miR-410 Regulates Helper T Cell Differentiation in Ovalbumin-Induced Asthma through the PI3K-AKT-VEGF Signaling Pathway.

INTRODUCTION: Asthma has been attributed to Th1/Th2 imbalance and inappropriate Th2 responses to environmental allergens. MicroRNAs (miRNAs), 21 to 23 RNA molecules, are first found in mammals and have been implicated in various biological activities. Our previous study found that miR-410 effectively ameliorates airway inflammation in the ovalbumin (OVA)-induced asthma murine model. However, the role of miR-410 in regulating helper T (Th) cell differentiation is not clear. In the present study, we aimed to explore the regulatory effects of miR-410 on the differentiation of Th cells through both in vivo and in vitro studies. METHODS: Dual-luciferase reporter assay was used to find if miR-410 has any direct binding position with VEGF mRNAs. PBMC and CD4+ T cells were isolated and stimulated with OVA. The miR-410 mimics and inhibitors were transfected into CD4+ T cells. The differentiation of Th cells was evaluated by enzyme-linked immunosorbent assay (ELISA) for the concentration of IL-4, IFN-γ, and TGF-ß levels in supernatants. Western Blot was used to detect protein expression and phosphorylation of PI3K and AKT. BALB/c mice were kept in a specific pathogen-free condition and received sterile OVA-free food and water. OVA-induced asthmatic mice model was established. ELISA was used to measure the bronchoalveolar lavage fluid (BALF) concentrations of IL-4, IFN-γ, TGF-ß, and VEGF. Hematoxylin and eosin staining and immunohistochemical staining were conducted to analyze inflammatory cell infiltration, pathological changes, and the expression of VEGF. RESULTS: Dual-luciferase reporter assay showed that miR-410 has no direct binding position with VEGF mRNAs. In the OVA-primed mononuclear cells compared to normal cells, IFN-γ and TGF-ß were decreased while IL-4 and VEGF were increased. This change was reversed while miRNA-410 mimics were transfected into CD4+ T cells. Besides, the OVA-primed CD4+ T cells treated with miR-410 decrease the proliferation of cytokine of Th2 cells as well as phosphorylation of PI3K, and AKT. In OVA-induced asthma mice, IFN-γ and TGF-ß were decreased in BALF while the IL-4 and VEGF were increased. OVA-induced mice with asthma treated with miR-410 mimics showed marked reductions in the infiltration of inflammatory cells as well as IL-4 and VEGF in BALF. The immunohistochemical staining of the expression of VEGF also decreased in OVA-induced asthma mice with the instillation of miR-410. CONCLUSIONS: In this study, we revealed that miR-410 could regulate the differentiation of Th cells via the PI3K-AKT-VEGF signaling pathway in asthma.

Acertannin Prevented Dextran Sulfate Sodium-induced Colitis by Inhibiting the Colonic Expression of IL-23 and TNF-α in C57BL/6J Mice.

The present study investigates the effects of acertannin on colitis induced by dextran sulfate sodium (DSS) and changes in the colonic levels of the cytokines interleukin (IL)-1ß, IL-6, IL-10, IL-23, tumor necrosis factor (TNF)-α, the chemokine monocyte chemoattractant protein (MCP)-1, and vascular endothelial growth factor (VEGF).We examine the following: inflammatory colitis was induced in mice by 2% DSS drinking water given ad libitum for 7 days. Red blood cell, platelets, and leukocyte counts and hematocrit (Ht), hemoglobin (Hb), and colonic cytokine and chemokine levels were measured. The disease activity index (DAI) was lower in DSS-treated mice orally administered acertannin (30 and 100 mg/kg) than in DSS-treated mice. Acertannin (100 mg/kg) inhibited reductions in the red blood cell count and Hb and Ht levels in DSS-treated mice. Acertannin prevented DDS-induced mucosal membrane ulceration of the colon and significantly inhibited the increased colonic levels of IL-23 and TNF-α. Our findings suggest that acertannin has potential as a treatment for inflammatory bowel disease (IBD).

Atypical posterior reversible encephalopathy syndrome associated with Lenvatinib therapy in a patient with metastatic thyroid cancer-A case report.

Posterior reversible encephalopathy syndrome (PRES) is a disorder of reversible subcortical vasogenic brain oedema in patients with acute neurological symptoms. Drug-induced PRES has been described with the usage of drugs that target receptors regulating vascular permeability or altering immune response. Lenvatinib is a receptor tyrosine kinase inhibitor that inhibits the kinase activities of vascular endothelial growth factor receptors implicated in cancer progression in addition to their normal cellular functions. The oedema associated with PRES is a consequence of disruption of cerebral blood flow autoregulation. Herein, we present a case of a 77-year-old lady who was on treatment with Lenvatinib for metastatic thyroid cancer who subsequently developed PRES. Her clinical and radiological findings improved after discontinuing Lenvatinib and the patient was switched to a different drug and remains asymptomatic on the same. This is the first such report of atypical findings of PRES in a patient on Lenvatinib therapy. Recognition of this entity is crucial for timely withdrawal of the drug and prevent further morbidity and mortality.

Transcriptomic analysis of bladder tissue in a rat model of ketamine-induced bladder fibrosis.

INTRODUCTION: Ketamine-induced cystitis (KIC) is a disease caused by ketamine that can cause lower urinary tract symptoms (LUTS). Its end-stage is bladder contracture, which is related to bladder fibrosis and poses a serious burden to patient lives. METHODS: We established a KIC model in female Sprague Dawley rats and verified bladder fibrosis in the model by Masson trichrome staining and western blot analysis. The bladders of the rats from the ketamine and control groups were used to perform transcriptome analysis. In particular, association analysis with metabolomics was also used to determine the potential mechanisms of ketamine-induced bladder fibrosis. RESULTS: A total of 685 differentially expressed messenger RNAs, 71 differentially expressed long noncoding RNAs, 23 differentially expressed microRNAs, and 68 differentially expressed circular RNAs were identified. We found that ribosome, Wnt signaling, vascular endothelial growth factor signaling, cytoskeleton organization, and cytoskeletal protein binding may be potential pathways in ketamine-induced bladder fibrosis as identified by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses. In addition, the mitogen-activated protein kinase pathway appeared to be closely related to the development of ketamine-induced bladder fibrosis according to association analysis. CONCLUSIONS: In this study, using transcriptomic and correlation analyses of metabolomics, we identified pathways that may be potential targets for the prevention and treatment of ketamine-induced bladder fibrosis.

Soluble Endoglin Stimulates Inflammatory and Angiogenic Responses in Microglia That Are Associated with Endothelial Dysfunction.

Increased soluble endoglin (sENG) has been observed in human brain arteriovenous malformations (bAVMs). In addition, the overexpression of sENG in concurrence with vascular endothelial growth factor (VEGF)-A has been shown to induce dysplastic vessel formation in mouse brains. However, the underlying mechanism of sENG-induced vascular malformations is not clear. The evidence suggests the role of sENG as a pro-inflammatory modulator, and increased microglial accumulation and inflammation have been observed in bAVMs. Therefore, we hypothesized that microglia mediate sENG-induced inflammation and endothelial cell (EC) dysfunction in bAVMs. In this study, we confirmed that the presence of sENG along with VEGF-A overexpression induced dysplastic vessel formation. Remarkably, we observed increased microglial activation around dysplastic vessels with the expression of NLRP3, an inflammasome marker. We found that sENG increased the gene expression of VEGF-A, pro-inflammatory cytokines/inflammasome mediators (TNF-α, IL-6, NLRP3, ASC, Caspase-1, and IL-1ß), and proteolytic enzyme (MMP-9) in BV2 microglia. The conditioned media from sENG-treated BV2 (BV2-sENG-CM) significantly increased levels of angiogenic factors (Notch-1 and TGFß) and pERK1/2 in ECs but it decreased the level of IL-17RD, an anti-angiogenic mediator. Finally, the BV2-sENG-CM significantly increased EC migration and tube formation. Together, our study demonstrates that sENG provokes microglia to express angiogenic/inflammatory molecules which may be involved in EC dysfunction. Our study corroborates the contribution of microglia to the pathology of sENG-associated vascular malformations.

Treatment with the Prolyl Hydroxylase Inhibitor JNJ Promotes Abdominal Aortic Aneurysm Progression in Diabetic Mice.

OBJECTIVE: Prolyl hydroxylase domain containing proteins (PHD) rigorously regulate intracellular hypoxia inducible factor-1 (HIF-1) protein expression and activity. Diabetes impairs PHD activity and attenuates abdominal aortic aneurysm (AAA) progression. The extent to which dysregulated PHD activity contributes to diabetes mediated AAA suppression remains undetermined. METHODS: AAAs were induced in diabetic and non-diabetic male C57BL/6J mice via intra-aortic elastase infusion. A PHD inhibitor (JNJ-42041935, aka "JNJ", 150 mmol/kg) or vehicle alone was administered daily starting one day prior to AAA induction for 14 days. Influences on AAA progression was assessed via ultrasonography and histopathology. Expression of aortic HIF-1α, three of its target genes and macrophage derived mediators were assayed via quantitative reverse transcription polymerase chain reaction. Aneurysmal sections from AAA patients with and without diabetes (two patients in each group) were immunostained for HIF-1α and vascular endothelial growth factor (VEGF)-A. RESULTS: Expression of HIF-1α target genes (erythropoietin, VEGF-A, and glucose transporter-1) was reduced by 45% - 95% in experimental diabetic aortas. Diameter enlargement was similarly limited, as were mural elastin degradation, leukocyte infiltration, and neo-angiogenesis (reduced capillary density and length) on histopathology. Pre-treatment with JNJ prior to AAA initiation augmented aortic HIF-1α target gene expression and aneurysm progression in diabetic mice, along with macrophage VEGF-A and matrix metalloproteinase 2 mRNA expression. No differences were noted in HIF-1α or VEGF-A expression on aortic immunohistochemical staining of human aortic tissue as a function of diabetes status. CONCLUSION: Small molecule PHD inhibitor treatment reduces or offsets impairment of experimental AAA progression in hyperglycemic mice, highlighting the potential contribution of dysregulated PHD activity to diabetes mediated aneurysm suppression.

Exploring the Mechanism of the miRNA-145/Paxillin Axis in Cell Metabolism During VEGF-A-Induced Corneal Angiogenesis.

Purpose: Paxillin (PXN) is a key component of focal adhesions and plays an important role in angiogenesis. The aim of the present study was to investigate the effect of PXN in vascular endothelial growth factor A (VEGF-A)-induced angiogenesis in human umbilical vein endothelial cells (HUVECs). Methods: HUVECs were transfected with PXN overexpression and PXN interference vectors. Biochemical detection was used to detect adenosine triphosphate and lactic acid production. The morphology of mitochondria was observed under an electron microscope, and flow cytometry was conducted to measure mitochondrial membrane potential. Transwell experiments were used to detect the migration and tube formation ability of each group of cells. The expression of hexokinase (HK)1, HK2, glucose transporter 1 (GLUT1), phosphorylated phosphatidylinositol 3-kinase (PI3K), phosphorylated AKT, and phosphorylated mechanistic target of rapamycin (mTOR) was evaluated by western blot. Results: PXN silencing reduced the levels of lactic acid and adenosine triphosphate, downregulated HK1, HK2, and GLUT1, suppressed PI3K/AKT/mTOR signaling activation, and inhibited VEGF-A-induced mitochondria injury in VEGF-A-induced HUVECs. We also determined that miR-145-5p decreased the VEGF-A-induced expression of PXN and inhibited the invasion and angiogenesis of HUVECs. Also, miR-145-5p inhibition blocked the protective effect of PXN interference on VEGF-A-induced HUVEC injury. Furthermore, PXN interference significantly decreased lactic acid and adenosine triphosphate levels, inhibited PI3K/AKT/mTOR activation, and decreased the levels of HK1, HK2, and GLUT1 in VEGF-A-treated mouse corneal. Conclusions: The results indicate that PXN silencing inhibited the VEGF-A-induced invasion and angiogenesis of HUVECs via regulation of cell metabolism and mitochondrial damage, suggesting that PXN may be a potential target for antiangiogenic therapies.

Correlation Between Vascular Endothelial Growth Factor and Long-Term Occurrence of HCV-Related Hepatocellular Carcinoma After Treatment with Direct-Acting Antivirals.

We aimed to evaluate the correlation between vascular endothelial growth factor (VEGF) and long-term occurrence of hepatocellular carcinoma after HCV treatment with direct-acting antivirals (DAAs) and the HCC stage. Two groups with HCV-related liver cirrhosis and HCC were included: group 1, HCC following DAAs; group 2, HCC did not receive DAAs. The serum level of VEGF and HCC staging was evaluated. The duration between DAAs and HCC was 21.81 ± 11.66 months. Portal vein thrombosis (PVT) was observed more in group 1 (31%). VEGF was relatively elevated in group 1 compared to group 2. HCC patients after DAAs, showed elevated VEGF with frequent PVT.

Xanthorrhizol Suppresses Vascular Endothelial Growth Factor-Induced Angiogenesis by Modulating Akt/eNOS Signaling and the NF-[Formula: see text]B-Dependent Expression of Cell Adhesion Molecules.

Angiogenesis plays a crucial role in tumor growth and metastasis. Vascular endothelial growth factor (VEGF)-stimulated endothelial cell proliferation and migration are critical steps in tumor angiogenesis. Here, we investigated the anti-angiogenic activity of xanthorrhizol, a sesquiterpenoid isolated from the Indonesian medicinal plant Curcuma xanthorrhiza. Xanthorrhizol at noncytotoxic concentrations inhibited the proliferation, migration, and formation of capillary-like tubes in VEGF-treated human umbilical vein endothelial cells (HUVECs). Xanthorrhizol inhibited the phosphorylation of Akt and endothelial nitric oxide synthase (eNOS) and the expression of vascular cell adhesion molecule (VCAM)-1 and E-selectin in VEGF-treated HUVECs. The expression and transcriptional activity of NF-[Formula: see text]B were downregulated by xanthorrhizol in VEGF-treated HUVECs. Furthermore, xanthorrhizol significantly inhibited VEGF-induced angiogenesis in the chorioallantoic membrane of fertilized eggs and Matrigel plugs subcutaneously injected into mice. Xanthorrhizol inhibited tumor volume and tumor-derived angiogenesis in mice inoculated with breast cancer cells. The in vitro and in vivo anti-angiogenic activities of xanthorrhizol were as potent as those of curcumin, a well-known anticancer agent derived from C. longa. Taken together, xanthorrhizol inhibits VEGF-induced angiogenesis of endothelial cells by blocking the activation of the PI3K/Akt/eNOS axis and subsequent upregulation of adhesion molecules induced by the transcriptional activation of NF-[Formula: see text]B. Xanthorrhizol is a promising anti-angiogenic agent and can serve as a beneficial agent to enhance anticancer treatments.

POST-TREATMENT PREDICTION OF OPTICAL COHERENCE TOMOGRAPHY USING A CONDITIONAL GENERATIVE ADVERSARIAL NETWORK IN AGE-RELATED MACULAR DEGENERATION.

PURPOSE: To develop a deep learning model to generate posttreatment optical coherence tomography (OCT) images of neovascular age-related macular degeneration. METHODS: Two hundred ninety-eight patients with neovascular age-related macular degeneration were included. The conditional generative adversarial network was trained using 15,183 augmented paired OCT B-scan images obtained from 723 scans of 241 patients at baseline and 1 month after 3 loading doses of an anti-vascular endothelial growth factor treatment. The network was also trained using baseline fluorescein angiography (FA) or indocyanine green angiography (ICGA) images together with baseline OCT images. A test set of 150 images of 50 eyes was used to evaluate its ability to predict the presence of intraretinal fluid, subretinal fluid, PED, and subretinal hyperreflective material. Posttreatment OCT images were compared with images generated from baseline OCT with or without FA and indocyanine green angiography images. RESULTS: The predicted images inferred from baseline OCT images achieved an acceptable accuracy, specificity, and negative predictive value for four lesions (range: 77.0-91.9, 94.1-95.1, and 54.7-96.5%, respectively). The addition of both FA and indocyanine green angiography images improved the accuracy, specificity, and negative predictive value (range: 80.7-96.3, 97.3-99.0, and 59.0-98.3%, respectively). CONCLUSION: A conditional generative adversarial network is able to generate posttreatment OCT images from baseline OCT, FA, and indocyanine green angiography images.

THE EFFECT OF ENDOPHTHALMITIS ON RECURRENCE OF MACULAR EDEMA IN EYES RECEIVING INTRAVITREAL ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR.

PURPOSE: Visual outcomes after postinjection endophthalmitis have been well-studied, but the effect of endophthalmitis on the underlying exudative disease process remains unclear. We investigate the need for continued anti-vascular endothelial growth factor injections after endophthalmitis. METHODS: Eyes that developed endophthalmitis after intravitreal injection of anti-vascular endothelial growth factor between January 1, 2016, and May 31, 2018, at a single academic retina practice were identified. Retrospective chart review was performed to determine 1) the proportion of eyes without recurrence of macular edema or subretinal fluid after endophthalmitis and 2) the proportion achieving a 12-week or greater interval between anti-vascular endothelial growth factor injections or exudation after endophthalmitis compared with internal controls before endophthalmitis. RESULTS: Of 50 eyes with endophthalmitis, seven (14.0%) had no fluid recurrence at a mean of 98.1 week. Of 43 eyes with recurrence, 48.0% achieved a >12-week recurrence-free interval after endophthalmitis (vs. 8.3% before endophthalmitis; P < 0.0001). Eyes with compared to those without choroidal neovascularization were more likely to achieve this interval (60.5% vs. 8.3%, respectively; P = 0.002). CONCLUSION: Endophthalmitis after anti-vascular endothelial growth factor injection is associated with relative stability of the underlying exudation. Further research is necessary to elucidate the mechanism, which may be useful in developing strategies and targets for the treatment of exudative macular diseases.

Intravitreal anti-VEGF agents and cardiovascular risk.

Antagonists of Vascular Endothelial Growth Factor (Anti-VEGF) are widely administered by intravitreal injection for the treatment of ocular pathologies such as Age-related Macular Degeneration, Diabetic Macular Edema, Proliferative Diabetic Retinopathy and occlusion of retinal vessels. Anti-VEGF agents, in particular bevacizumab, were introduced in oncology to inhibit tumor-induced angiogenesis feeding neoplastic tissues. Subsequently, other specific agents were developed for intraocular administration. Whereas systemic administration of anti-VEGF agents in oncology is burdened by increased risk of arterial hypertension and embolism, agents administered for ophthalmic indications are delivered locally into the eye globe in much smaller quantities. Nevertheless, clinical observations have raised the possibility that, even in these conditions, anti-VEGF agents may increase cardiovascular risk in patients who, being elderly and/or diabetic, are intrinsically prone to such events. This paper aims at reviewing the current knowledge on VEGF and its pharmacologic antagonists from mechanistic and side effect points of view, with specific reference to patients with sight-threatening conditions. Internists should be aware of the need to collaborate with ophthalmologists and pharmacovigilance operators to define as best as possible the risk/benefit balance of intravitreal agents in patients who might lose their sight if left untreated, or increase their risk of suffering a cardiovascular event if treated.

One-year outcomes of novel VEGF decoy receptor therapy with intravitreal conbercept in diabetic retinopathy-induced macular edema.

Purpose: Conbercept is a novel recombinant fusion protein designed as a decoy receptor for vascular endothelial growth factor (VEGF) and placental growth factor. The primary purpose was to investigate the effect and safety of conbercept, based on a practical protocol, in the eyes of patients with diabetic macular edema (DME), and the secondary aim was to evaluate the efficacy of low-dose triamcinolone acetonide in patients with refractory DME who had little response to conbercept. Methods: In this retrospective clinical study, 89 treatment eyes from 76 patients with clinically significant DME were initially treated with one to three consecutive monthly intravitreal conbercept (IVC) injections, followed by retreatment with conbercept or switch therapy to triamcinolone acetonide (TA) based on a 6-month observation of the curative effect of IVC. Results: Sixty eyes were initiated on conbercept treatment for DME throughout the entire 1-year assessment period. After at least three consecutive monthly IVC treatments, 29 eyes further received intravitreal triamcinolone acetonide (IVTA) injections at month 6. From baseline to 1 year, the mean number of conbercept injections in the IVC group (n=60) was 4.5±1.0, and the mean number of conbercept injections in the IVC plus IVTA group (n=29) was 3.1±0.3. The mean best-corrected visual acuity (BCVA) and central macular thickness (CMT) were statistically significantly improved at 1 and 3 months after IVC treatments in the IVC group, and gradually improved at 9 months after IVTA treatments in the IVC plus IVTA group. There were no severe complications or conbercept-related adverse ocular and systemic side effects. Conclusions: Conbercept could be effective for visual and anatomic improvements in DME eyes with relatively fewer intravitreal injections and longer treatment intervals in clinical practice. Low-dose TA may be useful for patients with refractory DME resistant to anti-VEGF therapy.

[Vitreomacular Traction Following Anti-VEGF Therapy - Two Cases]. / Vitreomakuläres Traktionssyndrom im Rahmen der Anti-VEGF-Therapie ­ 2 Kasuistiken.

Vitreomacular traction syndrome (VMTS) is defined as an incomplete or anomalous posterior vitreous detachment resulting in tractional forces at the macular region. In the context of anti-VEGF therapy, the formation of vitreoretinal traction has mainly been reported as a potential complication of VEGF inhibition in ischemic proliferative retinal disease, such as proliferative diabetic retinopathy. In this report, we present two patients who developed VMTS during anti-VEGF therapy for exudative age-related macular degeneration and diabetic macular edema. VMTS following anti-VEGF therapy of exudative macular diseases is rare. The exact pathomechanism remains unclear. However, there is a hypothesis that in eyes with adherent vitreous cortex, the induction of fibrosis as a result of the VEGF inhibition may lead to vitreomacular traction.

Anti-Angiogenesis Effects Induced by Octaminomycins A and B against HUVECs.

In the course of studies to discover natural products with anti-angiogenic properties, two cyclic octapeptides, octaminomycins A (1) and B (2), were isolated from the cultures of Streptomyces sp. RK85-270. Octaminomycins suppressed the vascular endothelial growth factor (VEGF)-induced proliferation, adhesion, tube formation, migration, and invasion of HUVECs. Anti-angiogenic activity was futher confirmed in vivo by the chicken chorioallantoic membrane assay. We also identified that 1 and 2 inhibited the phosphorylation of VEGF receptor 2, AKT, and ERK1/2 and the expression and activities of MMP-2 and MMP-9. These results suggest that 1 and 2 may serve as potential scaffolds for the development of therapeutic agents to angiogenesis-dependent diseases.

Local intra­articular injection of vascular endothelial growth factor accelerates articular cartilage degeneration in rat osteoarthritis model.

In the pathophysiology of osteoarthritis (OA), articular cartilage degeneration exhibits a significant role. Vascular endothelial growth factor (VEGF) is considered to be an effective angiogenic factor and a crucial regulator of articular cartilage degeneration in the development of OA. Therefore, the present study aimed to investigate the underlying influences of exogenous VEGF on articular cartilage degeneration in OA model rat. A total of 24 male Sprague­Dawley rats were randomly allocated into 3 groups. In the normal saline (NS) and VEGF groups, animals received bilateral anterior cruciate ligament (ACL) transection to establish the OA model; at 4 weeks post­surgery, the rats received local intra­articular injections of 100 µl NS or VEGF solution, respectively, every week for 4 weeks. The Control group received neither surgery nor injections. All animals were sacrificed at 12 weeks following surgery. Prominent cartilage degeneration was observed in rats in the NS­ and VEGF­injected groups. The extent and the grade of cartilage damage in the VEGF­injected group were notably more severe compared with those in the NS­treated group. Western blotting results demonstrated that the expression levels of aggrecan and type II collagen were significantly reduced in OA model rats that were treated with VEGF. In addition, the expression levels of matrix metalloproteinase (MMP)­3, MMP­9, MMP­13, a disintegrin and metalloproteinase with thrombospondin motifs (a disintegrin and metalloproteinase; ADAMTS)­4, ­5 and ­12, type III collagen and transforming growth factor­ß1 were significantly increased following VEGF administration. Results from the present study indicated that VEGF may exhibit a promoting role in the development of OA by destroying articular cartilage matrix.

Vasculitis retinal / Retinal vasculitis

La vasculitis retinal es una enfermedad inflamatoria que amenaza la visión y afecta los vasos retinales (capilares, venas y arterias). Puede ocurrir como una condición idiopática o como complicación de enfermedades infecciosas y neoplásicas o en asociación con enfermedades sistémicas inflamatorias. Sus manifestaciones clínicas típicas incluyen revestimiento perivascular, envainamiento, filltración vascular y oclusión. Puede estar asociada con signos de isquemia retinal (puntos algodonosos y hemorragias intraretinales). Es clasificada en diferentes estadíos: inflamación, isquemia, neovascularización y complicaciones. En su diagnóstico es importante la biomicroscopia, la oftalmoscopia del segmento posterior y la prueba de angiografía fluoresceínica. Se presenta un paciente de 30 años con buena historia de salud anterior. El paciente comenzó con enrojecimiento del ojo izquierdo y la observación de flotadores en ambos ojos. Fue examinado y los signos clínicos fueron descritos en el examen oftalmológico. El examen del fondo de ojo con lente de 90 dioptrias y el oftalmoscopio binocular indirecto fue realizado para un cuidadoso examen. La retinografía del fondo y las imágenes del test de angiografía y otros estudios complementarios indicados permitieron conocer que presentaba una vasculopatía obliterativa retinal ideopática (Enfermedad de Eales), y el diagnóstico diferencial fue discutido. El tratamiento indicado fue la fotocoagulación con láser y evaluar la indicación de los estudios bioquímicos del cultivo del vítreo, por antígenos de leucocito humano, factor de crecimiento endotelial vascular e interleukinas que han sido observados en este examen(AU)

Retinal vasculitis is an inflammatory disease that threatens vision and affects retinal vessels (capillaries, veins and arteries). It may occur as an isolated idiopathic condition and as a complication of infective or neoplastic disorders, in association with systemic inflammatory diseases. Typical clinical manifestations including perivascular sheathing or cuffing, vascular leakage and occlusion. It may be associated with signs of retinal ischemia (cotton-wool spots and intra-retinal hemorrhage). It is classified into different stages: lnflamation, ischemia, neovascularization and complications. In the diagnosis, biomicroscopy and ophtalmoscopic of the posterior segment and fluorescein angiography test are important. A case report is presented of a 30-year-old male patient with a history of good health. In October 2015 the patient had started out with reddening of his left eye and the viewing of floaters with both eyes. Funduscopy was performed with a 90-dioptric lens and a binocular indirect ophthalmoscope. Fundus retinography, angiographic imaging and other complementary studies revealed an idiopathic obliterative retinal vasculopathy (Eales disease). The treatment indicated was photocoagulation, as well as a recommendation to evaluate the biochemical studies of the vitreous culture, since the test had found human leukocyte antigens, vascular endothelial growth factor and interleukins(AU)

Incidence of medication-related osteonecrosis of the jaw in patients treated with both bone resorption inhibitors and vascular endothelial growth factor receptor tyrosine kinase inhibitors.

BACKGROUND: Several case reports and small case series have suggested a higher incidence of medication-related osteonecrosis of the jaw (MRONJ) in patients treated concomitantly with bone resorption inhibitors (BRIs) and vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs), as compared to patients treated with BRIs alone. We aimed to assess ONJ-incidence in patients exposed concomitantly to BRIs and VEGFR-TKIs. PATIENTS AND METHODS: We reviewed the records of all patients who received VEGFR-TKIs concomitantly with BRIs. Patients, who were treated with BRIs without VEGFR-TKI, served as a control group. Endpoints of the study were total MRONJ-incidence, MRONJ-incidence during the first and second year of exposure, and time-to-ONJ-incidence. RESULTS: Ninety patients were treated concomitantly with BRIs and VEGFR-TKIs with a median BRI-exposure of 5.0 months. Total MRONJ-incidence was 11.1%. During the first year of BRI-exposure (with a median concomitant exposure of 4.0 months), 6 out of 90 patients (6.7%) developed a MRONJ, compared to 1.1% in the control group (odds ratio 5.9; 95%CI 2.0-18.0; p = 0.0035). In Kaplan-Meier estimates, time-to-ONJ-incidence was significantly shorter in patients treated with BRIs and VEGFR-TKIs compared to BRIs alone (hazard ratio 9.5; 95%CI 3.1-29.6; p < 0.0001). MRONJs occurred earlier in patients treated concomitantly compared to patients treated with BRIs only (after a median exposure of 4.5 and 25.0 months, respectively; p = 0.0033). CONCLUSION: With a global MRONJ-incidence of 11%, patients receiving concomitant treatment with VEGFR-TKIs and BRIs have a five to ten times higher risk for development of MRONJ compared to patients treated with BRIs alone.

Antiangiogenic effect of dasatinib in murine models of oxygen-induced retinopathy and laser-induced choroidal neovascularization.

Purpose: Vascular endothelial growth factor (VEGF) is a principal mediator of pathological ocular neovascularization, which is the leading cause of blindness in various ocular diseases. As Src, a non-receptor tyrosine kinase, has been implicated as one of the major signaling molecules in VEGF-mediated neovascularization, the present study aimed to investigate whether dasatinib, a potent Src kinase inhibitor, could suppress pathological ocular neovascularization in murine models of oxygen-induced retinopathy (OIR) and choroidal neovascularization (CNV). Methods: Tube formation, scratch wounding migration, and cell proliferation assays were performed to measure the inhibitory effect of dasatinib on VEGF-induced angiogenesis in human retinal microvascular endothelial cells. Murine models of OIR and laser-induced CNV were used to assess the preventive effect of an intravitreal injection of dasatinib on pathological neovascularization in the retina and choroid. Neovascularization and Src phosphorylation were evaluated with immunofluorescence staining. Results: Dasatinib efficiently inhibited VEGF-induced endothelial proliferation, wounding migration, and tube formation. In mice with OIR and laser injury-induced CNV, eyes treated with a single intravitreal injection of dasatinib exhibited significant decreases in pathological neovascularization compared with that of controls injected with vehicle. The dasatinib-treated OIR mice also showed a decrease in Src phosphorylation in the periretinal tufts. The intravitreal injection of dasatinib did not cause ocular toxicity at the treatment dose administered. Conclusions: These results demonstrated that dasatinib suppressed pathological neovascularization in the mouse retina and choroid. Therefore, dasatinib may be indicated for the treatment of ischemia-induced proliferative retinopathy and neovascular age-related macular degeneration.