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Primary tumors of the lacrimal sac are extremely rare and predominantly epithelial in origin. We report a unique case of fibromyxoma of the lacrimal sac in an 86-year-old Caucasian woman who presented with 3 months of lower eyelid edema and 1 week of purulent discharge, epiphora, and acute pain. Examination revealed right lower eyelid erythema/edema and a tender, firm, palpable mass of the right lacrimal sac, which self-expressed a yellow, purulent discharge. On surgical exploration, a firm, rubbery, yellow mass was encountered and excised. Histopathologic analysis identified a nonencapsulated mass composed of loose interlacing fascicles and bundles of spindle-shaped cells with prominent myxoid changes; immunostaining was strongly positive for vimentin, weakly for smooth muscle actin, and negative for S-100 and muscle-specific actin. These findings were consistent with the diagnosis of a fibromyxoma of the lacrimal drainage system. After excision, the patient did well, with resolution of dacryocystitis.
Assuntos
Dacriocistite/diagnóstico , Neoplasias Oculares/diagnóstico , Fibroma/diagnóstico , Doenças do Aparelho Lacrimal/diagnóstico , Idoso de 80 Anos ou mais , Diagnóstico Diferencial , Neoplasias Oculares/cirurgia , Feminino , Fibroma/cirurgia , Humanos , Doenças do Aparelho Lacrimal/cirurgiaRESUMO
Purpose: To report a case of iatrogenic vitrectomy trochar-induced cyclodialysis cleft successfully treated with intraoperative argon endolaser. Observations: A 68-year-old Caucasian male with a history of high myopia underwent pars plana vitrectomy to clear symptomatic vitreous opacities but developed early postoperative hypotony that was recalcitrant to medical management for the first 6 postoperative months. Intraoperative gonioscopy demonstrated a cyclodialysis cleft and argon endolaser was applied to close the cleft. Conclusions and Importance: Endolaser is an effective treatment for cyclodialysis clefts and intraoperative gonioscopy allows direct visualization of the cleft in a controlled operating room setting. Placement of vitrectomy ports should be done with care in high myopes to avoid accidental piercing of the ciliary body and inducing a cyclodialysis cleft.
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Purpose: To determine if intravitreal anti-vascular endothelial growth factor (anti-VEGF) injections are associated with an increased risk of glaucoma drainage device (GDD) erosions. Patients and Methods: A retrospective chart review was conducted including patients with diabetic retinopathy and had a GDD implanted at a large academic institution. The rate of GDD erosions was compared between eyes that did or did not receive intravitreal anti-VEGF injections. A subanalysis was also performed the relationship between diabetic macular edema (DME) and intravitreal steroid injections and GDD erosions. Results: A total of 677 eyes from 608 patients was included. A total of 447 eyes received at least one anti-VEGF injection; 230 eyes never received such therapy. Twenty eyes (4.5%) receiving anti-VEGF had at least one erosion event, compared to 7 eyes (3.0%) of patients not receiving anti-VEGF therapy (OR 1.49, p=0.37). Diabetic macular edema was associated with a significantly increased rate of erosion in eyes not receiving anti-VEGF (71.4% versus 31.4%, p=0.034), but not in eyes receiving anti-VEGF (30.0% versus 40.7%, p=0.34). Receiving more than one specific anti-VEGF agent, an increased frequency or total number of anti-VEGF injections, or receiving intravitreal steroids were not associated with an increased risk of erosion (p>0.05). Conclusion: In patients with diabetic retinopathy, the use of anti-VEGF does not result in an increased rate of GDD erosions or recurrent erosions. Further research is needed over a longer follow-up period to determine if longer or more frequent anti-VEGF treatment is a risk factor for recurrent erosions.
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OBJECTIVE: Motivated by the central roles that vascular endothelial growth factor (VEGF) and transforming growth factor (TGF)-beta play in the assembly and maintenance of the vasculature, we examined the impact of systemic VEGF or TGF-beta signal inhibition on endothelial activation as detected by leukocyte-endothelial interactions. METHODS AND RESULTS: VEGF or TGF-beta inhibition, accomplished using adenovirus expression of soluble Flt1 (Ad-sFlt1) or soluble endoglin (Ad-sEng), resulted in a significant increase in the number of leukocytes rolling along the mesenteric venous endothelium and a significant decrease in rolling velocity in Ad-sEng mice. Neutralization of VEGF or TGF-beta resulted in endothelial surface expression of P-selectin and impaired peripheral vasodilatation. Neither inhibition of VEGF nor TGF-beta was associated with platelet or leukocyte activation, as detected by the activation markers platelet P-selectin and the active integrin alphaIIbbetaIII, or by leukocyte expression of L-selectin. Soluble vascular cell adhesion molecule (VCAM)-1 and E-selectin were increased in sEng-expressing mice, indicating higher levels of these adhesion receptors. CONCLUSIONS: VEGF or TGF-beta neutralization leads to impaired endothelium-mediated vasodilatation and elevated expression of surface adhesion molecules, resulting in increased leukocyte adhesion. These results indicate an essential role for both VEGF and TGF-beta in maintaining the endothelium in a nonactivated state and have implications for therapeutic approaches that neutralize VEGF or TGF-beta.
Assuntos
Endotélio Vascular/citologia , Leucócitos/metabolismo , Transdução de Sinais/fisiologia , Fator de Crescimento Transformador beta/antagonistas & inibidores , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Vasodilatação/fisiologia , Animais , Adesão Celular , Selectina E/biossíntese , Endotélio Vascular/metabolismo , Contagem de Leucócitos , Leucócitos/citologia , Veias Mesentéricas/citologia , Veias Mesentéricas/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Selectina-P/biossíntese , Fator de Crescimento Transformador beta/metabolismo , Molécula 1 de Adesão de Célula Vascular/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
BACKGROUND/AIMS: The main aim of this study was to evaluate the safety and efficacy of diode laser transscleral cyclophotocoagulation (TSCPC) in eyes with good visual acuity. PATIENTS AND METHODS: A retrospective chart review identified patients who underwent TSCPC for uncontrolled intraocular pressure (IOP) from 2014 to 2016. Enrollment criteria included pretreatment best-corrected visual acuity (BCVA) of 20 of 40 or better, and a minimum of 6 months of postoperative follow-up. RESULTS: Thirty-three eyes of 33 patients(mean age, 72.1±16.0 y) were enrolled (mean follow-up 12.6±6.1 mo). The mean (SD) IOP was reduced 48.3% from 27.1 mm Hg (7.8) at baseline to 13.1 mm Hg (4.2) at last follow-up. Reduction of ≥1 glaucoma medications was achieved in 17 eyes (51.5%) at last follow-up. The cumulative probability of complete success (BCVA loss <2 Snelling lines, 20% reduction IOP, no reoperation for glaucoma, no IOP<5 mm Hg) was 78.8% and 50% at months 6 and 12, respectively. The cumulative probability of qualified success (BCVA≥2 lines with ≥20% reduction IOP, no reoperation for glaucoma, no IOP<5 mm Hg) was 90.1% and 81.3% at month 6 and 1 year, respectively. Significant vision loss, defined as BCVA≥2 lines, occurred in 33% of patients. The most common complications were postoperative iritic (56.3%) and cystoid macular edema (12.5%). CONCLUSIONS: TSCPC demonstrates a strong reduction in IOP and glaucoma medication use. However, with significant vision loss in 33% of patients, future prospective studies with a comparison group receiving traditional glaucoma surgery are needed to determine comparative safety and efficacy.
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Glaucoma/cirurgia , Fotocoagulação a Laser/métodos , Lasers Semicondutores/uso terapêutico , Hipertensão Ocular/cirurgia , Procedimentos Cirúrgicos Oftalmológicos/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Corpo Ciliar/cirurgia , Feminino , Humanos , Pressão Intraocular/fisiologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Acuidade VisualRESUMO
BACKGROUND: By screening a plasmid library for proteins that could cause silencing when targeted to the HMR locus in Saccharomyces cerevisiae, we previously reported the identification of Rtt107/Esc4 based on its ability to establish silent chromatin. In this study we aimed to determine the mechanism of Rtt107/Esc4 targeted silencing and also learn more about its biological functions. RESULTS: Targeted silencing by Rtt107/Esc4 was dependent on the SIR genes, which encode obligatory structural and enzymatic components of yeast silent chromatin. Based on its sequence, Rtt107/Esc4 was predicted to contain six BRCT motifs. This motif, originally identified in the human breast tumor suppressor gene BRCA1, is a protein interaction domain. The targeted silencing activity of Rtt107/Esc4 resided within the C-terminal two BRCT motifs, and this region of the protein bound to Sir3 in two-hybrid tests. Deletion of RTT107/ESC4 caused sensitivity to the DNA damaging agent MMS as well as to hydroxyurea. A two-hybrid screen showed that the N-terminal BRCT motifs of Rtt107/Esc4 bound to Slx4, a protein previously shown to be involved in DNA repair and required for viability in a strain lacking the DNA helicase Sgs1. Like SLX genes, RTT107ESC4 interacted genetically with SGS1; esc4Delta sgs1Delta mutants were viable, but exhibited a slow-growth phenotype and also a synergistic DNA repair defect. CONCLUSION: Rtt107/Esc4 binds to the silencing protein Sir3 and the DNA repair protein Slx4 via different BRCT motifs, thus providing a bridge linking silent chromatin to DNA repair enzymes.
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Motivos de Aminoácidos/genética , Cromatina/metabolismo , Proteínas Nucleares/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/genética , Sequência de Aminoácidos , Sítios de Ligação/genética , Reparo do DNA , Endodesoxirribonucleases/genética , Endodesoxirribonucleases/metabolismo , Inativação Gênica , Dados de Sequência Molecular , Proteínas Nucleares/genética , Ligação Proteica , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Homologia de Sequência de Aminoácidos , Proteínas Reguladoras de Informação Silenciosa de Saccharomyces cerevisiae/genética , Proteínas Reguladoras de Informação Silenciosa de Saccharomyces cerevisiae/metabolismo , Técnicas do Sistema de Duplo-HíbridoRESUMO
Pericyte-endothelial cell (EC) interactions are critical to both vascular development and vessel stability. We have previously shown that TGF-beta signaling between EC and mural cells participates in vessel stabilization in vitro. We therefore investigated the role of TGF-beta signaling in maintaining microvessel structure and function in the adult mouse retinal microvasculature. TGF-beta signaling was inhibited by systemic expression of soluble endoglin (sEng) and inhibition was demonstrated by reduced phospho-smad2 in the adult retina. Blockade of TGF-beta signaling led to increased vascular and neural cell apoptosis in the retina, which was associated with decreased retinal function, as measured by electroretinogram (ERG). Perfusion of the inner retinal vasculature was impaired and was accompanied by defective autoregulation and loss of capillary integrity. Fundus angiography and Evans blue permeability assay revealed a breakdown of the blood-retinal-barrier that was characterized by decreased association between the tight junction proteins zo-1 and occludin. Inhibition of TGF-beta signaling in cocultures of EC and 10T1/2 cells corroborated the in vivo findings, with impaired EC barrier function, dissociation of EC from 10T1/2 cells, and endothelial cell death, supporting the role of EC-mesenchymal interactions in TGF-beta signaling. These results implicate constitutive TGF-beta signaling in maintaining the integrity and function of the adult microvasculature and shed light on the potential role of TGF-beta signaling in vasoproliferative and vascular degenerative retinal diseases.
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Endotélio Vascular/fisiologia , Homeostase , Receptores de Fatores de Crescimento Transformadores beta/fisiologia , Animais , DNA Complementar , Endotélio Vascular/ultraestrutura , Marcação In Situ das Extremidades Cortadas , Camundongos , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de SinaisRESUMO
Although the role of vascular endothelial growth factor (VEGF) in developmental and pathological angiogenesis is well established, its function in the adult is less clear. Similarly, although transforming growth factor (TGF) beta is involved in angiogenesis, presumably by mediating capillary (endothelial cell [EC]) stability, its involvement in quiescent vasculature is virtually uninvestigated. Given the neurological findings in patients treated with VEGF-neutralizing therapy (bevacizumab) and in patients with severe preeclampsia, which is mediated by soluble VEGF receptor 1/soluble Fms-like tyrosine kinase receptor 1 and soluble endoglin, a TGF-beta signaling inhibitor, we investigated the roles of VEGF and TGF-beta in choroid plexus (CP) integrity and function in adult mice. Receptors for VEGF and TGF-beta were detected in adult CP, as well as on ependymal cells. Inhibition of VEGF led to decreased CP vascular perfusion, which was associated with fibrin deposition. Simultaneous blockade of VEGF and TGF-beta resulted in the loss of fenestrae on CP vasculature and thickening of the otherwise attenuated capillary endothelium, as well as the disappearance of ependymal cell microvilli and the development of periventricular edema. These results provide compelling evidence that both VEGF and TGF-beta are involved in the regulation of EC stability, ependymal cell function, and periventricular permeability.
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Plexo Corióideo/metabolismo , Epêndima/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Adenoviridae/genética , Animais , Permeabilidade Capilar , Plexo Corióideo/ultraestrutura , Células Endoteliais/metabolismo , Epêndima/ultraestrutura , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos , Microscopia Eletrônica de Transmissão , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Receptor do Fator de Crescimento Transformador beta Tipo II , Receptores de Fatores de Crescimento Transformadores beta/genética , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Fator de Crescimento Transformador beta1/genética , Fator A de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismoRESUMO
BACKGROUND: Vascular endothelial growth factor (VEGF) is well known for its role in normal and pathologic neovascularization. However, a growing body of evidence indicates that VEGF also acts on non-vascular cells, both developmentally as well as in the adult. In light of the widespread use of systemic and intraocular anti-VEGF therapies for the treatment of angiogenesis associated with tumor growth and wet macular degeneration, systematic investigation of the role of VEGF in the adult retina is critical. METHODS AND FINDINGS: Using immunohistochemistry and Lac-Z reporter mouse lines, we report that VEGF is produced by various cells in the adult mouse retina and that VEGFR2, the primary signaling receptor, is also widely expressed, with strong expression by Müller cells and photoreceptors. Systemic neutralization of VEGF was accomplished in mice by adenoviral expression of sFlt1. After 14 days of VEGF neutralization, there was no effect on the inner and outer retina vasculature, but a significant increase in apoptosis of cells in the inner and outer nuclear layers. By four weeks, the increase in neural cell death was associated with reduced thickness of the inner and outer nuclear layers and a decline in retinal function as measured by electroretinograms. siRNA-based suppression of VEGF expression in a Müller cell line in vitro supports the existence of an autocrine role for VEGF in Müller cell survival. Similarly, the addition of exogenous VEGF to freshly isolated photoreceptor cells and outer-nuclear-layer explants demonstrated VEGF to be highly neuroprotective. CONCLUSIONS: These results indicate an important role for endogenous VEGF in the maintenance and function of adult retina neuronal cells and indicate that anti-VEGF therapies should be administered with caution.
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Células Fotorreceptoras de Vertebrados/fisiologia , Fator A de Crescimento do Endotélio Vascular/fisiologia , Visão Ocular/genética , Envelhecimento/genética , Envelhecimento/metabolismo , Animais , Apoptose/genética , Comunicação Autócrina/genética , Comunicação Autócrina/fisiologia , Sobrevivência Celular/genética , Óperon Lac , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Células Fotorreceptoras de Vertebrados/metabolismo , Retina/metabolismo , Retina/fisiologia , Neovascularização Retiniana/genética , Neovascularização Retiniana/metabolismo , Neurônios Retinianos/metabolismo , Neurônios Retinianos/fisiologia , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismoRESUMO
The role of VEGF during development and in pathology is well known, but its function in normal adult tissues is poorly understood. Adverse effects associated with the use of anti-angiogenic therapies targeting VEGF in human pathologies have begun to reveal potential functions of VEGF in quiescent vasculature. Further clues from expression studies of VEGF and its receptors in the adult, from the disease preeclampsia, and from experimental neutralization studies, have suggested that VEGF is involved in endothelial cell survival and fenestration, as well as in the signaling and maintenance of non-endothelial cells. The various biochemical properties of VEGF, and its interaction with other growth factors, may be an important point in determining whether VEGF functions as a maintenance factor versus an angiogenic factor. A thorough understanding of the function of VEGF in the adult may lead to more efficacious pro- and anti-angiogenic therapies.
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Fator A de Crescimento do Endotélio Vascular/fisiologia , Adulto , Inibidores da Angiogênese/farmacologia , Humanos , Receptores de Fatores de Crescimento do Endotélio Vascular/fisiologia , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
Although vascular endothelial growth factor (VEGF) has been well studied in both developmental and pathological angiogenesis, its role in mature blood vessels is poorly understood. A growing body of observations, including the side effects of anti-VEGF therapies as well as the role of soluble VEGFR1 in preeclampsia, points to an important role for VEGF in maintenance of stable blood vessels. To better understand the potential function of VEGF in mature vessels, a survey of VEGF localization in adult mice was conducted. In adult VEGF-lacZ mice, VEGF was expressed in a cell-specific manner by cells overlying fenestrated and sinusoidal blood vessels, including podocytes, choroid plexus epithelium, and hepatocytes, as well as in tissues with high metabolic demands or with secretory functions, such as cardiac and skeletal myocytes, Leydig cells, prostatic epithelium, and salivary serous epithelium. VEGF was not detected in most endothelium but was specifically expressed by aortic endothelial cells where VEGFR2 was found to be phosphorylated, indicating an autocrine loop. Additionally, VEGFR2 was constitutively phosphorylated in the liver, lung, adipose, and kidney in vivo, providing evidence consistent with a role for VEGF in adult tissues. These observations support the concept that VEGF acts in the adult to stabilize mature vessels.
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Epitélio/metabolismo , Epitélio/patologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Aorta/citologia , Aorta/metabolismo , Plexo Corióideo/citologia , Plexo Corióideo/metabolismo , Hepatócitos/citologia , Hepatócitos/metabolismo , Células Intersticiais do Testículo/citologia , Células Intersticiais do Testículo/metabolismo , Masculino , Camundongos , Células Musculares/citologia , Células Musculares/metabolismo , Fosforilação , Podócitos/metabolismo , Podócitos/patologia , Próstata/citologia , Próstata/metabolismo , Glândulas Salivares/citologia , Glândulas Salivares/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , beta-Galactosidase/genética , beta-Galactosidase/metabolismoRESUMO
The angiogenic molecule, vascular endothelial growth factor (VEGF), is a critical regulator of normal and pathologic angiogenesis. ErbB2, an epidermal growth factor receptor family member whose overexpression in mammary tumors is correlated with poor patient prognosis, has been implicated as a positive modulator of VEGF expression. Mammary tumor cells overexpressing ErbB2 (NAFA cells) and a normal mouse mammary cell line (HC11) transfected with ErbB2 expression vectors were used to study the effects of ErbB2 overexpression on VEGF regulation. We found that ErbB2 overexpression led to an increase in endogenous VEGF mRNA as well as ErbB3 protein levels in HC11 cells. Additionally, we determined that ErbB2 overexpression-mediated upregulation of VEGF involves at least two distinct promoter elements, one previously identified as the hypoxia responsive element and the other the core promoter region (-161 to -51bp), which is specifically controlled via two adjacent SP1 binding sites (-80 to -60bp).