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1.
J Neuroophthalmol ; 2024 Jun 27.
Artículo en Inglés | MEDLINE | ID: mdl-38926909

RESUMEN

ABSTRACT: A 46-year-old man presented with left eye blurring. Automated visual field testing showed an incongruous right hemianopia, with sparing of the lower temporal quadrant in the right eye. MRI revealed foci of gadolinium enhancement in the optic chiasm and optic tracts. Serologic testing (including myelin oligodendrocyte glycoprotein and neuromyelitis optica antibodies) and cerebrospinal fluid analysis were negative. Whole-body PET/CT scan found no malignancy. Biopsy of the optic chiasm revealed a moderately cellular neoplasm composed of atypical, discohesive cells with enlarged nuclei, prominent eosinophilic nucleoli, and abundant vacuolated cytoplasm. Immunohistochemical stains for CD68 and S100 were positive, whereas those for GFAP, OLIG2, SOX10, and multiple others were negative, supporting a diagnosis of histiocytic neoplasm. Five weeks later, results became available from next-generation sequencing targeting the coding regions of hundreds of malignancy-associated genes and select introns. Alterations associated with histiocytic neoplasms (i.e. BRAF and MAP2K1 mutations) were absent. However, there was a nonsense mutation in the PTEN gene, a hotspot mutation in the TERT gene promotor, and focal amplifications of the CDK4 and MDM2 genes. Additionally, there was chromosome 6q loss, 7 gain, and 10q loss. Based on these findings, the diagnosis was revised to glioblastoma, IDH-wildtype, CNS WHO grade 4. The patient began treatment with temozolomide while continuing radiation therapy. This case illustrates how next-generation sequencing can at times provide more accurate diagnostic information than standard tissue histopathology.

2.
J Neuroinflammation ; 16(1): 203, 2019 Nov 04.
Artículo en Inglés | MEDLINE | ID: mdl-31684959

RESUMEN

BACKGROUND: Retinal optical coherence tomography (OCT) is a clinical and research tool in multiple sclerosis, where it has shown significant retinal nerve fiber (RNFL) and ganglion cell (RGC) layer thinning, while postmortem studies have reported RGC loss. Although retinal pathology in experimental autoimmune encephalomyelitis (EAE) has been described, comparative OCT studies among EAE models are scarce. Furthermore, the best practices for the implementation of OCT in the EAE lab, especially with afoveate animals like rodents, remain undefined. We aimed to describe the dynamics of retinal injury in different mouse EAE models and outline the optimal experimental conditions, scan protocols, and analysis methods, comparing these to histology to confirm the pathological underpinnings. METHODS: Using spectral-domain OCT, we analyzed the test-retest and the inter-rater reliability of volume, peripapillary, and combined horizontal and vertical line scans. We then monitored the thickness of the retinal layers in different EAE models: in wild-type (WT) C57Bl/6J mice immunized with myelin oligodendrocyte glycoprotein peptide (MOG35-55) or with bovine myelin basic protein (MBP), in TCR2D2 mice immunized with MOG35-55, and in SJL/J mice immunized with myelin proteolipid lipoprotein (PLP139-151). Strain-matched control mice were sham-immunized. RGC density was counted on retinal flatmounts at the end of each experiment. RESULTS: Volume scans centered on the optic disc showed the best reliability. Retinal changes during EAE were localized in the inner retinal layers (IRLs, the combination of the RNFL and the ganglion cell plus the inner plexiform layers). In WT, MOG35-55 EAE, progressive thinning of IRL started rapidly after EAE onset, with 1/3 of total loss occurring during the initial 2 months. IRL thinning was associated with the degree of RGC loss and the severity of EAE. Sham-immunized SJL/J mice showed progressive IRL atrophy, which was accentuated in PLP-immunized mice. MOG35-55-immunized TCR2D2 mice showed severe EAE and retinal thinning. MBP immunization led to very mild disease without significant retinopathy. CONCLUSIONS: Retinal neuroaxonal damage develops quickly during EAE. Changes in retinal thickness mirror neuronal loss and clinical severity. Monitoring of the IRL thickness after immunization against MOG35-55 in C57Bl/6J mice seems the most convenient model to study retinal neurodegeneration in EAE.


Asunto(s)
Encefalomielitis Autoinmune Experimental/patología , Degeneración Nerviosa/patología , Neuronas/patología , Retina/patología , Tomografía de Coherencia Óptica/métodos , Animales , Ratones , Ratones Endogámicos C57BL
3.
Proc Natl Acad Sci U S A ; 113(51): 14781-14786, 2016 12 20.
Artículo en Inglés | MEDLINE | ID: mdl-27940915

RESUMEN

Aquaporin-4 (AQP4)-specific T cells are expanded in neuromyelitis optica (NMO) patients and exhibit Th17 polarization. However, their pathogenic role in CNS autoimmune inflammatory disease is unclear. Although multiple AQP4 T-cell epitopes have been identified in WT C57BL/6 mice, we observed that neither immunization with those determinants nor transfer of donor T cells targeting them caused CNS autoimmune disease in recipient mice. In contrast, robust proliferation was observed following immunization of AQP4-deficient (AQP4-/-) mice with AQP4 peptide (p) 135-153 or p201-220, peptides predicted to contain I-Ab-restricted T-cell epitopes but not identified in WT mice. In comparison with WT mice, AQP4-/- mice used unique T-cell receptor repertoires for recognition of these two AQP4 epitopes. Donor T cells specific for either determinant from AQP4-/-, but not WT, mice induced paralysis in recipient WT and B-cell-deficient mice. AQP4-specific Th17-polarized cells induced more severe disease than Th1-polarized cells. Clinical signs were associated with opticospinal infiltrates of T cells and monocytes. Fluorescent-labeled donor T cells were detected in CNS lesions. Visual system involvement was evident by changes in optical coherence tomography. Fine mapping of AQP4 p201-220 and p135-153 epitopes identified peptides within p201-220 but not p135-153, which induced clinical disease in 40% of WT mice by direct immunization. Our results provide a foundation to evaluate how AQP4-specific T cells contribute to AQP4-targeted CNS autoimmunity (ATCA) and suggest that pathogenic AQP4-specific T-cell responses are normally restrained by central tolerance, which may be relevant to understanding development of AQP4-reactive T cells in NMO.


Asunto(s)
Acuaporina 4/genética , Acuaporina 4/metabolismo , Autoantígenos/química , Epítopos de Linfocito T/inmunología , Neuromielitis Óptica/metabolismo , Linfocitos T/citología , Animales , Autoanticuerpos/inmunología , Enfermedades Autoinmunes/metabolismo , Proliferación Celular , Sistema Nervioso Central , Mapeo Epitopo , Femenino , Citometría de Flujo , Tolerancia Inmunológica , Inmunoglobulina G/inmunología , Inflamación , Leucocitos/citología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Bazo/citología , Células Th17/citología
4.
FASEB J ; 30(5): 1789-97, 2016 05.
Artículo en Inglés | MEDLINE | ID: mdl-26842854

RESUMEN

Dry eye disorders, including Sjögren's syndrome, constitute a common problem in the aging population, with limited effective therapeutic options available. The cAMP-activated Cl(-) channel cystic fibrosis transmembrane conductance regulator (CFTR) is a major prosecretory channel at the ocular surface. We investigated whether compounds that target CFTR can correct the abnormal tear film in dry eye. Small-molecule activators of human wild-type CFTR identified by high-throughput screening were evaluated in cell culture and in vivo assays, to select compounds that stimulate Cl(-)-driven fluid secretion across the ocular surface in mice. An aminophenyl-1,3,5-triazine, CFTRact-K089, fully activated CFTR in cell cultures with EC50 ∼250 nM and produced an ∼8.5 mV hyperpolarization in ocular surface potential difference. When delivered topically, CFTRact-K089 doubled basal tear volume for 4 h and had no effect in CF mice. CFTRact-K089 showed sustained tear film bioavailability without detectable systemic absorption. In a mouse model of aqueous-deficient dry eye produced by lacrimal ablation, topical administration of 0.1 nmol CFTRact-K089 3 times daily restored tear volume to basal levels, preventing corneal epithelial disruption when initiated at the time of surgery and reversing it when started after development of dry eye. Our results support the potential utility of CFTR-targeted activators as a novel prosecretory treatment for dry eye.-Flores, A. M., Casey, S. D., Felix, C. M., Phuan, P. W., Verkman, A. S., Levin, M. H. Small-molecule CFTR activators increase tear secretion and prevent experimental dry eye disease.


Asunto(s)
Regulador de Conductancia de Transmembrana de Fibrosis Quística/agonistas , Síndromes de Ojo Seco/prevención & control , Regulación de la Expresión Génica/efectos de los fármacos , Lágrimas/metabolismo , Animales , Células Cultivadas , Femenino , Humanos , Ratones , Ratones Endogámicos BALB C , Estructura Molecular , Mutación , Ratas , Ratas Endogámicas F344
5.
J Am Acad Dermatol ; 77(1): 109-117, 2017 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-28619551

RESUMEN

BACKGROUND: Acne fulminans (AF) is a severe variant of inflammatory acne. It typically manifests as an explosive worsening and ulceration of skin lesions, and can be associated with systemic symptoms. However, there is a paucity of evidence-based information and no clear guidelines concerning the classification and treatment of AF. OBJECTIVE: To better define the spectrum of AF and its variants, devise optimal therapeutic approaches, and identify areas of future research. METHODS: A panel of physicians with expertise in severe acne vulgaris was convened after a comprehensive literature review of severe acne variants. Priority topics were reviewed and presented by each panelist at a 5-hour conference. Following review of the audiotape and scribed notes from the conference, surveys were utilized to address points of controversy and to clarify consensus recommendations. RESULTS: Appropriate clinical case presentations and consensus survey questions were utilized to create final recommendations based on both the literature and the expert consensus. LIMITATIONS: Limited evidenced-based data and prospective studies in the literature concerning the treatment of AF is available. CONCLUSION: These guidelines better characterize AF and provide health care practitioners approaches to the classification, treatment, and prevention of AF and its variants.


Asunto(s)
Acné Vulgar/tratamiento farmacológico , Acné Vulgar/clasificación , Medicina Basada en la Evidencia , Humanos , Guías de Práctica Clínica como Asunto
8.
J Neuroinflammation ; 13(1): 275, 2016 10 20.
Artículo en Inglés | MEDLINE | ID: mdl-27765056

RESUMEN

BACKGROUND: Neuromyelitis optica (NMO), an autoimmune inflammatory disease of the central nervous system, is often associated with retinal abnormalities including thinning of the retinal nerve fiber layer and microcystic changes. Here, we demonstrate that passive transfer of an anti-aquaporin-4 autoantibody (AQP4-IgG) produces primary retinal pathology. METHODS: AQP4-IgG was delivered to adult rat retinas by intravitreal injection. Rat retinas and retinal explant cultures were assessed by immunofluorescence. RESULTS: Immunofluorescence showed AQP4-IgG deposition on retinal Müller cells, with greatly reduced AQP4 expression and increased glial fibrillary acidic protein by 5 days. There was mild retinal inflammation with microglial activation but little leukocyte infiltration and loss of retinal ganglion cells by 30 days with thinning of the ganglion cell complex. Interestingly, the loss of AQP4 was complement independent as seen in cobra venom factor-treated rats and in normal rats administered a mutated AQP4-IgG lacking complement effector function. Exposure of ex vivo retinal cultures to AQP4-IgG produced a marked reduction in AQP4 expression by 24 h, which was largely prevented by inhibitors of endocytosis or lysosomal acidification. CONCLUSIONS: Passive transfer of AQP4-IgG results in primary, complement-independent retinal pathology, which might contribute to retinal abnormalities seen in NMO patients.


Asunto(s)
Acuaporina 4/inmunología , Proteínas del Sistema Complemento/metabolismo , Inmunoglobulina G/toxicidad , Neuromielitis Óptica , Retina/metabolismo , Retina/patología , Animales , Acuaporina 4/metabolismo , Proteínas de Unión al Calcio/metabolismo , Citocinas/metabolismo , Modelos Animales de Enfermedad , Células Ependimogliales/metabolismo , Células Ependimogliales/patología , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/inmunología , Proteína Ácida Fibrilar de la Glía/metabolismo , Humanos , Inyecciones Intravítreas , Leucocitos/efectos de los fármacos , Leucocitos/fisiología , Masculino , Proteínas de Microfilamentos/metabolismo , Neuromielitis Óptica/etiología , Neuromielitis Óptica/inmunología , Neuromielitis Óptica/patología , Técnicas de Cultivo de Órganos , Ratas , Ratas Sprague-Dawley , Retina/efectos de los fármacos , Células Ganglionares de la Retina/metabolismo , Células Ganglionares de la Retina/patología
9.
J Neuroinflammation ; 11: 16, 2014 Jan 27.
Artículo en Inglés | MEDLINE | ID: mdl-24468108

RESUMEN

BACKGROUND: Although optic neuritis (ON) is a defining feature of neuromyelitis optica (NMO), appropriate animal models of NMO ON are lacking. Most NMO patients are seropositive for immunoglobulin G autoantibodies (NMO-IgG) against the astrocyte water channel aquaporin-4 (AQP4). METHODS: Several approaches were tested to develop a robust, passive-transfer mouse model of NMO ON, including NMO-IgG and complement delivery by: (i) retrobulbar infusion; (ii) intravitreal injection; (iii) a single intracranial injection near the optic chiasm; and (iv) 3-days continuous intracranial infusion near the optic chiasm. RESULTS: Little ON or retinal pathology was seen using approaches (i) to (iii). Using approach (iv), however, optic nerves showed characteristic NMO pathology, with loss of AQP4 and glial fibrillary acidic protein immunoreactivity, granulocyte and macrophage infiltration, deposition of activated complement, demyelination and axonal injury. Even more extensive pathology was created in mice lacking complement inhibitor protein CD59, or using a genetically modified NMO-IgG with enhanced complement effector function, including significant loss of retinal ganglion cells. In control studies, optic nerve pathology was absent in treated AQP4-deficient mice, or in wild-type mice receiving control (non-NMO) IgG and complement. CONCLUSION: Passive transfer of NMO-IgG and complement by continuous infusion near the optic chiasm in mice is sufficient to produce ON with characteristic NMO pathology. The mouse model of NMO ON should be useful in further studies of NMO pathogenesis mechanisms and therapeutics.


Asunto(s)
Acuaporina 4/inmunología , Enfermedades Desmielinizantes/etiología , Inmunización Pasiva/efectos adversos , Inmunoglobulina G/inmunología , Neuromielitis Óptica/inmunología , Animales , Acuaporina 4/deficiencia , Antígenos CD59/genética , Modelos Animales de Enfermedad , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neuromielitis Óptica/complicaciones , Neuromielitis Óptica/etiología , Nervio Óptico/inmunología , Nervio Óptico/metabolismo , Retina/inmunología , Retina/metabolismo , Retina/patología , Células Ganglionares de la Retina/metabolismo
10.
Ophthalmology ; 121(2): 588-95.e1, 2014 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-24332536

RESUMEN

PURPOSE: Among cases of visually significant uveitic macular edema (ME), to estimate the incidence of visual improvement and identify predictive factors. DESIGN: Retrospective cohort study. PARTICIPANTS: Eyes with uveitis, seen at 5 academic ocular inflammation centers in the United States, for which ME was documented to be currently present and the principal cause of reduced visual acuity (<20/40). METHODS: Data were obtained by standardized chart review. MAIN OUTCOME MEASURES: Decrease of ≥ 0.2 base 10 logarithm of visual acuity decimal fraction-equivalent; risk factors for such visual improvement. RESULTS: We identified 1510 eyes (of 1077 patients) with visual impairment to a level <20/40 attributed to ME. Most patients were female (67%) and white (76%), and had bilateral uveitis (82%). The estimated 6-month incidence of ≥ 2 lines of visual acuity improvement in affected eyes was 52% (95% confidence interval [CI], 49%-55%). Vision reduced by ME was more likely to improve by 2 lines in eyes initially with poor visual acuity (≤ 20/200; adjusted hazard ratio [HR] 1.5; 95% CI, 1.3-1.7), active uveitis (HR, 1.3; 95% CI, 1.1-1.5), and anterior uveitis as opposed to intermediate (HR, 1.2), posterior (HR, 1.3), or panuveitis (HR, 1.4; overall P = 0.02). During follow-up, reductions in anterior chamber or vitreous cellular activity or in vitreous haze each led to significant improvements in visual outcome (P <0.001 for each). Conversely, snowbanking (HR, 0.7; 95% CI, 0.4-0.99), posterior synechiae (HR, 0.8; 95% CI, 0.6-0.9), and hypotony (HR, 0.2; 95% CI, 0.06-0.5) each were associated with lower incidence of visual improvement with respect to eyes lacking each of these attributes at a given visit. CONCLUSIONS: These results suggest that many, but not all, patients with ME causing low vision in a tertiary care setting will enjoy meaningful visual recovery in response to treatment. Evidence of significant ocular damage from inflammation (posterior synechiae and hypotony) portends a lower incidence of visual recovery. Better control of anterior chamber or vitreous activity is associated with a greater incidence of visual improvement, supporting an aggressive anti-inflammatory treatment approach for ME cases with active inflammation.


Asunto(s)
Edema Macular/fisiopatología , Uveítis/fisiopatología , Baja Visión/fisiopatología , Agudeza Visual/fisiología , Adulto , Anciano , Femenino , Angiografía con Fluoresceína , Antígeno HLA-B27/sangre , Humanos , Incidencia , Edema Macular/complicaciones , Edema Macular/diagnóstico , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Tomografía de Coherencia Óptica , Uveítis/etiología , Baja Visión/etiología , Adulto Joven
11.
Cell Rep Med ; 5(3): 101437, 2024 Mar 19.
Artículo en Inglés | MEDLINE | ID: mdl-38428428

RESUMEN

Leber hereditary optic neuropathy (LHON) is a mitochondrial disease leading to rapid and severe bilateral vision loss. Idebenone has been shown to be effective in stabilizing and restoring vision in patients treated within 1 year of onset of vision loss. The open-label, international, multicenter, natural history-controlled LEROS study (ClinicalTrials.gov NCT02774005) assesses the efficacy and safety of idebenone treatment (900 mg/day) in patients with LHON up to 5 years after symptom onset (N = 199) and over a treatment period of 24 months, compared to an external natural history control cohort (N = 372), matched by time since symptom onset. LEROS meets its primary endpoint and confirms the long-term efficacy of idebenone in the subacute/dynamic and chronic phases; the treatment effect varies depending on disease phase and the causative mtDNA mutation. The findings of the LEROS study will help guide the clinical management of patients with LHON.


Asunto(s)
Atrofia Óptica Hereditaria de Leber , Ubiquinona/análogos & derivados , Humanos , Atrofia Óptica Hereditaria de Leber/tratamiento farmacológico , Atrofia Óptica Hereditaria de Leber/genética , Atrofia Óptica Hereditaria de Leber/diagnóstico , Antioxidantes/uso terapéutico , Ubiquinona/uso terapéutico , Ubiquinona/genética , Mutación
12.
J AAPOS ; 27(4): 233-236, 2023 08.
Artículo en Inglés | MEDLINE | ID: mdl-37355012

RESUMEN

Well-known risk factors for anterior segment ischemia (ASI) following strabismus surgery include ipsilateral surgery on three or more rectus muscles, older age, and vasculopathy. ASI is rarely reported in young patients following uneventful strabismus surgery on two ipsilateral rectus muscles. We report a 30-year-old transgender female on long-term estrogen therapy who underwent strabismus surgery involving recessions of both lateral rectus muscles, the right inferior rectus muscle, and the left superior rectus muscle. The left eye developed severe ASI with hypotony maculopathy that was resistant to topical medications, oral steroids, anterior chamber reformation, and intravitreal steroid injection. Following phacoemulsification with intraocular lens and capsular tension ring insertion 1 year later, intraocular pressure and hypotony maculopathy improved.


Asunto(s)
Extracción de Catarata , Degeneración Macular , Enfermedades de la Retina , Estrabismo , Humanos , Femenino , Adulto Joven , Adulto , Estrabismo/cirugía , Estrabismo/complicaciones , Segmento Anterior del Ojo , Músculos Oculomotores/cirugía , Isquemia/etiología , Extracción de Catarata/efectos adversos , Estrógenos/uso terapéutico
13.
Retina ; 32(7): 1295-301, 2012 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-22466465

RESUMEN

PURPOSE: The purpose of this study was to report the rate of intraocular pressure (IOP) elevation after intravitreal injections of anti-vascular endothelial growth factor agents for exudative age-related macular degeneration. METHODS: Retrospective chart review of all patients receiving intravitreal ranibizumab and/or bevacizumab injections for exudative age-related macular degeneration from November 2005 to June 2010. Delayed ocular hypertension (OHT) was defined as either an IOP ≥22 mmHg on 2 consecutive visits (with an increase from baseline >6 mmHg) or an IOP >26 mmHg on a single visit with a concomitant initiation or augmentation of IOP-lowering treatment. Noninjected fellow eyes served as controls. Incidence of delayed OHT was analyzed using survival analyses, with risk assessed by Cox proportional hazards regression models. Eyes with glaucoma were evaluated separately. RESULTS: Three hundred and two treated eyes and 226 control eyes met inclusion criteria. In eyes with exudative age-related macular degeneration without glaucoma, 3 of 270 injected eyes (0.51% incidence per eye-year) developed delayed OHT compared with 4 of 195 control eyes (1.00% incidence per eye-year), a difference that was not statistically significant (hazard ratio = 0.48; 95% confidence interval: 0.11-2.23). In eyes with exudative age-related macular degeneration and glaucoma, 2 of 32 injected eyes developed delayed OHT (3.1% incidence per eye-year) compared with 3 of 31 control eyes (5.7% incidence per eye-year), a difference that was not statistically significant (hazard ratio = 0.59; 95% confidence interval: 0.10-3.60). CONCLUSION: The incidence of delayed OHT after intravitreal anti-vascular endothelial growth factor injections was low and did not differ between injected and control eyes, including eyes with glaucoma. These results argue against a significant risk of IOP elevation because of repeated anti-vascular endothelial growth factor therapy.


Asunto(s)
Inhibidores de la Angiogénesis/administración & dosificación , Anticuerpos Monoclonales Humanizados/administración & dosificación , Presión Intraocular/efectos de los fármacos , Degeneración Macular Húmeda/tratamiento farmacológico , Anciano , Bevacizumab , Quimioterapia Combinada , Exudados y Transudados , Femenino , Glaucoma/complicaciones , Humanos , Incidencia , Inyecciones Intravítreas , Masculino , Hipertensión Ocular/inducido químicamente , Modelos de Riesgos Proporcionales , Ranibizumab , Estudios Retrospectivos , Factores de Tiempo , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Degeneración Macular Húmeda/complicaciones
15.
J Neuroophthalmol ; 32(4): 313-20, 2012 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-22684127

RESUMEN

BACKGROUND: In cases of progressive optic neuropathy, diagnostic uncertainty often persists despite extensive work-up. Optic nerve biopsy (ONB) can be considered, especially when visual decline of the affected or fellow eye ensues despite empiric therapy. We aimed to evaluate both diagnostic and therapeutic utilities of ONB based on the long-term experience at a tertiary care institution. METHODS: This was a retrospective chart review of biopsies over 20 years at a single institution involving intrinsic or adherent optic nerve masses. Main outcome measures included the impact of tissue sampling on reaching a diagnosis and on guiding treatment. Secondary measures included vision in the eye of the ONB and the fellow eye. RESULTS: Fifteen patients with a mean age of 51.7 ± 17.4 years underwent biopsies. At the time of biopsy, visual acuity was no light perception in 8 (53%) eyes, light perception to counting fingers in 5 (33%), and 20/400 or better in 2 (13%). The fellow eye of 7 patients (47%) experienced some degree of sequential vision loss before biopsy. Seven specimens included en bloc biopsy of the nerve, 7 contained the dural sheath (usually with a portion of the optic nerve), and 1 only of the compressive mass. Six patients (40%) had tumors. Six of 8 inflammatory lesions biopsied required further clinical data to arrive at specific diagnoses. In one case, a clinical diagnosis could not be made. No patients experienced further vision loss in the fellow eye at last follow-up (median, 8 months). CONCLUSIONS: In diverse circumstances of progressive optic neuropathy, ONB can be beneficial in establishing the diagnosis. ONB can help direct specific local or systemic treatment, particularly when infectious or inflammatory etiologies are identified. ONB, if considered early in the disease course, can potentially halt or prevent vision loss when the fellow eye is threatened.


Asunto(s)
Enfermedades del Nervio Óptico/diagnóstico , Nervio Óptico/patología , Adulto , Anciano , Biopsia , Citocinas/metabolismo , Progresión de la Enfermedad , Femenino , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Enfermedades del Nervio Óptico/fisiopatología , Estudios Retrospectivos , Agudeza Visual
16.
Transl Vis Sci Technol ; 9(11): 20, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-33117611

RESUMEN

Purpose: The epithelium lining the ocular surface, which includes corneal and conjunctival epithelia, expresses the prosecretory chloride channel cystic fibrosis transmembrane conductance regulator (CFTR) and the proabsorptive epithelial sodium channel (ENaC). Here, methodology was established to measure the millivolt (mV) potential differences at the ocular surface, called ocular surface potential difference (OSPD), in human subjects produced by ion transport. Methods: OSPD was measured in human subjects in which a fluid-filled measuring electrode contacted a fluid pool created by eversion of the lateral lower eyelid, with a reference electrode placed subcutaneously in the forearm. Through the use of a high-impedance voltmeter, OSPD was measured continuously over 10 to 15 minutes in response to a series of perfusate fluid exchanges. Results: Baseline OSPD (± SEM) in six normal human subjects was -21.3 ± 3.6 mV. OSPD depolarized by 1.7 ± 0.6 mV following the addition of the ENaC inhibitor amiloride, hyperpolarized by 6.8 ± 1.5 mV with a zero chloride solution, and further hyperpolarized by 15.9 ± 1.6 mV following CFTR activation by isoproterenol. The isoproterenol-induced hyperpolarization was absent in two cystic fibrosis subjects lacking functional CFTR. OSPD measurement produced minimal epithelial injury. Conclusions: Our results establish the feasibility and safety of OSPD measurement in humans and demonstrate robust CFTR activity, albeit minimal ENaC activity, at the ocular surface. OSPD measurement may be broadly applicable to investigate fluid transport mechanisms and test drug candidates to treat ocular surface disorders. Translational Relevance: To the best of our knowledge, this is the first measurement of the electrical potential generated by the ocular surface epithelium in human subjects, offering a new approach to study ocular surface function and health.


Asunto(s)
Fibrosis Quística , Canales Epiteliales de Sodio , Transporte Iónico , Fenómenos Fisiológicos Oculares , Amilorida , Canales Epiteliales de Sodio/metabolismo , Ojo , Humanos , Sujetos de Investigación
17.
J Ocul Pharmacol Ther ; 36(3): 147-153, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-31934802

RESUMEN

Purpose: Dry eye disorders are a major health care burden. We previously reported the identification of N-methyl-N-phenyl-6-(2,2,3,3-tetrafluoropropoxy)-1,3,5-triazine-2,4-diamine [cystic fibrosis transmembrane conductance regulator (CFTR)act-K267], which activated human wild-type CFTR chloride conductance with EC50 ∼ 30 nM. Here, we report in vivo evidence for CFTRact-K267 efficacy in an experimental mouse model of dry eye using a human compatible ophthalmic vehicle. Methods: CFTR activation in mice in vivo was demonstrated by ocular surface potential difference (OSPD) measurements. Ocular surface pharmacodynamics was measured in tear fluid samples obtained at different times after topical administration of CFTRact-K267. Dry eye was produced by lacrimal duct cautery (LDC) and corneal epithelial injury and was assessed by Lissamine green (LG) staining. Results: OSPD measurements demonstrated a hyperpolarization of -8.6 ± 3 mV (standard error of the mean, 5 mice) in response to CFTRact-K267 exposure in low chloride solution that was reversed by a CFTR inhibitor. Following single-dose topical administration of 2 nmol CFTRact-K267, tear fluid CFTRact-K267 concentration was >500 nM for more than 6 h. Following LDC, corneal surface epithelial injury, as assessed by LG staining, was substantially reversed in 10 of 12 eyes receiving 2 nmol CFTRact-K267 3 times daily starting on day 2, when marked epithelial injury had already occurred. Improvement was seen in 3 of 12 vehicle-treated eyes. Conclusion: These studies provide in vivo evidence in mice for the efficacy of a topical, human use compatible CFTRact-K267 formulation in stimulating chloride secretion and reversing corneal epithelial injury in dry eye.


Asunto(s)
Lesiones de la Cornea/tratamiento farmacológico , Regulador de Conductancia de Transmembrana de Fibrosis Quística/agonistas , Síndromes de Ojo Seco/tratamiento farmacológico , Triazinas/farmacología , Administración Tópica , Animales , Benzoatos/administración & dosificación , Benzoatos/farmacología , Cauterización/efectos adversos , Canales de Cloruro/efectos de los fármacos , Modelos Animales de Enfermedad , Femenino , Aparato Lagrimal/fisiopatología , Colorantes Verde de Lisamina/química , Ratones , Ratones Endogámicos BALB C , Nanotecnología , Lágrimas/efectos de los fármacos , Tiazolidinas/administración & dosificación , Tiazolidinas/farmacología , Resultado del Tratamiento , Triazinas/administración & dosificación , Triazinas/farmacocinética , Triazinas/uso terapéutico
18.
Prog Retin Eye Res ; 27(4): 420-33, 2008 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-18501660

RESUMEN

The aquaporins (AQPs) are integral membrane proteins whose main function is to transport water across cell membranes in response to osmotic gradients. At the ocular surface, AQP1 is expressed in corneal endothelium, AQP3 and AQP5 in corneal epithelium, and AQP3 in conjunctival epithelium. AQPs are also expressed in lens fiber cells (AQP0), lens epithelium (AQP1), ciliary epithelium (AQP1, AQP4) and retinal Müller cells (AQP4). Mutations in AQP0 produce congenital cataracts in humans. Analysis of knockout mice lacking individual AQPs suggests their involvement in maintenance of corneal and lens transparency, corneal epithelial repair, intraocular pressure (IOP) regulation, retinal signal transduction and retinal swelling following injury. The mouse phenotype findings implicate AQPs as potential drug targets for therapy of elevated IOP and ocular disorders involving the cornea, lens and retina. However, much research remains in defining cell-level mechanisms for the ocular AQP functions, in establishing the relevance to human eye disease of conclusions from knockout mice, and in developing AQP-modulating drugs.


Asunto(s)
Acuaporinas/fisiología , Ojo/metabolismo , Fenómenos Fisiológicos Oculares , Transporte Biológico Activo , Córnea/metabolismo , Humanos , Cristalino/metabolismo , Retina/metabolismo
19.
Am J Ophthalmol Case Rep ; 13: 136-139, 2019 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-30705997

RESUMEN

PURPOSE: To report a diagnostically challenging case of cranial neuropathy due to perineural invasion by a basal cell carcinoma presenting 7.5 years after treatment of the primary tumor with Mohs micrographic surgery. OBSERVATIONS: A 62-year-old male with a history of Mohs micrographic surgery for basal cell carcinoma (BCC) of the left brow presented with insidious onset of diplopia and paresthesia localizing to the ipsilateral cranial nerves V1, V2, and VI. He had no evidence of recurrent cutaneous BCC. Magnetic resonance imaging of the orbits and skull base identified equivocal, subtle abnormalities in the ipsilateral superior orbital fissure and cavernous sinus, with normal appearance of the clinically involved nerve branches. A radiographically normal branch of cranial nerve V was biopsied and histopathology identified perineural invasion by recurrent basal cell carcinoma. CONCLUSIONS AND IMPORTANCE: The diagnosis of perineural invasion by BCC can pose several challenges, including subtle to absent imaging findings of clinically involved nerves and a lengthy latent period following primary tumor treatment. This case represents, to our knowledge, the longest reported interval between primary treatment and biopsy-proven recurrence with perineural invasion by BCC.

20.
Biochim Biophys Acta ; 1768(7): 1815-21, 2007 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-17506977

RESUMEN

Expression of urea transporter UT-B confers high urea permeability to mammalian erythrocytes. Erythrocyte membranes also permeate various urea analogues, suggesting common transport pathways for urea and structurally similar solutes. In this study, we examined UT-B-facilitated passage of urea analogues and other neutral small solutes by comparing transport properties of wildtype to UT-B-deficient mouse erythrocytes. Stopped-flow light-scattering measurements indicated high UT-B permeability to urea and chemical analogues formamide, acetamide, methylurea, methylformamide, ammonium carbamate, and acrylamide, each with P(s)>5.0 x 10(-6) cm/s at 10 degrees C. UT-B genetic knockout and phloretin treatment of wildtype erythrocytes similarly reduced urea analogue permeabilities. Strong temperature dependencies of formamide, acetamide, acrylamide and butyramide transport across UT-B-null membranes (E(a)>10 kcal/mol) suggested efficient diffusion of these amides across lipid bilayers. Urea analogues dimethylurea, acryalmide, methylurea, thiourea and methylformamide inhibited UT-B-mediated urea transport by >60% in the absence of transmembrane analogue gradients, supporting a pore-blocking mechanism of UT-B inhibition. Differential transport efficiencies of urea and its analogues through UT-B provide insight into chemical interactions between neutral solutes and the UT-B pore.


Asunto(s)
Proteínas de Transporte de Membrana/metabolismo , Urea/análogos & derivados , Acrilamida/farmacología , Animales , Permeabilidad de la Membrana Celular , Difusión , Eritrocitos/metabolismo , Formamidas/farmacología , Membrana Dobles de Lípidos/metabolismo , Compuestos de Metilurea/farmacología , Ratones , Ratones Transgénicos , Tiourea/farmacología , Urea/metabolismo
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