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BACKGROUND/AIMS: To explore and characterise the clinical phenotype of acute anterior uveitis flares with delayed severity in patients with human leucocyte antigen B27 (HLA-B27)-associated anterior uveitis. METHODS: Retrospective chart review of patients with HLA-B27-associated anterior uveitis. Demographic and clinical data were recorded, as well as the clinical characteristics of acute anterior uveitis flares. A flare was considered to have delayed severity if any of the following criteria were met within 3-21 days of symptomatic onset: a two-step increase in anterior chamber inflammation on consecutive exams; a new development of hypopyon or fibrinoid aqueous reaction on consecutive examinations or a significant worsening of symptoms. RESULTS: A total of 371 patient charts were identified, of which 137 were included. 321 acute anterior uveitis flares were documented, with 36 (11.2%) meeting the criteria for a delayed severity flare. The average time from symptomatic onset was 10.2 days, and patients presented with an average anterior chamber cell grade of 3.5 in delayed severity flares compared with 1.6 in non-delayed severity flares. No significant difference in frequency of delayed severity presentation was noted based on the presence or absence of systemically associated rheumatological disease, papillitis on initial presentation and retinal vasculitis on initial presentation. The frequency of topical steroid therapy after symptomatic onset was not significantly different between the two flare phenotypes. CONCLUSIONS: Our study presents the novel characterisation of a delayed severity phenotype of HLA-B27-associated acute anterior uveitis flares.
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PURPOSE: To report a case of Cogan-Like Syndrome following treatment with nivolumab for metastatic cutaneous melanoma. METHODS: A case report. RESULTS: A 54-year-old female sought a second opinion from us regarding the recently diagnosed uveitis in both eyes. She had a diagnosis of metastatic cutaneous melanoma in the right arm and was undergoing treatment with nivolumab. Four weeks following the initiation of nivolumab therapy, she experienced tinnitus and bilateral sensorineural hearing loss, which was treated with oral and intratympanic steroids. While tapering the oral steroids, she developed iridocyclitis with papillitis in both eyes. This combination of vestibuloauditory symptoms and ocular inflammation was strikingly reminiscent of Cogan's syndrome. Because of the timing in relation to the nivolumab therapy and the steroid responsiveness of her presentation, this was speculated to be due to immune overactivation from the nivolumab. Given her complex condition, which involved toxicity and multiple metastases, the patient was advised to consider either topical and/or local corticosteroids or intravenous immunoglobulin. The patient chose to persist with corticosteroid therapy. CONCLUSION: Nivolumab could potentially be linked to an immune-related condition resembling Cogan syndrome. In cases involving patients with a complex condition necessitating nivolumab treatment, the use of topical and/or local corticosteroids or intravenous immunoglobulin, might constitute the sole viable treatment options.
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Enfermedades Autoinmunes , Síndromes Paraneoplásicos , Enfermedades de la Retina , Humanos , Enfermedades Autoinmunes/diagnóstico , Enfermedades Autoinmunes/tratamiento farmacológico , Enfermedades de la Retina/diagnóstico , Enfermedades de la Retina/tratamiento farmacológico , Inmunoglobulinas Intravenosas/uso terapéutico , AutoanticuerposRESUMEN
PURPOSE: To describe the course of care and outcomes for 3 uveitis patients formerly on Remicade that were non-medically switched to Inflectra. DESIGN: Retrospective observational case series. METHODS: â¢Setting: Tertiary care clinical practice.â¢Patient population: 3 Uveitis patients, observing both eyes for inflammation as applicable. Patients included if they had been on Inflectra for ≥2 infusions and history of Remicade use. Patients described herein had at least 1 adverse reaction to Inflectra and were switched to Remicade for medical necessity. Patients excluded if they were lost to follow-up or not examined for over 6 months during therapy.â¢Observation procedures/Interventions: Patients observed for adverse changes in clinical course while on Inflectra. Patients developing these changes on Inflectra were started or restarted on Remicade. RESULTS: The 3 patients described herein developed adverse complications while on Inflectra that required switching to Remicade. They were originally on Remicade, and their clinical course worsened beyond what had been controlled with Remicade alone. Our findings are limited by our small sample size, and further investigation is necessary to explore the scope of effects of non-medical biosimilar switching. CONCLUSION: Non-medical biosimilar switching from Remicade to Inflectra may induce detrimental side-effects and significant worsening of inflammation in patients with uveitis. Non-medical biosimilar switching from Remicade to Inflectra should be discouraged, and physician input should be sought in establishing an effective and medically-necessary treatment plan for patients with uveitis.
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Diabetic retinopathy (DR) is the most common diabetic microvascular complication and cause of blindness in adults under the age of 65. Our results suggest that, when comparing transcriptomes of cultures grown in hypoxic conditions versus room-air, cybrids containing mitochondria from African and Asian diabetic subjects ([Afr + Asi]/DM) have some uniquely different transcriptome profiles compared to European/diabetic (Euro/DM) cybrids (e.g., fatty acid metabolism: EnrichR rank 10 in [Afr + Asi]/DM, rank 85 in Euro/DM; Endocytosis: rank 25 in [Afr + Asi]/DM, rank 5 in Euro/DM; Ubiquitin Mediated Proteolysis: rank 34 in [Afr + Asi]/DM, rank 7 in Euro/DM). As determined by both RNA-seq and qRT-PCR results, transcription of the gene encoding oleoyl-ACP hydrolase (OLAH) was significantly increased in [Afr + Asi]/DM cybrids compared to Euro/DM cybrids in hypoxic conditions. Additionally, our results show that in hypoxic conditions, Euro/DM cybrids and [Afr + Asi]/DM cybrids show similar decreases in ROS production. All cybrids showed decreased ZO1-minus protein levels, but their phagocytic functions were not significantly altered in hypoxic conditions. In conclusion, our findings suggest that the "molecular memory" imparted by [Afr + Asi]/DM mtDNA may act through one of the molecular pathways seen in transcriptome analysis, such as fatty acid metabolism, without significantly changing essential RPE functions.
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Diabetes Mellitus , Retinopatía Diabética , Adulto , Humanos , Retinopatía Diabética/genética , Asiático , Población Negra , Hipoxia/genética , Ácidos Grasos , Diabetes Mellitus/genéticaRESUMEN
PURPOSE: The purpose of this review was to investigate the idea that inflammatory events of the conjunctiva and ocular surface may act as triggering events for the onset of ocular mucus membrane pemphigoid (oMMP). METHODS: A retrospective chart review of patients with biopsy-proven oMMP and no systemic pemphigoid disease. The presence, or absence, of the following inflammatory conditions at the time of OMMP diagnosis was noted: significant eyelid disease, significant atopic eye disease, Stevens-Johnson syndrome, graft-versus-host disease, viral keratitis, sarcoidosis with ocular involvement, chemical burns, medicamentosa, Sjogren syndrome, systemic lupus erythematosus with ocular involvement, and epidemic keratoconjunctivitis. Response to immunomodulatory therapy (IMT) was also recorded. RESULTS: A total of 779 patient records were identified. Conjunctival biopsy was present in 724 patients, with 646 (89.2%) being positive. One hundred thirty-nine patients (21.5%) with positive biopsies had extraocular pemphigoid disease and were excluded from further analysis. Of the 507 included patients, 154 (30.4%) had at least one of the specified inflammatory conditions present at the time of OMMP diagnosis. One hundred eighteen patients (23.3%) had only 1 such condition, 35 (6.9%) had 2, and 1 patient had 3. In patients with at least one of these conditions present, response to IMT was seen in 84.9% of patients with sufficient follow-up. CONCLUSIONS: Our study suggests that oMMP may arise as a secondary pathology to acute inflammatory events or chronic inflammatory states of the conjunctiva and ocular surface.
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Enfermedades de los Párpados , Penfigoide Benigno de la Membrana Mucosa , Penfigoide Ampolloso , Humanos , Estudios Retrospectivos , Penfigoide Ampolloso/complicaciones , Penfigoide Ampolloso/patología , Penfigoide Benigno de la Membrana Mucosa/complicaciones , Conjuntiva/patología , Enfermedades de los Párpados/patología , MocoRESUMEN
Diabetic retinopathy (DR) is the most common cause of blindness for individuals under the age of 65. This loss of vision can be due to ischemia, neovascularization, and/or diabetic macular edema, which are caused by breakdown of the blood-retina barrier at the level of the retinal pigment epithelium (RPE) and inner retinal vasculature. The prevalence of diabetes and its complications differ between Caucasian-Americans and certain minority populations, such as African-Americans and Asian-Americans. Individuals can be classified by their mitochondrial haplogroups, which are collections of single nucleotide polymorphisms (SNPs) in mitochondrial DNA (mtDNA) representing ancient geographic origins of populations. In this study, we compared the responses of diabetic human RPE cybrids, cell lines containing identical nuclei but mitochondria from either European (maternal European) or maternal African or Asian individuals, to hypoxia and high glucose levels. The African and Asian diabetic ([Afr+Asi]/DM) cybrids showed (1) resistance to both hyperglycemic and hypoxic stresses; (2) downregulation of pro-apoptotic indicator BAX; (3) upregulation of DNA methylation genes, such as DNMT3A and DNMT3B; and (4) resistance to DNA demethylation by the methylation inhibitor 5-Aza-2'-deoxycytidine (5-Aza-dC) compared to European diabetic (Euro/DM) cybrids. Our findings suggest that mitochondria from African and Asian diabetic subjects possess a "metabolic memory" that confers resistance against hyperglycemia, hypoxia, and demethylation, and that this "metabolic memory" can be transferred into the RPE cybrid cell lines in vitro.
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ADN Mitocondrial/genética , Retinopatía Diabética/genética , Edema Macular/genética , Mitocondrias/metabolismo , Epitelio Pigmentado de la Retina/citología , Adulto , Anciano , Pueblo Asiatico , Células Cultivadas , Diabetes Mellitus/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple/genética , Transducción de Señal/genética , Población BlancaRESUMEN
Botch promotes embryonic neurogenesis by inhibiting the initial S1 furin-like cleavage step of Notch maturation. The biochemical process by which Botch inhibits Notch maturation is not known. Here, we show that Botch has γ-glutamyl cyclotransferase (GGCT) activity that deglycinates Notch, which prevents the S1 furin-like cleavage. Moreover, Notch is monoglycinated on the γ-glutamyl carbon of glutamate 1,669. The deglycinase activity of Botch is required for inhibition of Notch signaling both in vitro and in vivo. When the γ-glutamyl-glycine at position 1,669 of Notch is degylcinated, it is replaced by 5-oxy-proline. These results reveal that Botch regulates Notch signaling through deglycination and identify a posttranslational modification of Notch that plays an important role in neurogenesis.
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Receptores Notch/antagonistas & inhibidores , gamma-Glutamilciclotransferasa/metabolismo , Animales , Encéfalo/metabolismo , Embrión de Mamíferos/enzimología , Células HEK293 , Humanos , Ratones , Neurogénesis , Estructura Terciaria de Proteína , Interferencia de ARN , ARN Interferente Pequeño/metabolismo , Receptores Notch/metabolismo , Transducción de Señal , gamma-Glutamilciclotransferasa/antagonistas & inhibidores , gamma-Glutamilciclotransferasa/químicaRESUMEN
Regulation of self-renewal and differentiation of neural stem cells is still poorly understood. Here we investigate the role of a developmentally expressed protein, Botch, which blocks Notch, in neocortical development. Downregulation of Botch in vivo leads to cellular retention in the ventricular and subventricular zones, whereas overexpression of Botch drives neural stem cells into the intermediate zone and cortical plate. In vitro neurosphere and differentiation assays indicate that Botch regulates neurogenesis by promoting neuronal differentiation. Botch prevents cell surface presentation of Notch by inhibiting the S1 furin-like cleavage of Notch, maintaining Notch in the immature full-length form. Understanding the function of Botch expands our knowledge regarding both the regulation of Notch signaling and the complex signaling mediating neuronal development.