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1.
J Chin Med Assoc ; 84(9): 827-832, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34292208

RESUMO

The Coronavirus disease 2019 (COVID-19) pandemic has caused unprecedented disruption to the normal operation of the healthcare system. On a worldwide scale, hospitals suspended nonurgent surgeries and outpatient visits to downsize clinical loadings to redistribute manpower to counteract the pandemic's impact. So far, there is no evidence-based guideline defining a clear line between urgent and nonurgent indications of intravitreal injections (IVI). Herein, we aimed to summarize IVI algorithm modifications and discuss the patient prioritization according to medical needs in the hostile environment in the COVID crisis. Assessing current literature, we found that neovascular age-related macular degeneration is considered the utmost priority among conditions that require IVI. Other conditions assigned with a high priority include monocular or quasi-monocular patients (only one eye > 20/40), neovascular glaucoma, and new patients with significant vision loss. Although patients with central retinal vein occlusion and proliferative diabetic retinopathy are not advised to delay treatments, we found no consistent evidence that correlated with a worse outcome. Diabetic macular edema and branch retinal vein occlusion patients undertaking treatment delay should be regularly followed up every 2 to 3 months. Serving as the principle of management behind the algorithm modifications, the reduction of both patient visit and IVI therapy counts should be reckoned together with the risk of permanent visual loss and COVID infection.


Assuntos
COVID-19/epidemiologia , Injeções Intravítreas/métodos , SARS-CoV-2 , Algoritmos , Humanos , Higiene , Segurança do Paciente
2.
Int J Mol Sci ; 22(11)2021 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-34070492

RESUMO

Inherited retinal dystrophies (IRDs) are rare but highly heterogeneous genetic disorders that affect individuals and families worldwide. However, given its wide variability, its analysis of the driver genes for over 50% of the cases remains unexplored. The present study aims to identify novel driver genes, disease-causing variants, and retinitis pigmentosa (RP)-associated pathways. Using family-based whole-exome sequencing (WES) to identify putative RP-causing rare variants, we identified a total of five potentially pathogenic variants located in genes OR56A5, OR52L1, CTSD, PRF1, KBTBD13, and ATP2B4. Of the variants present in all affected individuals, genes OR56A5, OR52L1, CTSD, KBTBD13, and ATP2B4 present as missense mutations, while PRF1 and CTSD present as frameshift variants. Sanger sequencing confirmed the presence of the novel pathogenic variant PRF1 (c.124_128del) that has not been reported previously. More causal-effect or evidence-based studies will be required to elucidate the precise roles of these SNPs in the RP pathogenesis. Taken together, our findings may allow us to explore the risk variants based on the sequencing data and upgrade the existing variant annotation database in Taiwan. It may help detect specific eye diseases such as retinitis pigmentosa in East Asia.


Assuntos
Catepsina D/genética , Predisposição Genética para Doença , Distrofias Retinianas/genética , Adulto , Idoso , Catepsina D/sangue , Feminino , Mutação da Fase de Leitura , Ontologia Genética , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Musculares/genética , Mutação de Sentido Incorreto , Linhagem , Perforina/genética , ATPases Transportadoras de Cálcio da Membrana Plasmática/genética , Polimorfismo de Nucleotídeo Único , Mapas de Interação de Proteínas , Distrofias Retinianas/congênito , Distrofias Retinianas/patologia , Retinite Pigmentosa/congênito , Retinite Pigmentosa/diagnóstico por imagem , Retinite Pigmentosa/genética , Retinite Pigmentosa/patologia , Fatores de Risco , Tomografia de Coerência Óptica , Sequenciamento Completo do Exoma
3.
World J Gastroenterol ; 27(22): 2979-2993, 2021 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-34168402

RESUMO

The landscape of gastrointestinal endoscopy continues to evolve as new technologies and techniques become available. The advent of image-enhanced and magnifying endoscopies has highlighted the step toward perfecting endoscopic screening and diagnosis of gastric lesions. Simultaneously, with the development of convolutional neural network, artificial intelligence (AI) has made unprecedented breakthroughs in medical imaging, including the ongoing trials of computer-aided detection of colorectal polyps and gastrointestinal bleeding. In the past demi-decade, applications of AI systems in gastric cancer have also emerged. With AI's efficient computational power and learning capacities, endoscopists can improve their diagnostic accuracies and avoid the missing or mischaracterization of gastric neoplastic changes. So far, several AI systems that incorporated both traditional and novel endoscopy technologies have been developed for various purposes, with most systems achieving an accuracy of more than 80%. However, their feasibility, effectiveness, and safety in clinical practice remain to be seen as there have been no clinical trials yet. Nonetheless, AI-assisted endoscopies shed light on more accurate and sensitive ways for early detection, treatment guidance and prognosis prediction of gastric lesions. This review summarizes the current status of various AI applications in gastric cancer and pinpoints directions for future research and clinical practice implementation from a clinical perspective.


Assuntos
Inteligência Artificial , Neoplasias Gástricas , Detecção Precoce de Câncer , Endoscopia Gastrointestinal , Humanos , Redes Neurais de Computação , Neoplasias Gástricas/diagnóstico por imagem
4.
Int J Mol Sci ; 22(9)2021 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-33926102

RESUMO

Inherited retinal dystrophies (IRDs) are a group of rare eye diseases caused by gene mutations that result in the degradation of cone and rod photoreceptors or the retinal pigment epithelium. Retinal degradation progress is often irreversible, with clinical manifestations including color or night blindness, peripheral visual defects and subsequent vision loss. Thus, gene therapies that restore functional retinal proteins by either replenishing unmutated genes or truncating mutated genes are needed. Coincidentally, the eye's accessibility and immune-privileged status along with major advances in gene identification and gene delivery systems heralded gene therapies for IRDs. Among these clinical trials, voretigene neparvovec-rzyl (Luxturna), an adeno-associated virus vector-based gene therapy drug, was approved by the FDA for treating patients with confirmed biallelic RPE65 mutation-associated Leber Congenital Amaurosis (LCA) in 2017. This review includes current IRD gene therapy clinical trials and further summarizes preclinical studies and therapeutic strategies for LCA, including adeno-associated virus-based gene augmentation therapy, 11-cis-retinal replacement, RNA-based antisense oligonucleotide therapy and CRISPR-Cas9 gene-editing therapy. Understanding the gene therapy development for LCA may accelerate and predict the potential hurdles of future therapeutics translation. It may also serve as the template for the research and development of treatment for other IRDs.


Assuntos
Amaurose Congênita de Leber/genética , Distrofias Retinianas/genética , Distrofias Retinianas/terapia , Dependovirus/genética , Proteínas do Olho/genética , Técnicas de Transferência de Genes , Terapia Genética , Vetores Genéticos , Humanos , Amaurose Congênita de Leber/terapia , Mutação , RNA , Retina/efeitos dos fármacos , Retina/metabolismo , Células Fotorreceptoras Retinianas Cones/efeitos dos fármacos , Células Fotorreceptoras Retinianas Cones/metabolismo
5.
Sci Rep ; 11(1): 6286, 2021 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-33737600

RESUMO

Age-related macular degeneration (AMD) is the primary cause of blindness in adults over 60 years of age, and clinical trials are currently assessing the therapeutic potential of retinal pigmented epithelial (RPE) cell monolayers on implantable scaffolds to treat this disease. However, challenges related to the culture, long-term storage, and long-distance transport of such implants currently limit the widespread use of adherent RPE cells as therapeutics. Here we report a xeno-free protocol to cryopreserve a confluent monolayer of clinical-grade, human embryonic stem cell-derived RPE cells on a parylene scaffold (REPS) that yields viable, polarized, and functional RPE cells post-thaw. Thawed cells exhibit ≥ 95% viability, have morphology, pigmentation, and gene expression characteristic of mature RPE cells, and secrete the neuroprotective protein, pigment epithelium-derived factor (PEDF). Stability under liquid nitrogen (LN2) storage has been confirmed through one year. REPS were administered immediately post-thaw into the subretinal space of a mammalian model, the Royal College of Surgeons (RCS)/nude rat. Implanted REPS were assessed at 30, 60, and 90 days post-implantation, and thawed cells demonstrate survival as an intact monolayer on the parylene scaffold. Furthermore, immunoreactivity for the maturation marker, RPE65, significantly increased over the post-implantation period in vivo, and cells demonstrated functional attributes similar to non-cryopreserved controls. The capacity to cryopreserve adherent cellular therapeutics permits extended storage and stable transport to surgical sites, enabling broad distribution for the treatment of prevalent diseases such as AMD.

6.
Curr Oncol ; 28(1): 918-927, 2021 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-33617508

RESUMO

Primary signet ring cell/histiocytoid carcinoma of the eyelid is a rare ocular malignancy and its diagnosis is often delayed. This neoplasm presents as an insidious, diffusely infiltrative mass in the periocular area that later infiltrates the orbit. An exenteration is usually indicated; however, nearly one-third of patients develop local recurrence or metastasis. Morphologically, it resembles signet ring cell carcinoma of the stomach and breast, raising the possibility of mutations in CDH1, the gene encoding E-cadherin. To determine whether primary signet ring cell/histiocytoid carcinoma harbors the CDH1 mutation or other actionable mutations, we analyzed the tumor tissue via next-generation sequencing. We identified only one case of primary signet ring cell carcinoma of the eyelid with adequate DNA quality for sequencing from the pathological archive during the period 2000 to 2020. A comprehensive evaluation including histopathology, immunohistochemistry, and next-generation sequencing assay was performed on tumor tissue. Immunohistochemically, the tumor exhibited E-cadherin membranous staining with the aberrant cytoplasmic staining of ß-catenin. Using next-generation sequencing, we demonstrated the mutation in the CDH1 gene. In addition, other clinically actionable mutations including ERBB2 and PIK3CA were also detected. The alterations in other actionable genes indicate a need for larger studies to evaluate the pathogenesis and potential therapies for primary signet ring cell/histiocytoid carcinoma of the eyelid.


Assuntos
Carcinoma de Células em Anel de Sinete , Recidiva Local de Neoplasia , Antígenos CD/genética , Caderinas/genética , Carcinoma de Células em Anel de Sinete/tratamento farmacológico , Carcinoma de Células em Anel de Sinete/genética , Pálpebras , Humanos , Mutação
7.
Int J Mol Sci ; 22(3)2021 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-33525682

RESUMO

Angiotensin-converting enzyme 2 (ACE2) was identified as the main host cell receptor for the entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its subsequent infection. In some coronavirus disease 2019 (COVID-19) patients, it has been reported that the nervous tissues and the eyes were also affected. However, evidence supporting that the retina is a target tissue for SARS-CoV-2 infection is still lacking. This present study aimed to investigate whether ACE2 expression plays a role in human retinal neurons during SARS-CoV-2 infection. Human induced pluripotent stem cell (hiPSC)-derived retinal organoids and monolayer cultures derived from dissociated retinal organoids were generated. To validate the potential entry of SARS-CoV-2 infection in the retina, we showed that hiPSC-derived retinal organoids and monolayer cultures endogenously express ACE2 and transmembrane serine protease 2 (TMPRSS2) on the mRNA level. Immunofluorescence staining confirmed the protein expression of ACE2 and TMPRSS2 in retinal organoids and monolayer cultures. Furthermore, using the SARS-CoV-2 pseudovirus spike protein with GFP expression system, we found that retinal organoids and monolayer cultures can potentially be infected by the SARS-CoV-2 pseudovirus. Collectively, our findings highlighted the potential of iPSC-derived retinal organoids as the models for ACE2 receptor-based SARS-CoV-2 infection.


Assuntos
Enzima de Conversão de Angiotensina 2/genética , COVID-19/genética , Expressão Gênica , Células-Tronco Pluripotentes Induzidas/citologia , Retina/citologia , SARS-CoV-2/fisiologia , Enzima de Conversão de Angiotensina 2/metabolismo , COVID-19/metabolismo , Técnicas de Cultura de Células , Linhagem Celular , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Organoides/citologia , Organoides/metabolismo , Retina/metabolismo , Serina Endopeptidases/genética , Serina Endopeptidases/metabolismo , Internalização do Vírus
8.
J Chin Med Assoc ; 83(12): 1102-1106, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33210900

RESUMO

BACKGROUND: Diabetic macular edema (DME) is a sight-threatening condition that needs regular examinations and remedies. Optical coherence tomography (OCT) is the most common used examination to evaluate the structure and thickness of the macula, but the software in the OCT machine does not tell the clinicians whether DME exists directly. Recently, artificial intelligence (AI) is expected to aid in diagnosis generation and therapy selection. We thus develop a smartphone-based offline AI system that provides diagnostic suggestions and medical strategies through analyzing OCT images from diabetic patients at the risk of developing DME. METHODS: DME patients receiving treatments in 2017 at Taipei Veterans General Hospital were included in this study. We retrospectively collected the OCT images of these patients from January 2008 to July 2018. We established the AI model based on MobileNet architecture to classify the OCT images conditions. The confusion matrix has been applied to present the performance of the trained AI model. RESULTS: Based on the convolutional neural network with the MobileNet model, our AI system achieved a high DME diagnostic accuracy of 90.02%, which is comparable to other AI systems such as InceptionV3 and VGG16. We further developed a mobile-application based on this AI model available at https://aicl.ddns.net/DME.apk. CONCLUSION: We successful integrated an AI model into the mobile device to provide an offline method to provide the diagnosis for quickly screening the risk of developing DME. With the offline property, our model could help those nonophthalmological healthcare providers in offshore islands or underdeveloped countries.

9.
Biomolecules ; 10(10)2020 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-33036304

RESUMO

OBJECTIVES: Retinal vein occlusions (RVO) are associated with systemic risk factors. However, the ocular occlusive events might also influence a patient's systemic condition. This study tried to investigate serum biomarkers associated with oxidative stress, before and after intravitreal anti-vascular endothelial growth factor (aVEGF) therapy in patients with RVOs. METHODS: Newly-onset RVO patients were categorized into two groups: comorbid with macular edema requiring aVEGF therapy (treatment group) and no edema (observation group). Age and sex-matched patients (who received cataract surgery) were included as the control group. Intravitreal ranibizumab with a pro-re-nata regimen were administered. Serum samples were collected prior to treatment, at 6 and 12 months after therapy/observation and were collected once before controls who received cataract surgery. mRNA expression of sirtuin-1, its downstream genes, anti-oxidative biomarkers, and proinflammatory cytokines were measured. RESULTS: There were 32, 26, and 34 patients enrolled in the treatment, observation, and control groups, respectively. The expressions of sirtuin-1 and its downstream genes were significantly lower in patients with RVO compared with the control group. Sirtuin-1 gene expression increased after 1 year of aVEGF therapy in the treatment group but remained unchanged in the observation group. Biomarkers of oxidative stress and proinflammatory cytokines were reduced after 1 year of aVEGF therapy. These biomarkers remained with no changes in the observation group. CONCLUSIONS: Our study showed that the systemic oxidative stress increased in RVO patients. The aVEGF therapy could alter the gene expression of anti-oxidative proteins and reduce systemic oxidative stress in these patients.

10.
J Chin Med Assoc ; 83(11): 1029-1033, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32898088

RESUMO

BACKGROUND: Age-related macular degeneration (AMD) is one of the leading causes of vision loss. Once the retinal pigment epithelium (RPE) layers are destroyed, the poor visual acuity and recognition are generally irreversible. Cell therapy that possesses enormous potential in regenerative medicine may provide an alternative treatment for several incurable diseases such as AMD. In this study, we developed an innovative polydimethylsiloxane (PDMS)-based biomimetic scaffolds with cylinder micropillars for the cultivation of induced pluripotent stem cell-derived RPEs (iPSC-RPEs). RPEs were cultured on the PDMS-based biomimetic scaffolds and validated the cells gene expression. METHODS: The biomimetic PDMS scaffold was fabricated through spin coating and lithography method. It was further modified on surface with biomolecules to improve cell affinity and stability. The iPSC-RPEs were seeded on the scaffold and analyzed with characteristic gene expression. RESULTS: PDMS biomimetic scaffold was analyzed with Fourier transform infrared spectroscopy and proved its chemical composition. iPSC-RPEs demonstrated confluent cell monolayer on the scaffold and maintained RPE-specific gene expression, which proved the PDMS-based biomimetic scaffold to be supportive for iPSC-RPEs growth. CONCLUSION: The PDMS interface allowed regular growth of iPSC-RPEs and the design of cylinder micropillars further provided the bioscaffold high motion resistance may improve the engraftment stability of iPSC-RPEs after transplantation. Taken together, this innovative PDMS-based biomimetic scaffold may serve as an ideal interface for in vitro iPSC-RPE cultivation and subsequent transplantation in vivo. This novel device exhibits better bioavailability than conventional injection of donor cells and may be an alternative option for the treatment of AMD.

11.
J Chin Med Assoc ; 83(10): 962-966, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32649414

RESUMO

BACKGROUND: A suitable fundus camera for telemedicine screening can expand the scale of eye care service. The purpose of this study was to compare a handheld nonmydriatic digital fundus camera and a conventional mydriatic fundus camera according to the image quality of their photographs and usability of those photographs to accurately diagnose various retinal diseases. METHODS: A handheld nonmydriatic fundus camera and conventional fundus camera were used to take fundus photographs of outpatients at an ophthalmic clinic before and after pupillary dilation. Image quality and diagnostic agreement of the photos were graded by two masked and experienced retinal specialists. RESULTS: A total of 867 photographs of 393 eyes of 200 patients were collected. Approximately 80% of photos taken under nonmydriasis status using the handheld nonmydriatic fundus camera had good (55.7%) or excellent (22.7%) image quality. The overall agreement of diagnoses between the doctors was more than 90%. When the handheld nonmydriatic fundus camera was used after mydriasis, the proportion of images with good (45%) or excellent (49.7%) quality reached 94.7% and diagnostic agreement was 93.4%. Lens opacity was associated with the quality of images obtained using the handheld camera (p = 0.041), and diagnosis disagreement for handheld camera images was associated with preexisting diabetes diagnosis (p = 0.009). Approximately 40% of patients expressed preference for use of the handheld nonmydriatic camera. CONCLUSION: This study demonstrated the effectiveness of the handheld nonmydriatic fundus camera in clinical practice and its feasibility for telemedicine screening of retinal diseases.

12.
Retina ; 2020 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-32516226

RESUMO

PURPOSE: To introduce a new surgical technique that can keep constant intraocular pressure of the eyeball during peeling epiretinal membrane under silicone oil status. METHODS: A viscoelastic agent was injected into the air pump of the constellation system via the metal tip. This procedure offers a buffer zone to keep constant pressure within the eyeball without disturbing the surgical field by an air bubble. RESULTS: Three cases were performed efficiently (15 ± 5 minutes) under this technique with improvement in anatomical feature and visual function after the surgery. CONCLUSION: Using this simple yet important technique can provide us the constant intraocular pressure without hypotony and avoid the traditional complicated procedures.

13.
J Chin Med Assoc ; 83(10): 898-899, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32520771

RESUMO

Artificial intelligence (AI) has been widely applied in the medical field and achieved enormous milestones in helping specialists to make diagnosis and remedy decisions, particularly in the field of eye diseases and ophthalmic screening. With the development of AI-based systems, the enormous hardware and software resources are required for optimal performance. In reality, there are many places on the planet where such resources are highly limited. Hence, the smartphone-based AI systems can be used to provide a remote control route to quickly screen eye diseases such as diabetic-related retinopathy or diabetic macular edema. However, the performance of such mobile-based AI systems is still uncharted territory. In this article, we discuss the issues of computing resource consumption and performance of the mobile device-based AI systems and highlight recent research on the feasibility and future potential of application of the mobile device-based AI systems in telemedicine.

14.
J Chin Med Assoc ; 83(11): 981-983, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32568967

RESUMO

Artificial intelligence (AI), Internet of Things (IoT), and telemedicine are deeply involved in our daily life and have also been extensively applied in the medical field, especially in ophthalmology. Clinical ophthalmologists are required to perform a vast array of image exams and analyze images containing complicated information, which allows them to diagnose the disease type and grade, make a decision on remedy, and predict treatment outcomes. AI has a great potential to assist ophthalmologists in their daily routine of image analysis and relieve their work burden. However, in spite of these prospects, the application of AI may also be controversial and associated with several legal, ethical, and sociological concerns. In spite of these issues, AI has indeed become an irresistible trend and is widely used by medical specialists in their daily routines in what we can call now, the era of AI. This review will encompass those issues and focus on recent research on the AI application in ophthalmology and telemedicine.

15.
Adv Sci (Weinh) ; 7(10): 1903432, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32440478

RESUMO

The homology-independent targeted integration (HITI) strategy enables effective CRISPR/Cas9-mediated knockin of therapeutic genes in nondividing cells in vivo, promising general therapeutic solutions for treating genetic diseases like X-linked juvenile retinoschisis. Herein, supramolecular nanoparticle (SMNP) vectors are used for codelivery of two DNA plasmids-CRISPR-Cas9 genome-editing system and a therapeutic gene, Retinoschisin 1 (RS1)-enabling clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein 9 (CRISPR/Cas9) knockin of the RS1 gene with HITI. Through small-scale combinatorial screenings, two SMNP vectors, with Cas9 and single guide RNA (sgRNA)-plasmid in one and Donor-RS1 and green fluorescent protein (GFP)-plasmid in the other, with optimal delivery performances are identified. These SMNP vectors are then employed for CRISPR/Cas9 knockin of RS1/GFP genes into the mouse Rosa26 safe-harbor site in vitro and in vivo. The in vivo study involves intravitreally injecting the two SMNP vectors into the mouse eyes, followed by repeated ocular imaging by fundus camera and optical coherence tomography, and pathological and molecular analyses of the harvested retina tissues. Mice ocular organs retain their anatomical integrity, a single-copy 3.0-kb RS1/GFP gene is precisely integrated into the Rosa26 site in the retinas, and the integrated RS1/GFP gene is expressed in the retinas, demonstrating CRISPR/Cas9 knockin of RS1/GFP gene.

16.
J Chin Med Assoc ; 83(11): 1034-1038, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32452907

RESUMO

BACKGROUND: Optical coherence tomography (OCT) is considered as a sensitive and noninvasive tool to evaluate the macular lesions. In patients with diabetes mellitus (DM), the existence of diabetic macular edema (DME) can cause significant vision impairment and further intravitreal injection (IVI) of anti-vascular endothelial growth factor (VEGF) is needed. However, the increasing number of DM patients makes it a big burden for clinicians to manually determine whether DME exists in the OCT images. The artificial intelligence (AI) now enormously applied to many medical territories may help reduce the burden on clinicians. METHODS: We selected DME patients receiving IVI of anti-VEGF or corticosteroid at Taipei Veterans General Hospital in 2017. All macular cross-sectional scan OCT images were collected retrospectively from the eyes of these patients from January 2008 to July 2018. We further established AI models based on convolutional neural network architecture to determine whether the DM patients have DME by OCT images. RESULTS: Based on the convolutional neural networks, InceptionV3 and VGG16, our AI system achieved a high DME diagnostic accuracy of 93.09% and 92.82%, respectively. The sensitivity of the VGG16 and InceptionV3 models was 96.48% and 95.15%., respectively. The specificity was corresponding to 86.67% and 89.63% for VGG16 and InceptionV3, respectively. We further developed an OCT-driven platform based on these AI models. CONCLUSION: We successfully set up AI models to provide an accurate diagnosis of DME by OCT images. These models may assist clinicians in screening DME in DM patients in the future.

17.
Hum Mol Genet ; 29(9): 1454-1464, 2020 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-32277753

RESUMO

The mutations in the genes encoding the subunits of complex I of the mitochondrial electron transport chain are the most common cause of Leber's hereditary optic neuropathy (LHON), a maternal hereditary disease characterized by retinal ganglion cell (RGC) degeneration. The characteristics of incomplete penetrance indicate that nuclear genetic and environmental factors also determine phenotypic expression of LHON. Therefore, further understanding of the role of mutant mitochondrial nicotinamide adenine dinucleotide dehydrogenase subunit proteins and nuclear genetic factors/environmental effects in the etiology of LHON is needed. In this study, we generated human-induced pluripotent stem cells (hiPSCs) from healthy control, unaffected LHON mutation carrier, and affected LHON patient. hiPSC-derived RGCs were used to study the differences between affected and unaffected carriers of mitochondrial DNA point mutation m.11778G > A in the MT-ND4 gene. We found that both mutated cell lines were characterized by increase in reactive oxygen species production, however, only affected cell line had increased levels of apoptotic cells. We found a significant increase in retrograde mitochondria and a decrease in stationary mitochondria in the affected RGC axons. In addition, the messenger RNA and protein levels of KIF5A in the LHON-affected RGCs were significantly reduced. Antioxidant N-acetyl-L-cysteine could restore the expression of KIF5A and the normal pattern of mitochondrial movement in the affected RGCs. To conclude, we found essential differences in the mutually dependent processes of oxidative stress, mitochondrial transport and apoptosis between two LHON-specific mutation carrier RGC cell lines, asymptomatic carrier and disease-affected, and identified KIF5A as a central modulator of these differences.

18.
Stem Cell Res Ther ; 10(1): 284, 2019 09 23.
Artigo em Inglês | MEDLINE | ID: mdl-31547874

RESUMO

BACKGROUND: Transient receptor potential vanilloid 1 (TRPV1), recognized as a hyperosmolarity sensor, is a crucial ion channel involved in the pathogenesis of neural and glial signaling. Recently, TRPV1 was determined to play a role in retinal physiology and visual transmission. In this study, we sought to clarify the role of TRPV1 and the downstream pathway in the osmotic stress-related retina ganglion cell (RGC) damage. METHODS: First, we modified the RGC differentiation protocol to obtain a homogeneous RGC population from human induced pluripotent stem cells (hiPSCs). Subsequently, we induced high osmotic pressure in the hiPSC-derived RGCs by administering NaCl solution and observed the behavior of the TRPV1 channel and its downstream cascade. RESULTS: We obtained a purified RGC population from the heterogeneous retina cell population using our modified method. Our findings revealed that TRPV1 was activated after 24 h of NaCl treatment. Upregulation of TRPV1 was noted with autophagy and apoptosis induction. Downstream protein expression analysis indicated increased phosphorylation of CREB and downregulated brain-derived neurotrophic factor (BDNF). However, hyperosmolarity-mediated defective morphological change and apoptosis of RGCs, CREB phosphorylation, and BDNF downregulation were abrogated after concomitant treatment with the PKA inhibitor H89. CONCLUSION: Collectively, our study results indicated that the TRPV1-PKA pathway contributed to cellular response under high levels of osmolarity stress; furthermore, the PKA inhibitor had a protective effect on RGCs exposed to this stress. Therefore, our findings may assist in the treatment of eye diseases involving RGC damage.


Assuntos
Células-Tronco Pluripotentes Induzidas/citologia , Pressão Osmótica , Células Ganglionares da Retina/metabolismo , Canais de Cátion TRPV/genética , Apoptose , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Diferenciação Celular , Células Cultivadas , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/antagonistas & inibidores , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Isoquinolinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Células Ganglionares da Retina/citologia , Células Ganglionares da Retina/efeitos dos fármacos , Transdução de Sinais , Sulfonamidas/farmacologia , Canais de Cátion TRPV/metabolismo , Regulação para Cima
20.
J Chin Med Assoc ; 82(8): 659-664, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31259835

RESUMO

BACKGROUND: Age-related macular degeneration (AMD) is a leading cause of blindness worldwide, for which intravitreal injection of anti-vascular endothelial growth factor (VEGF) is the primary treatment option. The purpose of the current study was to investigate the prioritization of anti-VEGF agents for wet AMD under the National Health Insurance (NHI) Program, and their clinical outcomes. METHODS: Patients who were diagnosed with active choroidal neovascularization caused by AMD, and who met the criteria for reimbursement for anti-VEGF therapy by the NHI program in Taiwan between August 1, 2014 and May 31, 2015, were included in the study. Factors potentially influencing the choice of treatment agent were analyzed, and clinical outcomes were compared between the two different agents and their protocols. RESULTS: A total of 166 treatment applications in 166 eyes from 159 patients were enrolled in the study. Age, laterality, presence of retinal pigment epithelial detachment, history of hypertension, coronary artery disease, and cerebral vascular accidents were significantly associated with the selection of the anti-VEGF agent. Treatment patterns and clinical outcomes were similar between the patients treated with ranibizumab and those treated with aflibercept. Significantly fewer injections were given during the follow-up period in those treated with aflibercept. CONCLUSION: Under the restrictive insurance program in Taiwan, more patients and ophthalmologists chose to treat wet AMD using aflibercept. However, in clinical practice, no significant differences in efficacy or clinical outcomes were found between the patients treated with ranibizumab and those treated with aflibercept.


Assuntos
Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Degeneração Macular Exsudativa/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Programas Nacionais de Saúde , Ranibizumab/uso terapêutico , Receptores de Fatores de Crescimento do Endotélio Vascular/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Estudos Retrospectivos , Taiwan
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