico/complicações , Doenças Retinianas/etiologia , Doenças Retinianas/terapia , Transtornos da Visão/etiologia , Criança , Dexametasona/administração & dosagem , Dexametasona/uso terapêutico , Feminino , Glaucoma Neovascular/epidemiologia , Glaucoma Neovascular/etiologia , Glucocorticoides/administração & dosagem , Glucocorticoides/uso terapêutico , Hemorragia , Humanos , Injeções Intravítreas , Fotocoagulação a Laser/métodos , Lúpus Eritematoso Sistêmico/diagnóstico , Lúpus Eritematoso Sistêmico/patologia , Nefrite Lúpica/complicações , Nefrite Lúpica/diagnóstico , Edema Macular , Oclusão da Artéria Retiniana/diagnóstico , Oclusão da Artéria Retiniana/etiologia , Doenças Retinianas/patologia , Oclusão da Veia Retiniana/diagnóstico , Oclusão da Veia Retiniana/etiologia , Resultado do Tratamento
15.
J Fr Ophtalmol ; 43(3): 243-255, 2020 Mar.
Artigo em Francês | MEDLINE | ID: mdl-32007311

RESUMO

Placoid pigment epitheliopathy and serpiginous choroiditis are among the white dot retinal syndromes and possess similarities that can cause confusion between these two diseases. However, they are very different in terms of their progression and prognosis, which requires a diagnosis of certainty in order to better manage the patients with the diseases and identify potentially serious progressive complications. The clinical presentation, results of testing, differential diagnoses and treatment of these two pathologies are discussed in this article.


Assuntos
Epitélio Pigmentado Ocular/patologia , Doenças Retinianas , Síndromes do Ponto Branco , Corioidite/diagnóstico , Corioidite/patologia , Corioidite/terapia , Diagnóstico Diferencial , Progressão da Doença , Humanos , Transtornos da Pigmentação/diagnóstico , Transtornos da Pigmentação/patologia , Transtornos da Pigmentação/terapia , Prognóstico , Doenças Retinianas/diagnóstico , Doenças Retinianas/patologia , Doenças Retinianas/terapia , Síndromes do Ponto Branco/diagnóstico , Síndromes do Ponto Branco/terapia
16.
J Fr Ophtalmol ; 43(4): 319-323, 2020 Apr.
Artigo em Francês | MEDLINE | ID: mdl-32093957

RESUMO

We aimed to describe the epidemiological, etiological and clinical features, treatment and clinical course of sickle cell retinopathy in children and to determine the risk factors for serious involvement. METHODS: This was a retrospective study including all children diagnosed with sickle cell retinopathy. Epidemiological, clinical and therapeutic characteristics, as well as clinical course, were analysed retrospectively by chart review. Two groups were defined: Group 1 (Goldberg stage 1 and 2); Group 2 (Goldberg stage 3, 4 and 5). In order to identify factors independently associated with severe sickle cell retinopathy, we conducted a logistic regression analysis in descending order. RESULTS: The frequency of sickle cell retinopathy was 14.48%. Forty-two patients (84 eyes) were included; among them 23 boys and 19 girls, aged 10 to 17 with a mean age of 14±1.98 years. Twenty patients were of genotype SS, 11 patients of genotype SC, 8 Sß and 3 SO Arab. The three patients in group 2 were all of SS genotype. The majority of patients (32) had an HbF level of less than 15%. All our patients had sickle cell retinopathy distributed as follows: 62% at stage 1; 31% at stage 2; 5% at stage 3 and 2% at stage 4. Multivariate analysis revealed a single risk factor independently linked to severe involvement - an HbF level<15%. CONCLUSION: Retinopathy is a frequent complication of sickle cell disease which may lead to blindness. The HbF level is negatively correlated with severe involvement.


Assuntos
Anemia Falciforme/epidemiologia , Doenças Retinianas/epidemiologia , Adolescente , Idade de Início , Anemia Falciforme/complicações , Anemia Falciforme/genética , Anemia Falciforme/patologia , Criança , Progressão da Doença , Feminino , Genótipo , Humanos , Masculino , Doenças Retinianas/etiologia , Doenças Retinianas/genética , Doenças Retinianas/patologia , Estudos Retrospectivos , Fatores de Risco
17.
Invest Ophthalmol Vis Sci ; 61(2): 5, 2020 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-32031577

RESUMO

Purpose: To investigate characteristics of the foveal pit and the foveal avascular zone (FAZ) in patients with Alport syndrome (AS), a rare monogenetic disease due to mutations in genes encoding for collagen type IV. Methods: Twenty-eight eyes of nine patients with AS, and five autosomal-recessive carriers and 15 eyes from 15 age-similar healthy control subjects were examined using optical coherence tomography (OCT) and OCT-angiography (OCT-A). Foveal configuration and FAZ measures including the FAZ area, circularity, and vessel density in the central 1° and 3° were correlated. Results: Foveal hypoplasia was found in 10 eyes from seven patients with either genotype. In contrast, a staircase foveopathy was found in seven eyes of four X-linked AS patients. The average FAZ area did not differ significantly between AS patients and control subjects (mean ± SD 0.24 ± 0.24 mm2 vs. 0.21 ± 0.09 mm2; P = 0.64). Five eyes showed absence or severe anomalies of the FAZ with crossing macular capillaries that was linked to the degree of foveal hypoplasia on OCT images leading to a significant inverse correlation of FAZ area and foveal thickness (r = -0.88; P < 0.001). In contrary, female patients with X-linked mutations exhibited a significantly greater FAZ area (0.48 ± 0.30 mm2 vs. 0.21 ± 0.09 mm2; P = 0.007), in line with OCT findings of a staircase foveopathy. Conclusions: The foveal phenotypic spectrum in AS ranges from foveal hypoplasia and absence of a FAZ to staircase foveopathy with an enlarged FAZ. Because the development of the FAZ and foveal pit are closely related, these findings suggest an important role for collagen type IV in foveal development and maturation.


Assuntos
Fóvea Central/anormalidades , Nefrite Hereditária/patologia , Doenças Retinianas/patologia , Adolescente , Adulto , Idoso , Estudos de Casos e Controles , Criança , Pré-Escolar , Colágeno Tipo IV/genética , Estudos Transversais , Feminino , Angiofluoresceinografia , Fóvea Central/crescimento & desenvolvimento , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Nefrite Hereditária/genética , Nefrite Hereditária/fisiopatologia , Fenótipo , Estudos Prospectivos , Doenças Retinianas/genética , Doenças Retinianas/fisiopatologia , Vasos Retinianos/patologia , Tomografia de Coerência Óptica , Acuidade Visual , Adulto Jovem
18.
J Fr Ophtalmol ; 43(2): e55-e66, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31932062

RESUMO

Placoid pigment epitheliopathy and serpiginous choroiditis are among the white dot retinal syndromes and possess similarities that can cause confusion between these two diseases. However, they are very different in terms of their progression and prognosis, which requires a diagnosis of certainty in order to better manage the patients with the diseases and identify potentially serious progressive complications. The clinical presentation, results of testing, differential diagnoses and treatment of these two pathologies are discussed in this article.


Assuntos
Doenças Retinianas , Epitélio Pigmentado da Retina/patologia , Síndromes do Ponto Branco , Diagnóstico Diferencial , Progressão da Doença , Humanos , Prognóstico , Doenças Retinianas/diagnóstico , Doenças Retinianas/epidemiologia , Doenças Retinianas/patologia , Doenças Retinianas/terapia , Resultado do Tratamento , Síndromes do Ponto Branco/diagnóstico , Síndromes do Ponto Branco/epidemiologia , Síndromes do Ponto Branco/patologia , Síndromes do Ponto Branco/terapia
19.
Stroke ; 51(1): 300-307, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31805844

RESUMO

Background and Purpose- Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S) is an autosomal dominant small vessel disease caused by C-terminal frameshift mutations in the TREX1 gene that encodes the major mammalian 3' to 5' DNA exonuclease. RVCL-S is characterized by vasculopathy, especially in densely vascularized organs, progressive retinopathy, cerebral microvascular disease, white matter lesions, and migraine, but the underlying mechanisms are unknown. Methods- Homozygous transgenic RVCL-S knock-in mice expressing a truncated Trex1 (three prime repair exonuclease 1) protein (similar to what is seen in patients) and wild-type littermates, of various age groups, were subjected to (1) a survival analysis, (2) in vivo postocclusive reactive hyperemia and ex vivo Mulvany myograph studies to characterize the microvascular and macrovascular reactivity, and (3) experimental stroke after transient middle cerebral artery occlusion with neurological deficit assessment. Results- The mutant mice show increased mortality starting at midlife (P=0.03 with hazard ratio, 3.14 [95% CI, 1.05-9.39]). The mutants also show a vascular phenotype as evidenced by attenuated postocclusive reactive hyperemia responses (across all age groups; F[1, 65]=5.7, P=0.02) and lower acetylcholine-induced relaxations in aortae (in 20- to 24-month-old mice; RVCL-S knock-in: Emax: 37±8% versus WT: Emax: 65±6%, P=0.01). A vascular phenotype is also suggested by the increased infarct volume seen in 12- to 14-month-old mutant mice at 24 hours after infarct onset (RVCL-S knock-in: 75.4±2.7 mm3 versus WT: 52.9±5.6 mm3, P=0.01). Conclusions- Homozygous RVCL-S knock-in mice show increased mortality, signs of abnormal vascular function, and increased sensitivity to experimental stroke and can be instrumental to investigate the pathology seen in patients with RVCL-S.


Assuntos
Exodesoxirribonucleases , Leucoencefalopatias , Fosfoproteínas , Doenças Retinianas , Doenças Vasculares , Animais , Modelos Animais de Doenças , Exodesoxirribonucleases/genética , Exodesoxirribonucleases/metabolismo , Técnicas de Introdução de Genes , Humanos , Leucoencefalopatias/enzimologia , Leucoencefalopatias/genética , Leucoencefalopatias/patologia , Camundongos , Camundongos Mutantes , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Doenças Retinianas/enzimologia , Doenças Retinianas/genética , Doenças Retinianas/patologia , Doenças Vasculares/enzimologia , Doenças Vasculares/genética , Doenças Vasculares/patologia
20.
Cell Mol Life Sci ; 77(7): 1251-1266, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31586239

RESUMO

In vertebrate central nervous systems (CNSs), highly diverse neurons are selectively connected via synapses, which are essential for building an intricate neural network. The vertebrate retina is part of the CNS and is comprised of a distinct laminar organization, which serves as a good model system to study developmental synapse formation mechanisms. In the retina outer plexiform layer, rods and cones, two types of photoreceptor cells, elaborate selective synaptic contacts with ON- and/or OFF-bipolar cell terminals as well as with horizontal cell terminals. In the mouse retina, three photoreceptor subtypes and at least 15 bipolar subtypes exist. Previous and recent studies have significantly progressed our understanding of how selective synapse formation, between specific subtypes of photoreceptor and bipolar cells, is designed at the molecular level. In the ON pathway, photoreceptor-derived secreted and transmembrane proteins directly interact in trans with the GRM6 (mGluR6) complex, which is localized to ON-bipolar cell dendritic terminals, leading to selective synapse formation. Here, we review our current understanding of the key factors and mechanisms underlying selective synapse formation of photoreceptor cells with bipolar and horizontal cells in the retina. In addition, we describe how defects/mutations of the molecules involved in photoreceptor synapse formation are associated with human retinal diseases and visual disorders.


Assuntos
Neurogênese , Células Fotorreceptoras de Vertebrados/fisiologia , Sinapses/fisiologia , Animais , Dendritos/fisiologia , Humanos , Modelos Biológicos , Doenças Retinianas/patologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA