RESUMEN
BACKGROUND: The use of cerebral oximetry monitoring in the care of extremely preterm infants is increasing. However, evidence that its use improves clinical outcomes is lacking. METHODS: In this randomized, phase 3 trial conducted at 70 sites in 17 countries, we assigned extremely preterm infants (gestational age, <28 weeks), within 6 hours after birth, to receive treatment guided by cerebral oximetry monitoring for the first 72 hours after birth or to receive usual care. The primary outcome was a composite of death or severe brain injury on cerebral ultrasonography at 36 weeks' postmenstrual age. Serious adverse events that were assessed were death, severe brain injury, bronchopulmonary dysplasia, retinopathy of prematurity, necrotizing enterocolitis, and late-onset sepsis. RESULTS: A total of 1601 infants underwent randomization and 1579 (98.6%) were evaluated for the primary outcome. At 36 weeks' postmenstrual age, death or severe brain injury had occurred in 272 of 772 infants (35.2%) in the cerebral oximetry group, as compared with 274 of 807 infants (34.0%) in the usual-care group (relative risk with cerebral oximetry, 1.03; 95% confidence interval, 0.90 to 1.18; P = 0.64). The incidence of serious adverse events did not differ between the two groups. CONCLUSIONS: In extremely preterm infants, treatment guided by cerebral oximetry monitoring for the first 72 hours after birth was not associated with a lower incidence of death or severe brain injury at 36 weeks' postmenstrual age than usual care. (Funded by the Elsass Foundation and others; SafeBoosC-III ClinicalTrials.gov number, NCT03770741.).
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Recien Nacido Extremadamente Prematuro , Enfermedades del Prematuro , Oximetría , Humanos , Lactante , Recién Nacido , Lesiones Encefálicas/diagnóstico por imagen , Lesiones Encefálicas/etiología , Displasia Broncopulmonar/etiología , Circulación Cerebrovascular , Enfermedades del Prematuro/diagnóstico , Enfermedades del Prematuro/mortalidad , Enfermedades del Prematuro/terapia , Oximetría/métodos , Cerebro , Ultrasonografía , Retinopatía de la Prematuridad/etiología , Enterocolitis Necrotizante/etiología , Sepsis Neonatal/etiologíaRESUMEN
Retinal neovascularization impairs visual function and is a hallmark of several neovascular eye diseases, including retinopathy of prematurity (ROP) and proliferative diabetic retinopathy (PDR). Current treatments include intravitreal injections of anti-vascular endothelial growth factor (VEGF) biologics, but these therapeutics are often accompanied by high treatment burden and resistance to therapy. Prior studies indicate that APE1/Ref-1, a multifunctional protein with both endonuclease (APE1) and redox-mediated transcriptional regulatory activity (Ref-1), activates multiple pro-angiogenic and pro-inflammatory signaling pathways by chemically reducing key cysteine residues in transcription factors, thereby activating them. Here, we investigated the previously unexplored role of Ref-1 in retinal neovascularization. We demonstrate that Ref-1 is highly expressed in endothelial cells in human PDR and in the oxygen-induced retinopathy (OIR) mouse model of retinal neovascularization. Ref-1 is also highly expressed in microglia and astrocytes in OIR. A small molecule Ref-1 redox inhibitor, APX2009, decreased retinal neovascularization in OIR after systemic delivery. In vitro, hypoxic endothelial cells did not exhibit upregulation of Ref-1 but rather increased Ref-1 nuclear localization. APX2009 decreased hypoxic endothelial cell proliferation and HIF-1α transcriptional activation. Thus, Ref-1 redox activity may be a novel therapeutic target for the treatment of retinal neovascularization, making APX2009 a promising systemic therapeutic approach for the treatment of vascular retinopathies such as ROP and PDR.
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ADN-(Sitio Apurínico o Apirimidínico) Liasa , Subunidad alfa del Factor 1 Inducible por Hipoxia , Oxidación-Reducción , Neovascularización Retiniana , Animales , Humanos , Neovascularización Retiniana/metabolismo , Neovascularización Retiniana/genética , Neovascularización Retiniana/patología , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Ratones , ADN-(Sitio Apurínico o Apirimidínico) Liasa/metabolismo , ADN-(Sitio Apurínico o Apirimidínico) Liasa/genética , Activación Transcripcional , Ratones Endogámicos C57BL , Retinopatía Diabética/metabolismo , Retinopatía Diabética/genética , Retinopatía Diabética/patología , Retinopatía de la Prematuridad/metabolismo , Retinopatía de la Prematuridad/patología , Retinopatía de la Prematuridad/genética , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Células Endoteliales/metabolismoRESUMEN
Retinopathy of prematurity (ROP) is a proliferative retinal vascular disorder that critically affects the visual development of premature infants, potentially leading to irreversible vision loss or even blindness. Despite its significance, the underlying mechanisms of this disease remain insufficiently understood. In this study, we utilized the oxygen-induced retinopathy (OIR) mouse model and conducted endothelial functional assays to explore the role of Sterol Regulatory Element-Binding Protein 1 (SREBF1) in ROP pathogenesis. SREBF1 expression levels, along with its downstream targets, were investigated through Western blotting, RT-qPCR, and immunofluorescence staining techniques. Furthermore, Co-Immunoprecipitation (Co-IP) was employed to examine the molecular mechanisms involved. Our results demonstrated a significant increase in SREBF1 expression in both the OIR mouse model and hypoxic primary human retinal microvascular endothelial cells (HRMECs). Interventions conducted both in vivo and in vitro showed notable efficacy in reducing pathological neovascularization. Importantly, we discovered that SREBF1 plays a key role in modulating lipid metabolism in HRMECs by regulating the expression of ACC1 and FASN, leading to cellular reprogramming. This reprogramming influences HRMEC proliferation, migration, and tube formation through the HIF-1α/TGF-ß signaling pathway, ultimately contributing to pathological retinal neovascularization. These findings provide new insights into the role of SREBF1 in angiogenesis within the context of ROP, offering potential therapeutic targets for the management and treatment of this disease.
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Western Blotting , Modelos Animales de Enfermedad , Ácidos Grasos , Ratones Endogámicos C57BL , Neovascularización Retiniana , Retinopatía de la Prematuridad , Proteína 1 de Unión a los Elementos Reguladores de Esteroles , Animales , Neovascularización Retiniana/metabolismo , Neovascularización Retiniana/patología , Ratones , Humanos , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/metabolismo , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/genética , Ácidos Grasos/metabolismo , Retinopatía de la Prematuridad/metabolismo , Retinopatía de la Prematuridad/patología , Células Cultivadas , Vasos Retinianos/metabolismo , Vasos Retinianos/patología , Células Endoteliales/metabolismo , Células Endoteliales/patología , Animales Recién Nacidos , Regulación de la Expresión Génica/fisiología , Endotelio Vascular/metabolismo , Endotelio Vascular/patología , Proliferación Celular/fisiología , Metabolismo de los Lípidos/fisiología , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
Retinopathy of prematurity is characterised by abnormal retinal neovascularization in response to hypoxia stress. Prolyl 4-hydroxylase domain protein 3 (PHD3) is a well-known molecular oxygen sensor. However, the role that PHD3 plays in retinopathy of prematurity remains unclear. In this work, a mouse model of oxygen-induced retinopathy (OIR) was used for in vivo studies. Compared with the mice in room air, OIR mice showed sprouting of retinal neovascularization and increased level of PHD3. It was further found that PHD3 overexpression weakened OIR-induced retinal neovascularization and promoted cell apoptosis in the retina, indicating a mitigative effect on retinopathy. More importantly, OIR-induced upregulation of hypoxia inducible factor-1 alpha (HIF-1α) and vascular endothelial growth factor (VEGFA) was offset by PHD3 overexpression. In in vitro experiments, mouse retinal microvascular endothelial cells (MRMECs) were cultured under hypoxic conditions. The functions of endothelial cells including cell proliferation, cell migration, and tube formation ability were suppressed by PHD3, suggesting an anti-angiogenesis effect of PHD3. In line with in vivo experiments, the expression of HIF-1α and VEGFA levels declined in endothelial cells when PHD3 was overexpressed. Taken together, PHD3 alleviates retinopathy of prematurity through anti-angiogenesis, and the core mechanism may involve cell apoptosis of retina endothelial cell and HIF-1α-VEGFA axis. These findings provide exciting new insights into the pathogenesis of retinopathy of prematurity, and could offer new treatment directions.
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Apoptosis , Neovascularización Retiniana , Retinopatía de la Prematuridad , Animales , Neovascularización Retiniana/metabolismo , Neovascularización Retiniana/patología , Retinopatía de la Prematuridad/metabolismo , Retinopatía de la Prematuridad/patología , Ratones , Factor A de Crecimiento Endotelial Vascular/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Prolina Dioxigenasas del Factor Inducible por Hipoxia/metabolismo , Prolina Dioxigenasas del Factor Inducible por Hipoxia/genética , Humanos , Ratones Endogámicos C57BL , Animales Recién Nacidos , Proliferación Celular , Movimiento Celular , Células Endoteliales/metabolismo , Células Endoteliales/patología , Procolágeno-Prolina DioxigenasaRESUMEN
BACKGROUND: To analyze the demographic characteristics of retinopathy of prematurity (ROP) in China, attempting to propose optimized screening criteria and hopefully providing valuable information for future updates to the ROP guideline. METHODS: A multicenter, retrospective-cohort study was conducted. The study included infants born between January 1, 2018, and July 31, 2023, who underwent ROP screening and were diagnosed with ROP at seven screening centers in China. Examinations were carried out in accordance with the ROP guidelines in 2014: infants with a gestational age (GA)<32 weeks and/or birth weight (BW)<2000 g, or infants who were suspected to be at risk of ROP. ROP treatment followed the recommendations of the Early Treatment for Retinopathy of Prematurity Cooperative Group. We utilized receiver operating characteristic (ROC) curves to determine the optimal predictive model, and conducted internal validation as well as compared the model to current standards. RESULTS: Among the 4770 infants diagnosed with ROP after fundus screening, 1330 (27.9%) infants received treatment. The mean GA at birth for all enrolled infants was 29.67 ± 2.45 weeks, with a mean BW of 1295.89 ± 403.64 g. This study proposed the optimization of guidelines to be ≤ 30 weeks of GA and ≤ 1600 g of BW, achieving a sensitivity of 99.4%, as high as the current standard, with an 18.0% reduction in screening requirements. CONCLUSION: Considering the decrease in both GA and BW among the population requiring ROP treatment in China, it is imperative to contemplate updating the ROP screening guideline.
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Tamizaje Neonatal , Retinopatía de la Prematuridad , Femenino , Humanos , Recién Nacido , Masculino , Peso al Nacer , China/epidemiología , Edad Gestacional , Tamizaje Neonatal/métodos , Retinopatía de la Prematuridad/diagnóstico , Retinopatía de la Prematuridad/epidemiología , Estudios Retrospectivos , Curva ROCRESUMEN
BACKGROUND: The aim of the study was to investigate the quantitative differences between severe stage 3 and stage 4A retinopathy of prematurity (ROP) by evaluating the pre-treatment fundus photographs. METHODS: Thirty-three eyes with clinical diagnosed as severe stage 3 were classified as severe stage 3 group. Twenty-two eyes with retinal detachment without foveal involvement were classified as stage 4A group. Quantitative measurements were performed on pre-treatment 130 degree fundus photographs. RESULTS: In the severe Stage 3 group, dense fibrous membranes, vertical tractional bands, and dragging were detected in 18 eyes (55%), in 5 eyes (15%), and in none of the eyes, respectively. In the stage 4A group, dense fibrous membranes, vertical tractional bands, and dragging were detected in 21 eyes (96%), in 22(100%) eyes, and in 17 eyes (77%), respectively. Dragging and vertical tractional bands were higher in the Stage 4A group than in the severe stage 3 group (p = 0.000). Disc-to-fovea distance, the width of the fibrous membranes, the total area of the fibrous membranes, total retinoschisis, and detachment areas were significantly higher in the stage 4A group than in the severe stage 3 group (respectively, p = 0.000,p = 0.006, p = 0.024,p = 0.000). CONCLUSIONS: Fibrous membranes and tractional bands can be detected in severe stage 3 ROP, but the width and the total area of the fibrous membranes and total retinoschisis-detachment area were found to be higher in stage 4A eyes. The dragging of the posterior pole can be an important diagnostic indicator for the diagnosis of stage 4A. Therefore this finding may be a simple auxiliary finding for diagnosis and prognosis of stage 4A ROP.
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Fondo de Ojo , Edad Gestacional , Fotograbar , Retinopatía de la Prematuridad , Humanos , Retinopatía de la Prematuridad/diagnóstico , Femenino , Recién Nacido , Masculino , Fotograbar/métodos , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Desprendimiento de Retina/diagnósticoRESUMEN
BACKGROUND: This study aimed to investigate the long-term effects of retinopathy of prematurity (ROP) on visual function and ocular anatomy. We compared biometric values, foveal thickness, and choroidal thickness among children with a history of ROP (stratified by treatment status), premature infants without ROP, and term-born children. METHODS: This cross-sectional study was conducted between september 2021 and february 2022 at the Ophthalmology Department of Ankara Bilkent City Hospital. The study included 54 eyes from 29 children who received laser photocoagulation treatment for ROP (ROP-Tx Group), 52 eyes from 26 children who developed ROP but did not require treatment (ROP-nonTx Group), 51 eyes from 25 children born prematurely without ROP (Premature Group), and 54 eyes from 27 healthy term children of the same age group (Control Group). One eye of a single premature infant was included in the ROP-nonTx group, while the other eye was included in the Premature group. The first three groups included patients who were followed up under the Retinopathy of Prematurity protocol at Zekai Tahir Burak Hospital between 2008 and 2016, while the control group consisted of 5-12 years old who presented for a routine eye examination without any ocular complaints or history of prematurity. Non-cycloplegic and cycloplegic refractive errors, best corrected visual acuity (BCVA), keratometry, axial length (AL) and anterior chamber depth (ACD), optical coherence tomography (OCT) central macula and choroid thickness measurements were performed in all cases. RESULTS: Premature infants treated with laser photocoagulation for retinopathy of prematurity exhibited significant differences in all measured ocular parameters compared to the term-born control group (p < 0.05). These parameters included reduced best corrected visual acuity (0.1 logMar), steeper keratometry values (K2: 47.95 Dioptre, K1: 45.83 Dioptre), more myopic spherical equivalent (-0.87 Dioptre), shorter axial length (21.67 mm), decreased anterior chamber depth (3.04 mm), as well as increased central macular thickness (300.50 µm) and decreased central choroidal thickness (268.27 µm). Infants who developed ROP but did not require laser treatment also exhibited significant differences compared to the control group, including steeper keratometry values (K2: 46.62 Dioptre, K1: 45.24 Dioptre) shorter axial length (22.01 mm), and increased central macular thickness (250.05 µm). Interestingly, anterior chamber depth was significantly unexpected way different (3.47 mm) only in the premature group without ROP compared to the term-born controls (p < 0.05). CONCLUSIONS: The study found that prematurity, ROP, and eye development are closely connected. Premature infants who treated with laser photocoagulation for ROP had the most significant differences in eye structure and vision compared to full-term infants. Even premature infants who showed spontaneous regression of ROP still demonstrated differences in ocular anatomy. These results emphasize the importance of closely monitoring premature infants, especially those treated for ROP, to ensure their vision develops properly.
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Biometría , Coroides , Refracción Ocular , Retinopatía de la Prematuridad , Tomografía de Coherencia Óptica , Agudeza Visual , Humanos , Retinopatía de la Prematuridad/cirugía , Retinopatía de la Prematuridad/fisiopatología , Retinopatía de la Prematuridad/diagnóstico , Agudeza Visual/fisiología , Coroides/patología , Coroides/diagnóstico por imagen , Masculino , Femenino , Refracción Ocular/fisiología , Estudios Transversales , Tomografía de Coherencia Óptica/métodos , Niño , Preescolar , Retina/fisiopatología , Retina/patología , Recién Nacido , Edad Gestacional , Recien Nacido Prematuro , Coagulación con LáserRESUMEN
PURPOSE: To evaluate the macular development in preterm infants with spontaneously regressed retinopathy of prematurity (ROP) utilizing handheld spectral domain optical coherence tomography (SD-OCT) during the early postnatal period. DESIGN: A cross-sectional observational study. METHODS: Using handheld SD-OCT, OCT images were acquired in non-sedated infants ages about 37 weeks(w) post-menstrual-age (PMA = gestational age in weeks + chronological age). Central foveal thickness (CFT), mean parafoveal thickness (PT, mean of the temporal and nasal-lateral retinal thickness 1000 µm from the foveal center), the thickness of inner retina layers (IRL) and outer retina layers (ORL) of the foveal center and parafoveal, the depth of the macular fovea (FD), and the angle of the macular fovea (FA) were measured and analyzed. RESULTS: In contrast to the infants without ROP (group 1), OCT images of the infants with spontaneously regressed ROP (group 2) were more immature. The FD of Group 2 was shallower than Group 1 (P < 0.05); CFT and the foveal center IRL (FIRL) of Group 2 were thicker than Group 1 (P < 0.05); conversely, PT and the mean parafoveal IRL (PIRL) of Group 2 were thinner than Group 1 (P < 0.05); FA of Group 2 was bigger than Group 1 (P < 0.05); however, there was no significant difference in the foveal center ORL (FORL) and the mean parafoveal ORL (PORL) between Groups 1 and 2 (P > 0.05). Furthermore, in preterm infants, ROP was moderately correlated with FD, CFT, PT, FIRL, and PIRL (P < 0.05). CONCLUSIONS: The spontaneously regressed ROP resulted in immature macular development in the early postnatal period. The inner retinal layers mainly contribute to this but not the outer retinal layers, indicating that the macular fovea's inner and outer retina layers developed asynchronously. ROP is an influential factor in macular development and maturation. This may be associated with the higher probability of visual impairment in children with a history of spontaneous regression of ROP at a prior time.
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Edad Gestacional , Recien Nacido Prematuro , Mácula Lútea , Retinopatía de la Prematuridad , Tomografía de Coherencia Óptica , Humanos , Retinopatía de la Prematuridad/fisiopatología , Retinopatía de la Prematuridad/diagnóstico , Tomografía de Coherencia Óptica/métodos , Estudios Transversales , Femenino , Masculino , Recién Nacido , Mácula Lútea/diagnóstico por imagen , Mácula Lútea/patología , Agudeza Visual/fisiología , Remisión Espontánea , Fóvea Central/diagnóstico por imagen , Fóvea Central/patologíaRESUMEN
BACKGROUND: The principal objective of our study is to evaluate the characteristics of babies with type 1 ROP, screening practices and treatment trends in a tertiary care centre in Pakistan. METHODS: This prospective study at Mayo Hospital, Lahore (July 2022-July 2024), included 89 preterm infants with type 1 ROP, selected using non-probability sampling. Infants were categorized based on international (GA < 32weeks or BW < 1500 g) and local screening criteria (GA < 35 weeks or BW < 2000 g), and treatment outcomes were evaluated across three groups: Anti-VEGF, combination therapy (Anti-VEGF followed by laser), and laser therapy. Statistical analysis was performed using SPSS version 27.0, significance was set at p < 0.05. RESULTS: Out of 355 infants screened, 89 (25.1%) met the inclusion criteria for type 1 ROP. The cohort included 55 males (61.8%) and 34 females (38.2%), with a mean gestational age of 31.31 weeks and a mean birth weight of 1602.25 g. Zone 1 ROP was found in 36% of cases, associated with lower birth weight (P = 0.029) and earlier gestational age (P = 0.037), while Zone 2 ROP, found in 64%, was linked to higher birth weight and later gestational age. Zone 1 infants were more likely to receive anti-VEGF or combination therapy, whereas Zone 2 infants predominantly received laser therapy (p < 0.000). Preterm infants (born before 32 weeks) mostly received Anti-VEGF or combination therapy, while those with higher birth weights primarily received laser therapy (p < 0.010). Among the treated babies, 63 (70.8%) met international screening criteria and were more likely to have Zone 1 ROP and receive Anti-VEGF or combination therapy. Conversely, 26 (29.2%) did not meet these criteria, had predominantly Zone 2 ROP and were more likely to receive laser therapy (p = 0.007). CONCLUSION: International screening criteria effectively identify severe type 1 ROP cases, particularly Zone 1, which often require Anti-VEGF therapy. Local criteria capture additional cases, predominantly Zone 2, which are more likely to need laser treatment. These findings highlight the need for tailored screening and treatment approaches to improve ROP management and outcomes for preterm infants.
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Inhibidores de la Angiogénesis , Edad Gestacional , Retinopatía de la Prematuridad , Centros de Atención Terciaria , Factor A de Crecimiento Endotelial Vascular , Humanos , Retinopatía de la Prematuridad/diagnóstico , Retinopatía de la Prematuridad/terapia , Femenino , Masculino , Pakistán , Estudios Prospectivos , Recién Nacido , Centros de Atención Terciaria/estadística & datos numéricos , Inhibidores de la Angiogénesis/uso terapéutico , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Inyecciones Intravítreas , Coagulación con Láser , Tamizaje Neonatal , Recien Nacido Prematuro , Peso al Nacer , Bevacizumab/uso terapéutico , Ranibizumab/uso terapéutico , Ranibizumab/administración & dosificaciónRESUMEN
INTRODUCTION: Our study investigated the association between hematocrit in the first two hours (HCT2h) of life and retinopathy of prematurity (ROP). METHODS: Data were obtained from an observational study of the DRYAD database. The study was conducted at the Santa Clara Valley Medical Center (SCVMC). Data on preterm babies whose gestational age (GA) was < 34 weeks were collected prospectively from January 2008 to February 2014. Logistic regression was applied to explore the association between HCT2h and ROP. RESULTS: A total of 326 very preterm infants born at or earlier than 34 weeks were included. The incidence of any ROP was 23.9%, and the incidence of severe ROP was 4.6%. The HCT2h, birth weight, GA, Apgar1 min, and Apgar5 min of any ROP group were significantly lower than those of preterm babies without ROP (p < 0.001). Sex differences, the rate of multiples, and delivery mode between the two groups were not statistically significant (p > 0.05). We classified HCT2h into three levels, and after multivariate logistic regression, we found that high HCT2h remained a significant protective factor against ROP (p < 0.001). Through subgroup analysis, we observed that among preterm infants with a GA of 28 weeks or more, there was a significant inverse association between a 1% increase in HCT2h and a 17% reduction in the occurrence of ROP. CONCLUSION: We found that HCT2h may be an effective biomarker for identifying the risk of ROP of very preterm infants born between 28 and 34 weeks of gestation. TRIAL REGISTRATION: This was a retrospective study and the data were from the DRYAD database. Santa Clara Valley Medical Center's (SCVMC) ethical committee reviewed and approved the studies involving human participants. Informed consent was waived for this study. We did not perform any extra interventions.
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Retinopatía de la Prematuridad , Humanos , Retinopatía de la Prematuridad/epidemiología , Retinopatía de la Prematuridad/sangre , Retinopatía de la Prematuridad/etiología , Recién Nacido , Estudios Retrospectivos , Femenino , Masculino , Hematócrito , Incidencia , Recien Nacido Prematuro , Modelos Logísticos , Edad Gestacional , Factores de Riesgo , Puntaje de Apgar , Bases de Datos FactualesRESUMEN
Retinal neurodevelopment, vascularization, homeostasis, and stress response are influenced by factors such as nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), tyrosine hydroxylase (TH), and erythropoietin (EPO). As retinopathy of prematurity (ROP) is a neurovascular retinal disease, this study analyzed the contributions of NGF (rs6330), BDNF (rs7934165), TH (rs10770141), and EPO (rs507392) genetic functional polymorphisms to the modulation of hematological and biochemical parameters of the first week of life and their association with ROP development. A multicenter cohort of 396 preterm infants (gestational age < 32 weeks or birth weight < 1500 g) was genotyped using MicroChip DNA and iPlex MassARRAY® platform. Multivariate regression followed univariate assessment of ROP risk factors. NGF (GG) genotype was associated with a higher ROP risk (OR = 1.79), which increased further (OR = 2.38) when epistatic interactions with TH (allele C) and BDNF (allele G) were present. Significant circulating biomarker differences, including bilirubin, erythrocytes, monocytes, neutrophils, lymphocytes, and platelet markers, were found between ROP and non-ROP groups, with variations depending on the polymorphism. These findings suggest that NGF (rs6330) and its interactions with related genes contribute to ROP risk, providing valuable insights into the genetic and biological mechanisms underlying the disease and identifying potential predictive biomarkers.
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Factor Neurotrófico Derivado del Encéfalo , Eritropoyetina , Factor de Crecimiento Nervioso , Polimorfismo de Nucleótido Simple , Retinopatía de la Prematuridad , Humanos , Retinopatía de la Prematuridad/genética , Recién Nacido , Masculino , Factor Neurotrófico Derivado del Encéfalo/genética , Femenino , Eritropoyetina/genética , Eritropoyetina/metabolismo , Factor de Crecimiento Nervioso/genética , Tirosina 3-Monooxigenasa/genética , Tirosina 3-Monooxigenasa/metabolismo , Recien Nacido Prematuro , Predisposición Genética a la Enfermedad , Genotipo , Factores de Crecimiento Nervioso/genética , Factores de Crecimiento Nervioso/metabolismo , Neurotransmisores/metabolismo , Neurotransmisores/genética , Biomarcadores , Factores de RiesgoRESUMEN
Aim: To evaluate the role of paediatric ocular imaging in paediatric ophthalmology through a case series, defining the retinal features observed in various paediatric pathological and trauma-related (abusive or non-abusive) conditions in patients aged four weeks to 16 years in a tertiary paediatric hospital in Dublin, Ireland. Methods: A retrospective record-based study was conducted at Children's Health Ireland (CHI) at Temple Street, analysing ocular images of patients aged four weeks to 16 years, spanning five years, from 2018 to 2022. Following pupillary dilation, retinal examinations were performed using the 'RetCam 3', a handheld device for supine examinations in younger children, or the 'Topcon KR 800' for older patients. Images were reviewed with haemorrhages categorised by number, size, and location. Demographic and clinical details were tabulated, with counts and percentages calculated for categorical variables. Odds ratios and 95% confidence intervals (CI) were derived using the Mantel-Haenszel method, with statistical significance set at p-value <0.05. Results: Of the 25 cases that met the age category of four weeks to 16 years, RHs were most common in infants (16 cases). Retinopathy of prematurity (ROP) was identified in nine cases (age range: 2 mo - 19 mo, mean age 7 mo), presumed trauma in five cases (age range: 2 mo - 10 mo, mean age 6 mo), metabolic/genetic conditions in four cases (age range: 8 mo - 8 years), infections in two cases, tumours in two cases, and three cases with no confirmed diagnosis. Most RHs were few, intraretinal, located in the posterior pole and periphery of the eye. RH incidence was significantly higher in ROP and trauma cases (p = 0.027), with an odds ratio of 1.4 (95% CI: 0.08 - 25.14). ROP cases showed small, localised haemorrhages, while cases of presumed trauma had multilayer and large (> 5 disc diameter (DD)) haemorrhages (p = 0.058) that extend to the ora serrata (p = 0.018). Discussion: The study highlights paediatric ocular imaging's role in documenting RH patterns, aiding differential diagnosis across paediatric conditions. Paediatric ocular imaging's detailed capabilities provide clinical insights, reducing the need for multiple exams while promoting standardised documentation. Integrating ocular imaging technology supports establishing national guidelines and training programs that improve accessibility across diverse healthcare settings. Future research should validate these findings through multi-modal approaches and standardised practices, exploring paediatric ocular imaging utility in routine paediatric care. Additionally, advancements in artificial intelligence (AI) can further improve retinal examination efficiency, ultimately enhancing paediatric ophthalmology and child welfare in Ireland.
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Hemorragia Retiniana , Humanos , Niño , Preescolar , Lactante , Estudios Retrospectivos , Adolescente , Hemorragia Retiniana/diagnóstico por imagen , Hemorragia Retiniana/etiología , Masculino , Femenino , Irlanda/epidemiología , Recién Nacido , Retinopatía de la Prematuridad/diagnóstico , Retinopatía de la Prematuridad/diagnóstico por imagenRESUMEN
Background and Objectives: This study investigated and compared with European literature data the incidence, severity, and perinatal risk factors of retinopathy of prematurity (ROP) in preterm infants admitted to the Premature Department of Mures County Clinical Hospital over a two-year period (January 2022-December 2023). Materials and Methods: ROP screening was performed in 96 infants (76.8%) according to professional guidelines. A literature review was conducted to compare our findings with national and European data. Significant differences were identified in comparisons with studies from Cluj-Napoca (p = 0.0125), TimiÈoara, and Bucharest (p < 0.0074), as well as Serbia and Croatia when stratified by gestational age limits. The variations in GA thresholds (32 vs. 34 weeks) between studies required stratified analyses to ensure meaningful comparisons. The included European studies provided data on screening criteria, prevalence, and associated risk factors, offering a comprehensive perspective on screening effectiveness. Results: Among the 149 admitted patients, 125 were preterm (n = 125). Of the screened patients, 20 (20.83%) infants were diagnosed with ROP, including 13 boys (65%) and 7 girls (35%), all requiring prolonged respiratory support, and 55% of them needed blood transfusion. The average birth weight of affected infants was 1030.5 g (550-1700 g ), and the mean gestational age was 28.3 weeks (25-34 weeks). In those found to have stage 2 and 3 ROP in zone II with plus disease (n = 6), intravitreal anti-VEGF injections and/or retinal laser treatments were performed. Notably, no cases of ROP-related blindness were recorded. Conclusions: To our knowledge, this is the first study to compare ROP prevalence and screening outcomes across Romanian national centers. Identified risk factors in this cohort, such as respiratory distress syndrome, oxygen therapy, blood transfusion, and intraventricular hemorrhage, are consistent with the existing literature data. These findings underscore the importance of standardized screening criteria and effective management protocols to prevent ROP-related blindness. The comparative approach of this study highlights the necessity of harmonized internationally applied criteria to facilitate robust comparisons and, more importantly, improve patient care outcomes.
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Recien Nacido Prematuro , Retinopatía de la Prematuridad , Humanos , Retinopatía de la Prematuridad/epidemiología , Rumanía/epidemiología , Factores de Riesgo , Estudios Retrospectivos , Recién Nacido , Femenino , Masculino , Prevalencia , Edad Gestacional , Europa (Continente)/epidemiología , Estudios de CohortesRESUMEN
BACKGROUND: Retinopathy of prematurity (ROP) is a major cause of childhood blindness worldwide, highlighted by retinal neovascularization. Ubiquitin is present throughout the retina. The deubiquitinating enzyme ubiquitin-specific protease 39 (USP39) has been reported to be involved in angiogenesis. Here, this study aimed to investigate the effects of USP39 on ROP and its associated mechanism. METHODS: Hypoxia-induced human retinal microvascular endothelial cells (hRMECs) were adopted for functional analyses. Detection of mRNA and protein was conducted using quantitative real-time PCR and western blotting. Cell migration, invasion and angiogenesis were evaluated using transwell and tube formation assays. Protein interaction was determined by immunoprecipitation assay. Oxygen-induced retinopathy (OIR) mouse models were used for in vivo analysis. RESULTS: USP39 level was higher in hypoxia-induced hRMECs, functionally, USP39 silencing reversed hypoxia-induced migration, invasion and angiogenesis in hRMECs. In further mechanism analysis, we found that USP39 stabilized SIRT2 protein expression in hRMECs by inducing SIRT2 deubiquitination. Moreover, SIRT2 up-regulation abated hypoxia-evoked migration, invasion and angiogenesis in hRMECs. Besides that, the inhibitory effects of USP39 silencing on hypoxia-induced metastatic and angiogenic behaviors were abolished after SIRT2 overexpression. In addition, USP39 silencing blocked the activation of phosphoinositide 3-kinase (PI3K)/protein kinase B pathway (AKT) by regulating SIRT2. In vivo assay showed that levels of USP39, SIRT2, matrix metalloproteinase (MMP)-2 (MMP-2), MMP-9 and Vascular endothelial growth factor A (VEGFA) were increased in the retinas of OIR mice, while intravitreal injection of USP39 short hairpin RNA (shRNA) could reduce their expression. CONCLUSION: USP39 stabilized SIRT2 expression by deubiquitination and promoted hypoxia-induced metastatic and angiogenic behaviors of RMECs in vitro, as well as retinal angiogenesis in vivo.
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Modelos Animales de Enfermedad , Neovascularización Retiniana , Retinopatía de la Prematuridad , Sirtuina 2 , Ubiquitinación , Retinopatía de la Prematuridad/metabolismo , Retinopatía de la Prematuridad/patología , Retinopatía de la Prematuridad/genética , Ratones , Neovascularización Retiniana/metabolismo , Neovascularización Retiniana/patología , Neovascularización Retiniana/genética , Neovascularización Retiniana/etiología , Animales , Humanos , Sirtuina 2/metabolismo , Sirtuina 2/genética , Sirtuina 2/biosíntesis , Proteasas Ubiquitina-Específicas/genética , Proteasas Ubiquitina-Específicas/metabolismo , Proteasas Ubiquitina-Específicas/biosíntesis , Movimiento Celular/fisiología , Células Cultivadas , Ratones Endogámicos C57BL , Western Blotting , Animales Recién Nacidos , Recién Nacido , Regulación de la Expresión Génica , Vasos Retinianos/patología , Vasos Retinianos/metabolismoRESUMEN
PURPOSE: The purpose of this study is to investigate the role of Secretogranin III (Scg3) in the pathogenesis of intraocular neovascular diseases and assess its potential as a therapeutic target for novel treatment strategies. METHODS: A literature review was conducted to examine the expression of Scg3 in intraocular neovascular diseases. We reviewed studies on the interaction of Scg3 with its homologous receptors and its effect on endothelial cell proliferation, migration, and vascular permeability-key processes involved in angiogenesis and neovascularization. RESULTS: Scg3 was found to be upregulated in the tissues affected by diabetic retinopathy (DR), retinopathy of prematurity (ROP), and choroidal neovascularization. In DR, Scg3 expression was linked to retinal neovascularization, where it facilitated endothelial cell proliferation and migration, essential processes for the formation of new blood vessels. Similarly, in ROP, Scg3 was associated with fibrovascular tissue proliferation within avascular retinal zones, contributing to the pathological neovascularization seen in premature infants. In the context of age-related macular degeneration (AMD), Scg3 appeared to play a role in choroidal neovascularization, where it promoted the invasion of choroidal capillaries into the retinal pigment epithelium. Furthermore, Scg3's binding to its homologous receptors was shown to enhance vascular permeability, potentially exacerbating fluid leakage and edema in these diseases, which is a hallmark of exudative conditions. Collectively, these findings suggest that Scg3 plays a pivotal role in driving angiogenesis and vascular permeability in intraocular neovascular diseases CONCLUSION: The upregulation of Scg3 in DR, ROP, and choroidal neovascularization highlights its potential as a novel therapeutic target. Inhibition of Scg3 could offer a new avenue for treating these sight-threatening conditions.
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Cromograninas , Humanos , Cromograninas/metabolismo , Cromograninas/genética , Neovascularización Coroidal/metabolismo , Neovascularización Coroidal/tratamiento farmacológico , Neovascularización Retiniana/metabolismo , Retinopatía de la Prematuridad/metabolismo , Retinopatía Diabética/metabolismoRESUMEN
Oxygen-induced retinopathy (OIR) animal model is widely used for retinopathy of prematurity (ROP) researches. The purpose of this study was to identify proteins and related pathways of OIR with or without anti-vascular endothelial growth factor (VEGF) treatment, for use as biomarkers in diagnosing and treating ROP. Nine samples were subjected to proteomic analysis. Retina specimens were collected from 3 OIR mice, 3 OIR mice with anti-VEGF treatment and 3 normal mice (control group). Liquid chromatography-tandem mass spectrometry analysis was performed using the 4D label-free technique. Statistically significant differentially expressed proteins, gene ontology (GO) terms, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway representations, InterPro (IPR) and protein interactions were analyzed. In total, 4585 unique proteins were identified as differentially expressed proteins (DEPs). Enrichment analysis of the GO and KEGG indicated functional clusters related to peptide biosynthetic and metabolic process, cellular macromolecule biosynthetic process and nucleic acid binding in OIR group. For anti-VEGF treatment group, DEPs were clustered in DNA replication, PI3K/Akt signaling pathway and Jak/STAT signaling pathway. Proteomic profiling is useful for the exploration of molecular mechanisms of OIR and mechanisms of anti-VEGF treatment. These findings may be useful for identification of novel biomarkers for ROP pathogenesis and treatment.
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Oxígeno , Proteómica , Retinopatía de la Prematuridad , Factor A de Crecimiento Endotelial Vascular , Animales , Oxígeno/metabolismo , Ratones , Proteómica/métodos , Factor A de Crecimiento Endotelial Vascular/metabolismo , Factor A de Crecimiento Endotelial Vascular/genética , Retinopatía de la Prematuridad/tratamiento farmacológico , Retinopatía de la Prematuridad/metabolismo , Transducción de Señal/efectos de los fármacos , Modelos Animales de Enfermedad , Espectrometría de Masas en Tándem , Ontología de Genes , Cromatografía Liquida , Retina/metabolismo , Retina/efectos de los fármacos , Retina/patologíaRESUMEN
Retinopathy of prematurity (ROP) is a retinal disease-causing retinal neovascularization that can lead to blindness. Oxygen-induced retinopathy (OIR) is a widely used ROP animal model. Icariin (ICA) has anti-oxidative and anti-inflammation properties; however, whether ICA has a regulatory effect on OIR remains unclear. In this study, ICA alleviated pathological neovascularization, microglial activation and blood-retina barrier (BRB) damage in vivo. Further results indicated that endothelial cell tube formation, migration and proliferation were restored by ICA treatment in vitro. Proteomic microarrays and molecular mimicry revealed that ICA can directly bind to hexokinase 2 (HK2) and decrease HK2 protein expression in vivo and in vitro. In addition, ICA inhibited the AKT/mTOR/HIF1α pathway activation. The effects of ICA on pathological neovascularization, microglial activation and BRB damage disappeared after HK2 overexpression in vivo. Similarly, the endothelial cell function was revised after HK2 overexpression. HK2 overexpression reversed ICA-induced AKT/mTOR/HIF1α pathway inhibition in vivo and in vitro. Therefore, ICA prevented pathological angiogenesis in OIR in an HK2-dependent manner, implicating ICA as a potential therapeutic agent for ROP.
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Flavonoides , Hexoquinasa , Microglía , Oxígeno , Neovascularización Retiniana , Retinopatía de la Prematuridad , Transducción de Señal , Serina-Treonina Quinasas TOR , Animales , Humanos , Ratones , Movimiento Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Flavonoides/farmacología , Flavonoides/uso terapéutico , Hexoquinasa/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Ratones Endogámicos C57BL , Microglía/efectos de los fármacos , Microglía/metabolismo , Oxígeno/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Neovascularización Retiniana/tratamiento farmacológico , Neovascularización Retiniana/metabolismo , Neovascularización Retiniana/patología , Retinopatía de la Prematuridad/tratamiento farmacológico , Retinopatía de la Prematuridad/metabolismo , Retinopatía de la Prematuridad/patología , Transducción de Señal/efectos de los fármacos , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
Extremely preterm infants are at risk of developing retinopathy of prematurity (ROP), characterized by neovascularization and neuroinflammation leading to blindness. Polyunsaturated fatty acid (PUFA) supplementation is recommended in preterm infants to lower the risk of ROP, however, with no significant improvement in visual acuity. Reasonably, this could be as a result of the non-consideration of PUFA metabolizing enzymes. We hypothesize that abnormal metabolism of the arachidonic acid (AA) pathway may contribute to severe stages of ROP. The present study investigated the AA-metabolizing enzymes in ROP pathogenesis by a targeted gene expression analysis of blood (severe ROP = 70, No/Mild = 56), placenta (preterm placenta = 6, full term placenta = 3), and human primary retinal cell cultures and further confirmed at the protein level by performing IHC in sections of ROP retina. The lipid metabolites were identified by LC-MS in the vitreous humor (VH; severe ROP = 15, control = 15). Prostaglandins D2 (p = 0.02), leukotrienes B5 (p = 0.0001), 11,12-epoxyeicosatrienoic acid (p = 0.01), and lipid-metabolizing enzymes of the AA pathway such as CYP1B1, CYP2C8, COX2, and ALOX15 were significantly upregulated while EPHX2 was significantly (0.04) downregulated in ROP cases. Genes involved in hypoxic stress, angiogenesis, and apoptosis showed increased expression in ROP. An increase in the metabolic intermediates generated from the AA metabolism pathway further confirmed the role of these enzymes in ROP, while metabolites for EPHX2 activity were low in abundance. Inflammatory lipid intermediates were higher compared to anti-inflammatory lipids in VH and showed an association with enzyme activity. Both the placenta of preterm infants who developed ROP and hypoxic retinal cultures showed a reduced expression of EPHX2. These findings suggested a strong involvement of EPHX2 in regulating retinal neovascularization and inflammation. The study results underscore the role of arachidonic acid metabolism in the development of ROP and as a potential target for preventing vision loss among preterm-born infants.
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Ácido Araquidónico , Recien Nacido Prematuro , Retinopatía de la Prematuridad , Humanos , Retinopatía de la Prematuridad/metabolismo , Ácido Araquidónico/metabolismo , Recién Nacido , Femenino , Masculino , Retina/metabolismo , Retina/patología , Embarazo , Células CultivadasRESUMEN
BACKGROUND: Retinopathy of prematurity (ROP), which often presents with bronchopulmonary dysplasia (BPD), is among the most common morbidities affecting extremely premature infants and is a leading cause of severe vision impairment in children worldwide. Activations of the inflammasome cascade and microglia have been implicated in playing a role in the development of both ROP and BPD. Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) is pivotal in inflammasome assembly. Utilizing mouse models of both oxygen-induced retinopathy (OIR) and BPD, this study was designed to test the hypothesis that hyperoxia induces ASC speck formation, which leads to microglial activation and retinopathy, and that inhibition of ASC speck formation by a humanized monoclonal antibody, IC100, directed against ASC, will ameliorate microglial activation and abnormal retinal vascular formation. METHODS: We first tested ASC speck formation in the retina of ASC-citrine reporter mice expressing ASC fusion protein with a C-terminal citrine (fluorescent GFP isoform) using a BPD model that causes both lung and eye injury by exposing newborn mice to room air (RA) or 85% O2 from postnatal day (P) 1 to P14. The retinas were dissected on P14 and retinal flat mounts were used to detect vascular endothelium with AF-594-conjugated isolectin B4 (IB4) and citrine-tagged ASC specks. To assess the effects of IC100 on an OIR model, newborn ASC citrine reporter mice and wildtype mice (C57BL/6 J) were exposed to RA from P1 to P6, then 75% O2 from P7 to P11, and then to RA from P12 to P18. At P12 mice were randomized to the following groups: RA with placebo PBS (RA-PBS), O2 with PBS (O2-PBS), O2 + IC100 intravitreal injection (O2-IC100-IVT), and O2 + IC100 intraperitoneal injection (O2-IC100-IP). Retinal vascularization was evaluated by flat mount staining with IB4. Microglial activation was detected by immunofluorescence staining for allograft inflammatory factor 1 (AIF-1) and CD206. Retinal structure was analyzed on H&E-stained sections, and function was analyzed by pattern electroretinography (PERG). RNA-sequencing (RNA-seq) of the retinas was performed to determine the transcriptional effects of IC100 treatment in OIR. RESULTS: ASC specks were significantly increased in the retinas by hyperoxia exposure and colocalized with the abnormal vasculature in both BPD and OIR models, and this was associated with increased microglial activation. Treatment with IC100-IVT or IC100-IP significantly reduced vaso-obliteration and intravitreal neovascularization. IC100-IVT treatment also reduced retinal microglial activation, restored retinal structure, and improved retinal function. RNA-seq showed that IC100 treatment corrected the induction of genes associated with angiogenesis, leukocyte migration, and VEGF signaling caused by O2. IC100 also corrected the suppression of genes associated with cell junction assembly, neuron projection, and neuron recognition caused by O2. CONCLUSION: These data demonstrate the crucial role of ASC in the pathogenesis of OIR and the efficacy of a humanized therapeutic anti-ASC antibody in treating OIR mice. Thus, this anti-ASC antibody may potentially be considered in diseases associated with oxygen stresses and retinopathy, such as ROP.
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Oxígeno , Retinopatía de la Prematuridad , Animales , Retinopatía de la Prematuridad/patología , Retinopatía de la Prematuridad/tratamiento farmacológico , Retinopatía de la Prematuridad/metabolismo , Ratones , Anticuerpos Monoclonales Humanizados/farmacología , Ratones Endogámicos C57BL , Animales Recién Nacidos , Modelos Animales de Enfermedad , Humanos , Hiperoxia/patología , Hiperoxia/complicaciones , Retina/patología , Retina/metabolismo , Retina/efectos de los fármacos , Proteínas Adaptadoras de Señalización CARD/metabolismo , Ratones Transgénicos , Neovascularización Retiniana/patología , Neovascularización Retiniana/metabolismo , Neovascularización Retiniana/tratamiento farmacológico , Microglía/patología , Microglía/metabolismo , Microglía/efectos de los fármacosRESUMEN
Pathological neovascularization in retinopathy of prematurity (ROP) can cause visual impairment in preterm infants. Current ROP treatments which are not preventative and only address late neovascular ROP, are costly and can lead to severe complications. We showed that topical 0.1% dexamethasone eye drops administered prior to peak neovessel formation prevented neovascularization in five extremely preterm infants at high risk for ROP and suppressed neovascularization by 30% in mouse oxygen-induced retinopathy (OIR) modeling ROP. In contrast, in OIR, topical dexamethasone treatment before any neovessel formation had limited efficacy in preventing later neovascularization, while treatment after peak neovessel formation had a non-statistically significant trend to exacerbating disease. Optimally timed topical dexamethasone suppression of neovascularization in OIR was associated with increased retinal mitochondrial gene expression and decreased inflammatory marker expression, predominantly found in immune cells. Blocking mitochondrial ATP synthetase reversed the inhibitory effect of dexamethasone on neovascularization in OIR. This study provides new insights into topical steroid effects in retinal neovascularization and into mitochondrial function in phase II ROP, and suggests a simple clinical approach to prevent severe ROP.