RESUMO
BACKGROUND: Late infantile neuronal ceroid lipofuscinosis (LINCL), one form of Batten's disease is a progressive neurodegenerative disorder resulting from a CLN2 gene mutation. The spectrum of ophthalmic manifestations of LINCL and the relationship with neurological function has not been previously described. METHODS: Patients underwent ophthalmic evaluations, including anterior segment and dilated exams, optical coherence tomography, fluorescein and indocyanine green angiography. Patients were also assessed with the LINCL Neurological Severity Scale. Ophthalmic findings were categorized into one of five severity scores, and the association of the extent of ocular disease with neurological function was assessed. RESULTS: Fifty eyes of 25 patients were included. The mean age at the time of exam was 4.9 years (range 2.5 to 8.1). The mean ophthalmic severity score was 2.6 (range 1 to 5). The mean neurological severity score was 6.1 (range 2 to 11). Significantly more severe ophthalmic manifestations were observed among older patients (p<0.005) and patients with more severe neurological findings (p<0.03). A direct correlation was found between the Ophthalmic Severity Scale and the Weill Cornell Neurological Scale (p<0.002). A direct association was also found between age and the ophthalmic manifestations (p<0.0002), with older children having more severe ophthalmic manifestations. CONCLUSIONS: Ophthalmic manifestations of LINCL correlate closely with the degree of neurological function and the age of the patient. The newly established LINCL Ophthalmic Scale may serve as an objective marker of LINCL severity and disease progression, and may be valuable in the evaluation of novel therapeutic strategies for LINCL, including gene therapy.
Assuntos
Oftalmopatias/etiologia , Oftalmopatias/patologia , Oftalmopatias/fisiopatologia , Lipofuscinoses Ceroides Neuronais/complicações , Lipofuscinoses Ceroides Neuronais/patologia , Lipofuscinoses Ceroides Neuronais/fisiopatologia , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Aminopeptidases/genética , Dipeptidil Peptidases e Tripeptidil Peptidases/genética , Oftalmopatias/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Lipofuscinoses Ceroides Neuronais/genética , Serina Proteases/genética , Índice de Gravidade de Doença , Tripeptidil-Peptidase 1Assuntos
Epinefrina/efeitos adversos , Procedimentos Cirúrgicos Nasais , Doenças Retinianas/induzido quimicamente , Vasoconstritores/efeitos adversos , Doença Aguda , Adulto , Eletrorretinografia , Angiofluoresceinografia , Humanos , Masculino , Septo Nasal/cirurgia , Doenças Retinianas/diagnóstico , Escotoma/induzido quimicamente , Escotoma/diagnóstico , Tomografia de Coerência Óptica , Conchas Nasais/cirurgia , Acuidade VisualRESUMO
PURPOSE: To describe the utility of using ultra-widefield digital fundus photography and ultra-widefield fluorescein angiography (UWFA) in the pediatric patient population to evaluate peripheral retinal pathology and to manage Coats' disease and familial exudative vitreoretinopathy (FEVR). METHODS: Retrospective review of pediatric retinal patients with FEVR or Coats' disease who underwent ultra-widefield fundus photography and UWFA. RESULTS: Eight patients were included in this case series. Five patients had the clinical diagnosis of FEVR, and two eyes of two patients with FEVR received UWFA-guided laser photocoagulation. Three patients were diagnosed as having Coats' disease and received UWFA-guided laser photocoagulation. CONCLUSIONS: Ultra-widefield fundus photography and UWFA can be used successfully as an outpatient procedure in the pediatric patient population without the necessity of examination under anesthesia and can aid the physician in the documentation and evaluation of peripheral retinal pathology. UWFA can also assist in directing laser photocoagulation in the treatment of pediatric retinal diseases.
Assuntos
Angiofluoresceinografia , Fotocoagulação a Laser , Osteoporose/diagnóstico , Telangiectasia Retiniana/diagnóstico , Vitreorretinopatia Proliferativa/diagnóstico , Adolescente , Criança , Diagnóstico por Imagem , Vitreorretinopatias Exsudativas Familiares , Humanos , Masculino , Osteoporose/fisiopatologia , Osteoporose/cirurgia , Fotografação , Telangiectasia Retiniana/fisiopatologia , Telangiectasia Retiniana/cirurgia , Estudos Retrospectivos , Tomografia de Coerência Óptica , Acuidade Visual/fisiologia , Vitreorretinopatia Proliferativa/fisiopatologia , Vitreorretinopatia Proliferativa/cirurgiaRESUMO
The synthesis and biological evaluation of novel Tie-2 kinase inhibitors are presented. Based on the pyrrolopyrimidine chemotype, several new series are described, including the benzimidazole series by linking a benzimidazole to the C5-position of the 4-amino-pyrrolopyrimidine core and the ketophenyl series synthesized by incorporating a ketophenyl group to the C5-position. Medicinal chemistry efforts led to potent Tie-2 inhibitors. Compound 15, a ketophenyl pyrrolopyrimidine urea analog with improved physicochemical properties, demonstrated favorable in vitro attributes as well as dose responsive and robust oral tumor growth inhibition in animal models.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Descoberta de Drogas , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Pirróis/farmacologia , Receptor TIE-2/antagonistas & inibidores , Animais , Antineoplásicos/administração & dosagem , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Masculino , Estrutura Molecular , Neoplasias/enzimologia , Neoplasias/patologia , Inibidores de Proteínas Quinases/administração & dosagem , Pirimidinas/síntese química , Pirimidinas/química , Pirróis/síntese química , Pirróis/química , Ratos , Ratos Sprague-Dawley , Receptor TIE-2/metabolismo , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
PURPOSE: To determine the relationship between retinal ischaemia and the presence of macular oedema (DMO) in patients with diabetic retinopathy (DR) using ultra-widefield fluorescein angiography (UWFA) imaging. METHODS: A retrospective review of 122 eyes of 70 treatment-naïve diabetic patients who underwent diagnostic UWFA using the Optos 200Tx imaging system. Two independent, masked graders quantified the area of retinal ischaemia. Based on clinical examination and optical coherence tomography (OCT), each patient was given a binary classification as either having DMO or no DMO. McNemar's test (with Yates' correction as indicated) and a two-sample test of proportions were used to determine the relationship between DMO and ischaemia for binary and proportional data, respectively. Linear and logistic models were constructed using generalised estimating equations to test relationships between independent variables, covariates and outcomes while controlling for inter-eye correlation, age, gender, haemoglobin A1c, mean arterial pressure and dependence on insulin. RESULTS: Seventy-six eyes (62%) exhibited areas of retinal ischaemia. There was a significant direct correlation between DMO and peripheral retinal ischaemia as seen on UWFA (p<0.001). In addition, patients with retinal ischaemia had 3.75 times increased odds of having DMO compared with those without retinal ischaemia (CI 1.26 to 11.13, p<0.02). CONCLUSION: Retinal ischaemia is significantly correlated with DMO in treatment-naïve patients with DR. UWFA is a useful tool for detecting peripheral retinal ischaemia, which may have direct implications in the diagnosis, follow-up and treatment such as targeted peripheral photocoagulation.
Assuntos
Retinopatia Diabética/fisiopatologia , Angiofluoresceinografia , Isquemia/fisiopatologia , Edema Macular/fisiopatologia , Vasos Retinianos/fisiopatologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Retinopatia Diabética/diagnóstico , Feminino , Humanos , Isquemia/diagnóstico , Edema Macular/diagnóstico , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Tomografia de Coerência Óptica , Adulto JovemRESUMO
PURPOSE: To evaluate patients with diabetic retinopathy using ultra-wide-field fluorescein angiography and to compare the visualized retinal pathology with that seen on an overly of conventional 7 standard field (7SF) imaging. METHODS: Two hundred and eighteen eyes of 118 diabetic patients who underwent diagnostic fluorescein angiography using the Optos Optomap Panoramic 200A imaging system were included. The visualized area of the retina, retinal nonperfusion, retinal neovascularization, and panretinal photocoagulation were quantified by two independent masked graders. The respective areas identified on the ultra-wide-field fluorescein angiography image were compared with an overly of a modified 7SF image as outlined in the Early Treatment Diabetic Retinopathy Study. RESULTS: Ultra-wide-field fluorescein angiograms imaging, on average, demonstrated 3.2 times more total retinal surface area than 7SF. When compared with 7SF, ultra-wide-field fluorescein angiography showed 3.9 times more nonperfusion (P < 0.001), 1.9 times more neovascularization (P = 0.036), and 3.8 times more panretinal photocoagulation (P < 0.001). In 22 eyes (10%), ultra-wide-field fluorescein angiography demonstrated retinal pathology (including nonperfusion and neovascularization) not evident in an 7SF overly. CONCLUSION: Compared with conventional 7SF imaging, ultra-wide-field fluorescein angiography reveals significantly more retinal vascular pathology in patients with diabetic retinopathy. Improved retinal visualization may alter the classification of diabetic retinopathy and may therefore influence follow-up and treatment of these patients.
Assuntos
Retinopatia Diabética/diagnóstico , Angiofluoresceinografia/métodos , Oftalmoscopia/métodos , Idoso , Retinopatia Diabética/classificação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
The synthesis and structure-activity relationships for a novel series of 6-amino-4-(pyrimidin-4-yl)pyridones derived from a high throughput screening hit are discussed. Optimization of lead matter afforded compounds with good potency, selectivity and central nervous system (CNS) exposure.
Assuntos
Quinases da Glicogênio Sintase/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Piridonas/síntese química , Sistema Nervoso Central/efeitos dos fármacos , Cristalografia por Raios X , Humanos , Concentração Inibidora 50 , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/farmacologia , Piridonas/química , Piridonas/farmacologia , Relação Estrutura-AtividadeRESUMO
A 46-year-old woman presented after blunt facial trauma for evaluation of bilateral orbital floor fractures, which were confirmed by clinical and radiographic examination. In addition, findings of right traumatic mydriasis and left traumatic ptosis were seen. On close investigation, miosis was noted on the side of the traumatic ptosis. Therefore, a workup for Horner syndrome was obtained, including neuro-ophthalmic consultation and magnetic resonance angiography of the neck. The magnetic resonance angiography showed an internal carotid pseudoaneurysm, an uncommon but potentially fatal complication of blunt carotid injury. The authors describe an interesting case where a life-threatening diagnosis was nearly masked by more common, benign pathology.
Assuntos
Blefaroptose/patologia , Lesões das Artérias Carótidas/diagnóstico , Artéria Carótida Interna/patologia , Traumatismos Faciais/patologia , Síndrome de Horner/diagnóstico , Midríase/patologia , Ferimentos não Penetrantes/patologia , Técnicas de Diagnóstico Oftalmológico , Traumatismos Oculares/patologia , Feminino , Humanos , Angiografia por Ressonância Magnética , Pessoa de Meia-Idade , Fraturas Orbitárias/patologia , Tomografia Computadorizada por Raios XRESUMO
PURPOSE: To describe a case of Lisch dystrophy; review the clinical, histopathologic, and electron microscopic features of this entity; and discuss a novel treatment approach using photorefractive keratectomy (PRK) and mitomycin C (MMC). METHODS: A 45-year-old man with a feathery, comet-shaped, right-sided, corneal lesion was treated with excimer laser PRK and 20 seconds of MMC. The uninvolved fellow eye underwent traditional PRK without the use of MMC. Epithelial scrapings were sent for histopathologic analysis. RESULTS: Histopathologic analysis showed vacuolated cells in the epithelial layer. Electron microscopy revealed empty intracytoplasmic vacuoles, electron-dense whorled inclusions, and reduced tonofilaments. Surface ablation and MMC was successful in treating the initial lesion, with only minimal recurrence noted in the affected eye. Surprisingly, a new asymptomatic lesion was noted in the unaffected eye but dissipated over time. CONCLUSIONS: Although the whorled inclusions represent a novel finding, the overall clinical and microscopic analysis was consistent with Lisch dystrophy. Surface ablation with MMC should be considered as a treatment option for this disease.
Assuntos
Alquilantes/uso terapêutico , Distrofias Hereditárias da Córnea/tratamento farmacológico , Distrofias Hereditárias da Córnea/cirurgia , Lasers de Excimer/uso terapêutico , Mitomicina/uso terapêutico , Ceratectomia Fotorrefrativa , Terapia Combinada , Distrofias Hereditárias da Córnea/patologia , Humanos , Masculino , Microscopia Confocal , Pessoa de Meia-Idade , Acuidade VisualRESUMO
As exemplified by the lead compound 2, octahydrophenanthrene-2,7-diol analogues exhibit the profile of a pathway-selective or "dissociated" agonist of the glucocorticoid receptor (GR), retaining the potent activity that glucocorticoids have for transrepression (as measured by inhibition of IL-1 induced MMP-13 expression) but showing an attenuated capacity for transactivation (as measured in an MMTV luciferase reporter assay). With the guidance of a homology model of the GR ligand binding domain, structural modifications to 2 were carried out that were successful in replacing the allyl and propynyl side chains with groups likely to be more chemically stable and less likely to produce toxic metabolites. Key to success was the introduction of an additional hydroxyl group onto the tricyclic carbon framework of the series.
Assuntos
Descoberta de Drogas , Fenantrenos/farmacologia , Receptores de Glucocorticoides/agonistas , Cromatografia Líquida de Alta Pressão , Cristalografia por Raios X , Espectrometria de Massas , Modelos Moleculares , Fenantrenos/químicaRESUMO
A 90-year-old man reported a 1-year history of tearing and irritation in the left eye. Ophthalmic examination was significant for bloody mucopurulent material expressed from the left nasolacrimal duct. The patient underwent external dacryocystorhinostomy with excision of a soft-tissue mass. Initial histopathologic examination of the specimen revealed an atypical lymphoid infiltrate. Subsequent immunohistochemistry suggested that the mass was reactive lymphoid hyperplasia. Lymphoid hyperplasia should be considered in the differential diagnosis of bloody epiphora, in addition to primary malignancy of the nasolacrimal duct, hematologic abnormalities, coagulopathies, vascular tumors, and giant papillary conjunctivitis.
Assuntos
Hemorragia Ocular/diagnóstico , Doenças do Aparelho Lacrimal/diagnóstico , Ducto Nasolacrimal/patologia , Pseudolinfoma/diagnóstico , Idoso de 80 Anos ou mais , Dacriocistorinostomia , Humanos , Doenças do Aparelho Lacrimal/cirurgia , Masculino , Pseudolinfoma/cirurgiaRESUMO
The design, synthesis, and biological evaluation of potent inhibitors of the TrkA kinase is presented. A homology model is created to aid in the enhancement of potency and selectivity of isothiazole inhibitors found during a high-throughput screen. Three different syntheses are utilized to make diverse analogs within this series. Aminoheterocycles are found to be good urea surrogates, whereas bicyclic substituents on the C3 thio group were found to be extremely potent TrkA inhibitors in kinase and cell assays.
Assuntos
Simulação por Computador , Inibidores Enzimáticos , Receptor trkA/antagonistas & inibidores , Tiazóis , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos , Modelos Moleculares , Estrutura Molecular , Estereoisomerismo , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/química , Tiazóis/farmacologiaRESUMO
A series of ligands with varying heterocyclic cores and substituents that display a range of selectivity's (up to >100x) for ER-beta over ER-alpha are reported.
Assuntos
Receptor beta de Estrogênio/metabolismo , Compostos Heterocíclicos/farmacocinética , Linhagem Celular Tumoral , Cristalografia por Raios X , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/química , Compostos Heterocíclicos/síntese química , Humanos , Indicadores e Reagentes , Cinética , Ligantes , Moduladores Seletivos de Receptor Estrogênico/química , Relação Estrutura-AtividadeRESUMO
The discovery of small molecule kinase inhibitors for use as drugs is a promising approach for the treatment of cancer and other diseases, but the discovery of highly specific agents is challenging because over 850 kinases are expressed in mammalian cells. Systematic modification of the 4-anilino functionality of a selective quinazoline inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase can invert selectivity to favor inhibition of the highly homologous erbB2 tyrosine kinase. The selectivity pattern was demonstrated in assays of recombinant kinases and recapitulated in measures of kinase activity in intact cells. The most potent and selective erbB2 inhibitor of the analog series has anti-proliferative activity against an erbB2-overexpressing cell line that was lacking in the original EGFR-selective compound. Subtle changes to the molecular structure of ATP-competitive small molecule inhibitors of tyrosine kinases can yield dramatic changes in potency and selectivity. These results suggest that the discovery of highly selective small molecule inhibitors of very homologous kinases is achievable.