Browsing by Author "Urzúa, Cristhian"
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Item Association of retinal detachment with age 50 years or younger at onset in patients with acute retinal necrosis(2021) Urzúa, Cristhian; Knickelbein, Jared; Cuitino, Loreto; Moreno, Uriel; Anguita, Rodrigo; Velásquez, Víctor; Concha, Luz Elena; Morales, Sergio; Villarroel, Francisco; Sen, H Nida; Arellanes, LourdesBackground Due to the guarded prognosis of acute retinal necrosis (ARN), it is relevant to develop a strategy to earlycategorize those patients in a higher risk of worse outcomes. The purpose of this study is to describe clinical features andpredictive factors for retinal detachment (RD) in patients with ARN. Methods Retrospective observational case series of 34 adult patients (38 eyes) with ARN examined between January 2005 and July 2015 in the National Eye Institute (Bethesda, USA), the Department of Ophthalmology, University of Chile (Santiago, Chile), and APEC (CDMX, Mexico). Results A total of 16 males and 18 females with a mean age at presentation of 44.5±16.8 years were included. Twentyseven patients (79.4%) received intravenous acyclovir as frst-line treatment, and 7 patients received either oral antiviral (4 patients) or oral plus intravitreal antiviral (3 patients). All subjects were treated with prednisone, with a mean initial dose of 57.7±16.3 mg per day. Seventeen patients (50.0%) developed retinal detachment. An association of retinal detachment with age at onset was observed (p=0.04), with patients younger than 50 years presenting a higher risk (OR=14.86, p=0.0009). Additionally, patients in this higher risk group had more infammation in both anterior chamber and vitreous (p=0.04 and 0.03, respectively). No other predictive factor for retinal detachment was found in the present study. Conclusions RD represents an important complication in patients with ARN. Younger patients may be at higher risk of this complication, possibly secondary to the presence of a higher level of infammation.Item Definition of Uveitis Refractory to Treatment: A Systematic Review in the Absence of a Consensus(2020) Valenzuela, Rodrigo A.; Flores, Iván; Pujol, Myriam; Llanos, Carolina; Carreño, Ester; Rada, Gabriel; Herbort Jr, Carl P.; Cuitino, Loreto; Urzúa, CristhianPurpose: To evaluate the different definition of refractoriness in uveitis in the literature. Methods: We systematically searched the literature in order to identify definitions of refractory noninfectious uveitis in adult patients. A search strategy in the databases of MEDLINE and Scopus was used to find articles published between January 2005 and October 2018. Results: Definitions of corticosteroids-refractoriness were related to two main concepts: persistence of inflammation despite the use of corticosteroid and recurrences above a dosage threshold. In terms of immunomodulatory therapy and biologic agents, we observed a great variety of definitions: persistence of inflammation, number of attacks, side effects or complications, symptoms, and best-corrected visual acuity. Conclusions: The results of this systematic review demonstrate the current lack of consensus on the definition for refractory uveitis, regardless of the treatment being used and revealed a new terminology based on a comprehensive and operational definition for each specific category of refractoriness.Item Glucocorticoid Receptor-α and MKP-1 as Candidate Biomarkers for Treatment Response and Disease Activity in Vogt-Koyanagi-Harada Disease(Elsevier Inc, 2019) Urzúa, Cristhian; Chen, Ping; Chaigne-Delalande, Benjamin; Liu, Baoying; Anguita, Rodrigo; Guerrero, Julia; Sabat, Pablo; Velásquez, Víctor; Sen, Nida; Lee, Richard; Goecke, AnnelisePurpose To investigate the potential of utilizing the expression of genes for glucocorticoid receptor (GR) and mitogen-activated protein kinase phosphatase-1 (MKP-1) as biomarkers of corticosteroid (CS) refractoriness and disease activity in patients with Vogt-Koyanagi-Harada (VKH) disease. Design Prospective cohort study. Methods Twenty VKH patients receiving their first cycle of CS treatment in the absence of additional systemic immunosuppressive therapy and a control group of fifteen healthy volunteers were recruited from the University of Chile (Santiago, Chile) and US National Institutes of Health (Bethesda, United States). Intraocular inflammation was clinically quantified at enrolment and all follow-up visits. CS refractoriness was defined as an ocular reactivation of VKH upon CS withdrawal at a daily oral prednisone dose of 10 mg or more. Quantitative Reverse transcription polymerase chain reaction (qRT-PCR) was performed to measure the mRNA levels of the alpha (α) and beta (β) isoforms of GR and MKP-1 in peripheral blood mononuclear cells (PBMC) after in vitro stimulation with either anti-CD3/anti-CD28 antibodies, lipopolysaccharide (LPS), or phytohemagglutinin (PHA), in the presence or absence of dexamethasone (Dex). Results After 6 hours of stimulation in the presence of Dex, PBMC from CS-refractory VKH patients had an impaired elevation in GRα expression (P = .03). Furthermore, inactive patients showed a significant Dex-induced upregulation of MKP-1 (P = .005). Conclusions In this pilot study, the expression of GR isoforms and MKP-1 corresponded with patients' clinical response to systemic CS treatment and disease activity, respectively. Hence, these candidate biomarkers have potential clinical utility in the early identification of CS refractoriness and subclinical inflammation in patients with VKH disease.Item Initial-onset acute and chronic recurrent stages are two distinctive courses of VogtKoyanagi-Harada disease(2020) Urzúa, Cristhian; Herbort Jr., Carl; Valenzuela, Rodrigo A.; El-Asrar, Ahmed M. Abu; Arellanes-Garcia, Lourdes; Schlaen, Ariel; Yamamoto, Joyce; Pavesio, CarlosPurpose: To describe distinctive stages of Vogt-Koyanagi-Harada (VKH) disease: initial-onset acute versus chronic recurrent disease. Methods: A comprehensive literature review regarding stages and clinical presentations of VKH disease was conducted. Results: Despite a list of signs that has been described as characteristic features of early or late phases of VKH disease, the current classification -developed by an international committee and published in 2001- does not consider a distinction regarding the time from onset of disease symptoms, and specific findings observed at certain time point from the symptoms presentation and outcomes related to the stage of VKH disease. In that sense, chronic recurrent VKH disease is more refractory to treatment and is associated with a higher rate of complications. Accordingly, this subset of VKH patients has poorer functional and anatomical outcomes than patients with an initial-onset acute disease. Conclusions: An early clear distinction of VKH phenotype [Initial-onset acute versus chronic recurrent disease] should be considered in each clinical scenario, evaluating the delay in diagnosis and the clinical presentation, since it may help clinicians to perform a correct disease prognosis categorization and thus to make treatment decisions in terms of potential refractoriness or expected clinical outcomes.Item Intravitreal administration of multipotent mesenchymal stromal cells triggers a cytoprotective microenvironment in the retina of diabetic mice(BioMed Central, 2016) Ezquer, Marcelo; Urzúa, Cristhian; Montecino, Scarleth; Leal, Karla; Conget, Paulette; Ezquer, FernandoDiabetic retinopathy is a common complication of diabetes and the leading cause of irreversible vision loss in the Western world. The reduction in color/contrast sensitivity due to the loss of neural cells in the ganglion cell layer of the retina is an early event in the onset of diabetic retinopathy. Multipotent mesenchymal stromal cells (MSCs) are an attractive tool for the treatment of neurodegenerative diseases, since they could differentiate into neuronal cells, produce high levels of neurotrophic factors and reduce oxidative stress. Our aim was to determine whether the intravitreal administration of adipose-derived MSCs was able to prevent the loss of retinal ganglion cells in diabetic mice. METHODS: Diabetes was induced in C57BL6 mice by the administration of streptozotocin. When retinal pro-damage mechanisms were present, animals received a single intravitreal dose of 2 × 10(5) adipose-derived MSCs or the vehicle. Four and 12 weeks later we evaluated: (a) retinal ganglion cell number (immunofluorescence); (b) neurotrophic factor levels (real-time quantitative polymerase chain reaction (RT-qPCR) and enzyme-linked immunosorbent assay (ELISA)); (c) retinal apoptotic rate (TUNEL); (d) retinal levels of reactive oxygen species and oxidative damage (ELISA); (e) electrical response of the retina (electroretinography); (f) pro-angiogenic and anti-angiogenic factor levels (RT-qPCR and ELISA); and (g) retinal blood vessels (angiography). Furthermore, 1, 4, 8 and 12 weeks post-MSC administration, the presence of donor cells in the retina and their differentiation into neural and perivascular-like cells were assessed (immunofluorescence and flow cytometry). RESULTS: MSC administration completely prevented retinal ganglion cell loss. Donor cells remained in the vitreous cavity and did not differentiate into neural or perivascular-like cells. Nevertheless, they increased the intraocular levels of several potent neurotrophic factors (nerve growth factor, basic fibroblast growth factor and glial cell line-derived neurotrophic factor) and reduced the oxidative damage in the retina. Additionally, MSC administration has a neutral effect on the electrical response of the retina and did not result in a pathological neovascularization. CONCLUSIONS: Intravitreal administration of adipose-derived MSCs triggers an effective cytoprotective microenvironment in the retina of diabetic mice. Thus, MSCs represent an interesting tool in order to prevent diabetic retinopathy.Item miRNA Landscape in Pathogenesis and Treatment of Vogt-Koyanagi-Harada Disease(2021) Vega, Fabian; Bustamante, Mario; Valenzuela, Rodrigo; Urzúa, Cristhian; Cuitino, LoretomiRNAs, one of the members of the noncoding RNA family, are regulators of gene expression in inflammatory and autoimmune diseases. Changes in miRNA pool expression have been associated with differentiation of CD4+ T cells toward an inflammatory phenotype and with loss of self-tolerance in autoimmune diseases. Vogt-Koyanagi-Harada (VKH) disease is a chronic multisystemic pathology, affecting the uvea, inner ear, central nervous system, and skin. Several lines of evidence support an autoimmune etiology for VKH, with loss of tolerance against retinal pigmented epithelium-related self-antigens. This deleterious reaction is characterized by exacerbated inflammation, due to an aberrant T H 1 and T H 17 polarization and secretion of their proinflammatory hallmark cytokines interleukin 6 (IL-6), IL-17, interferon γ, and tumor necrosis factor α, and an impaired CD4+ CD25 high FoxP3+ regulatory T cell function. To restrain inflammation, VKH is pharmacologically treated with corticosteroids and immunosuppressive drugs as first and second line of therapy, respectively. Changes in the expression of miRNAs related to immunoregulatory pathways have been associated with VKH development, whereas some genetic variants of miRNAs have been found to be risk modifiers of VKH. Furthermore, the drugs commonly used in VKH treatment have great influence on miRNA expression, including those miRNAs associated to VKH disease. This relationship between response to therapy and miRNA regulation suggests that these small noncoding molecules might be therapeutic targets for the development of more effective and specific pharmacological therapy for VKH. In this review, we discuss the latest evidence regarding regulation and alteration of miRNA associated with VKH disease and its treatment.Item New Pharmacological Strategies for the Treatment of Non-Infectious Uveitis. A Minireview(2020-05) Valenzuela, Rodrigo A.; Flores, Iván; Urrutia, Beatríz; Fuentes, Francisca; Sabat, Pablo E.; Llanos, Carolina; Cuitino, Loreto; Urzúa, CristhianNon-infectious uveitis (NIU) is a group of disorders characterized by intraocular inflammation at different levels of the eye. NIU is a leading cause of irreversible blindness in working-age population in the developed world. The goal of uveitis treatment is to control inflammation, prevent recurrences, and preserve vision, as well as minimize the adverse effects of medications. Currently, the standard of care for NIU includes the administration of corticosteroids (CS) as first-line agents, but in some cases a more aggressive therapy is required. This includes synthetic immunosuppressants, such as antimetabolites (methotrexate, mycophenolate mofetil, and azathioprine), calcineurinic inhibitors (cyclosporine, tacrolimus), and alkylating agents (cyclophosphamide, chlorambucil). In those patients who become intolerant or refractory to CS and conventional immunosuppressive treatment, biologic agents have arisen as an effective therapy. Among the most evaluated treatments, TNF-α inhibitors, IL blockers, and anti-CD20 therapy have emerged. In this regard, anti-TNF agents (infliximab and adalimumab) have shown the strongest results in terms of favorable outcomes. In this review, we discuss latest evidence concerning to the effectiveness of biologic therapy, and present new therapeutic approaches directed against immune components as potential novel therapies for NIU.Publication Precise, simplified diagnostic criteria and optimised management of initial-onset Vogt–Koyanagi–Harada disease: an updated review(2022) Herbort, Carl; Tugal, Ilknur; Abu, Ahmed; Gupta, Amod; Takeuchi, Masaru; Fardeau, Christine; Hedayatfar, Alireza; Urzúa, Cristhian; Papasavvas, IoannisVogt-Koyanagi-Harada (VKH) disease is a primary autoimmune stromal choroiditis. This review aimed to provide a novel perspective of the disease. We took into account recent developments in the understanding of the disease and crucial progress in investigational modalities of the choroid, which has led to new, simpler diagnostic criteria. We analysed recent novel notions in the literature and new diagnostic tools for VKH. We identified the following updates for VKH disease: (1) A crucial differentiation between the acute initial-onset and the chronic forms of the disease; (2) the integration of new, precise imaging methods to assess choroidal inflammation; (3) the promotion of simplified, more reliable diagnostic criteria for acute initial-onset of the disease, based on the sine qua non presence of diffuse choroiditis, detected with indocyanine green angiography (ICGA) and/or Enhanced Depth Imaging OCT (EDI-OCT); and (4) treatment optimisation through early, vigorous, sustained corticosteroid and nonsteroidal immunosuppression, as the first line of treatment for initial-onset VKH disease, and monitoring subclinical choroidal inflammation during follow-ups. Several studies have shown that most patients could discontinue treatment without an inflammation relapse. ICGA and EDI-OCT represented the methods of choice for precisely monitoring disease evolution. Simplified, precise, new diagnostic criteria allow early diagnosis of VKH. In VKH disease, inflammation exclusively originates in the choroidal stroma. Therefore, in many cases, early, sustained treatment, with dual corticosteroid and nonsteroidal immunosuppressive therapy can result in full "healing", which obviates chronic, uncontrolled, subclinical choroidal inflammation.Publication Successful treatment of cytomegalovirus retinitis with oral/ intravitreal antivirals in HIV-negative patients with lymphoma(2022) Tasiopoulou, Anastasia; Urzúa, Cristhian; Lightman, SusanObjectives: To report patients with systemic lymphoma and cytomegalovirus (CMV) retinitis, treated with a combination of oral and intravitreal antiviral agents on an outpatient basis. Methods: Retrospective cases series. Information was gathered from the database of the Uveitis clinics at Moorfields Eye Hospital, United Kingdom from December 2014 to December 2018. The inclusion criteria comprised the diagnosis of systemic lymphoma, associated with a diagnosis of CMV retinitis. Exclusion criteria were alternative ocular diagnosis, human immunodeficiency virus (HIV), primary intraocular lymphoma, or other causes of immunosuppression. Results: All seven subjects had been under oncologist care for systemic lymphoma. CMV retinitis presented with a median of 61 months after the systemic lymphoma diagnosis. Five patients underwent a vitreous biopsy, and four of them returned PCR positive for CMV and the fifth patient had PCR positive in a blood sample. All patients were treated with oral Valganciclovir, with an induction dose of 900 mg every 12 h for up to 3 weeks until disease resolution and a maintenance dose thereafter. All but one received additional intravitreal Foscarnet injections, with a dose of 2.4 mg /0.1 ml. Conclusions: The management of patients with systemic lymphoma and CMV retinitis with oral and intravitreal antiviral agents, resulted in effective disease control.Publication Vogt-Koyanagi-Harada disease: the stepby-step approach to a better understanding of clinicopathology, immunopathology, diagnosis, and management: a brief review(2022) Urzúa, Cristhian; Herbort, Carl; Takeuchi, Masaru; Schlaen, Ariel; Concha, Luz; Usui, Yoshihiko; Cuitino, Loreto; Papasavvas, IoannisBackground: Appraisals of Vogt-Koyanagi-Harada disease (VKH) have become progressively more complete, since its first description in 1906. The availability of new investigational methods has improved our knowledge of the immunopathology, clinicopathology, diagnosis, and management of VKH disease. This review aimed to describe some of the steps that led to better characterization of VKH as a clinical entity. Methods: We searched on PubMed for articles that described the history of VKH disease and analyzed the progress in disease appraisal with new investigational and imaging methods. In particular, we searched for articles that investigated the clinicopathology, diagnosis, and management of VKH. Findings: The following developments were considered essential for improving the appraisal and understanding of VKH: (1) the history of the disease, (2) immunopathological mechanisms, (3) clinicopathology, (4) the importance of distinguishing initial-onset from chronic disease, (5) relevant imaging modalities, among which indocyanine green angiography is crucial, (6) diagnostic criteria that facilitate early diagnosis, and (7) the need for early, prolonged, aggressive treatment that combines steroidal and non-steroidal immunosuppression. Conclusion: Based on these findings, the definition of VKH has improved. VKH disease starts in the choroidal stroma and later involves other structures when it is not diagnosed and treated early. Indocyanine green angiography and enhanced depth imaging optical coherence tomography facilitate early diagnosis and precise monitoring of choroidal inflammation. ICGA is clearly the gold standard for appraisals and follow-ups in VKH disease, however EDI-OCT should be especially considered in those areas where ICGA is not fully available. These modalities have contributed substantially to a "cure" for VKH, when treatment is introduced within the therapeutic window of opportunity.Publication "White dot syndromes", an inappropriate and outdated misnomer(2022) Neri, Piergiorgio; Herbort, Carl; Hedayatfar, Alireza; Tugal, Ilknur; Cimino, Luca; Urzúa, Cristhian; Papasavvas, Ioannis; Takeuchi, Masuru; Lages, VaniaAlong the years, examples of drifts in medical thought were not so rare. Approximative and imprecise views or inconsiderate notions are voiced by opinion leaders in high-impact journals, which can negatively affect the appraisal of a disease or a group of diseases for years or decades.