Evaluation of the retinal vasculature of patients with branch retinal vein occlusion using optical coherence tomography angiography / Avaliação da vasculatura da retina em pacientes com oclusão de ramo da veia central da retina utilizando a angiografia por tomografia de coerência óptica

ABSTRACT Purpose: To evaluate vascular density in super­ficial and deep capillary plexuses of the retina, measured using optical coherence tomography angiography in patients with branch retinal vein occlusion. Affected eyes were compared with the contralateral eye of the same patient and both were compared with normal eyes. Methods: A cross-sectional study including 16 previously untreated patients with branch retinal vein occlusion. Patients with poor quality examinations, bilateral disease, high refractive error, or any other retinal or choroidal disease were excluded. A total of 31 patients without eye disease were also selected as a comparison group. All participants underwent five optical coherence tomography angiographies, and only those with at least two good quality examinations were selected. The Kruskal-Wallis, Wilcoxon signed-rank, and Mann-Whitney U tests were used for the statistical analysis. Results: Vascular density was lower in affected eyes compared with contralateral eyes: whole density (p=0.020 for capillary plexuses superficial; p=0.049 for deep capillary plexuses) and parafoveal density (p=0.020 for capillary plexuses superficial; p=0.011 for deep capillary plexuses). Vascular density was also lower in affected eyes compared with normal eyes: whole density (p<0.001 for capillary plexuses superficial and deep) and parafoveal density (p<0.001 for capillary plexuses superficial and deep). Whole density (p=0.001 for capillary plexuses superficial and deep) and parafoveal density (p=0.001 for capillary plexuses superficial; p<0.001 for deep capillary plexuses) were both lower in the contralateral eyes compared with normal eyes. Following adjustment for arterial hypertension, this difference was no longer observed. Conclusions: Vascular density in capillary plexuses and deep capillary plexuses was lower in the eyes affected by branch retinal vein occlusion. Furthermore, the lower vascular density noted in the contralateral eyes indicates that changes most likely occurred in these eyes prior to the appearance of any clinically detectable alterations, reflecting the early signs of hypertensive retinopathy.

RESUMO Objetivo: Avaliar a densidade vascular do plexo capilar superficial e profundo da retina, usando angiografia por tomografia de coerência óptica em pacientes com oclusão de ramo da veia central da retina, comparando o olho afetado com o contralateral do mesmo paciente e ambos com olhos normais. Métodos: Estudo transversal. Incluídos dezesseis pacientes com oclusão de ramo da veia central da retina sem tratamento prévio. Pacientes com exames de baixa qualidade, altas ametropias, outras patologias de retina ou coróide foram excluídos. Para comparação, trinta e um pacientes sem doença ocular foram selecionados. Todos foram submetidos a cinco exames angiografia por tomografia de coerência óptica, apenas aqueles com pelo menos dois exames de boa qualidade permaneceram no estudo. Os testes Kruskal-Wallis, Wilcoxon, e Mann-Whitney foram utilizados. Resultados: Densidades vasculares mais baixas do plexo capilar superficial e plexo capilar profundo foram observadas quando olhos com oclusão de ramo da veia central da retina foram comparados com os contralaterais: densidade total (p=0,02 para plexo capilar superficial, p=0,049 para plexo capilar profundo), densidade parafoveal (p=0,02 para plexo capilar superficial, p=0,011 para plexo capilar profundo). Comparando olhos acometidos com olhos normais, também foram observadas densidades vasculares mais baixas de plexo capilar superficial e plexo capilar profundo: densidade total (ambos com p<0,001) e densidade parafoveal (ambos com p<0,001). Quando os olhos contralaterais foram comparados aos normais, tanto a densidade total do plexo capilar superficial e plexo capilar profundo (ambos com p=0,001) quanto a densidade parafoveal (plexo capilar superficial com p=0,001, plexo capilar profundo com p<0,001) foram menores. Ao se realizar uma subanálise, minimizando o fator hipertensão arterial, esta diferença não se manteve. Conclusões: Densidades vasculares mais baixas do plexo capilar superficial e do plexo capilar profundo foram observadas em olhos com oclusão de ramo da veia central da retina. Além disso, a presença de densidades vasculares mais baixas nos olhos contralaterais mostra que já existem altera­ções nesses olhos antes das alterações clínicas, devido a al­terações inicias da retinopatia hipertensiva.

Three versus five intravitreal aflibercept injections as the initial loading phase in the treatment of diabetic macular edema: one-year results / Três versus cinco injeções intravítreas de aflibercept como carga inicial do tratamento de edema macular diabético: resultados de um ano

ABSTRACT Purpose: To compare the efficacy of three initial monthly intravitreal aflibercept injections followed by pro re nata (3+PRN) dosing versus five initial monthly intravitreal aflibercept injections followed by pro re nata (5+PRN) dosing in patients with diabetic macular edema. Methods: A total of 60 treatment-naïve patients with macular edema who underwent intravitreal aflibercept injections (2 mg/0.05 mL) with at least one year of follow-up were analyzed in this retrospective and comparative study. The patients were divided into two groups according to the number of intravitreal aflibercept injections administered in the loading phase. The 3+PRN group comprised 27 patients, whereas the 5+PRN group comprised 33 patients. The visual and anatomical outcomes were compared between the two groups at baseline and at 3, 6, 9, and 12 months. Results: Both 3+PRN and 5+PRN, showed statistically significant improvements in the best-corrected visual acuity and central macular thicknesse throughout the study period (p<0.001 and, p<0.001, respectively). There were no significant differences between the two groups in terms of changes in the best-corrected visual acuity and central macular thickness (p=0.453 and, p=0.784, respectively). The mean number of intravitreal aflibercept injections was significantly greater in the 5+PRN group (6.1 ± 0.8) than in the 3+PRN group (3.9 ± 0.8) (p<0.001). Conclusion: The 3+PRN and 5+PRN regimens showed similar 12-month visual and anatomical outcomes following treatment with intravitreal aflibercept injections in patients with macular edema.

RESUMO Objetivo: Comparar a eficácia de três injeções intravítreas mensais iniciais de aflibercept, seguidas de dosagem de pro re nata (3+PRN) versus cinco injeções mensais iniciais intravítreas de aflibercept, seguidas de doses de pro re nata (5 + PRN) em pacientes com edema macular diabético. Métodos: Foram analisados neste estudo retrospectivo e comparativo 60 pacientes que não receberam tratamento prévio com edema macular e foram submetidos a injeções intravítreas de aflibercept (2 mg/0,05 mL) com pelo menos um ano de acompanhamento. Os pacientes foram divididos em dois grupos de acordo com o número de injeções intravítreas de aflibercept administradas na fase inicial. O grupo 3+PRN compreendeu 27 pacientes, enquanto o grupo 5+PRN compreendeu 33 pacientes. Os resultados visuais e anatômicos foram comparados entre os dois grupos no período inicial e aos 3, 6, 9 e 12 meses. Resultados: Tanto os grupos 3+PRN quanto 5+PRN mostraram melhoras estatisticamente significativas na acuidade visual melhor corrigida e na espessura macular central ao longo do período de estudo (p<0,001 e p <0,001, respectivamente). Não houve diferenças significativas entre os dois grupos em termos de alterações na acuidade visual melhor corrigida e na espessura macular central (p=0,453 e p=0,784, respectivamente). O número médio de injeções intravítreas de aflibercept foi significativamente maior no grupo 5+PRN (6,1 ± 0,8) do que no grupo 3+PRN (3,9 ± 0,8) (p <0,001). Conclusão: Os regimes 3+PRN e 5+PRN mostraram resultados visuais e anatômicos semelhantes em 12 meses após o tratamento com injeções intravítreas de aflibercept em pacientes com edema macular.

Aflibercept versus dexametasona en edema macular secundario a la oclusión de la vena central de la retina / Aflibercept versus dexamethasone for macular edema secondary to central retinal vein occlusion

INTRODUCCIÓN El edema macular es una complicación frecuente de la oclusión de la vena central de la retina que clínicamente provoca deterioro de la agudeza visual. Los tratamientos más utilizados son el implante de dexametasona y los fármacos anti factor del crecimiento endotelial vascular, destacando aflibercept dentro de estos. Sin embargo, no existe consenso acerca de qué tratamiento constituye la mejor alternativa. MÉTODOS Realizamos una búsqueda en Epistemonikos, la mayor base de datos de revisiones sistemáticas en salud, la cual es mantenida mediante el cribado de múltiples fuentes de información, incluyendo MEDLINE, EMBASE, Cochrane, entre otras. Extrajimos los datos desde las revisiones identificadas, analizamos los datos de los estudios primarios, realizamos un meta análisis y preparamos una tabla de resumen de los resultados utilizando el método GRADE. RESULTADOS Y CONCLUSIONES Identificamos dos revisiones sistemáticas que en conjunto incluyeron cuatro estudios primarios, todos ensayos aleatorizados. Concluimos que no es posible establecer si aflibercept es superior a dexametasona en términos de mejora de agudeza visual y seguridad, debido a que la certeza de la evidencia existente ha sido evaluada como muy baja.

INTRODUCTION Macular edema is a frequent complication of central retinal vein occlusion that might lead to deterioration of visual acuity. The most commonly used treatments are dexamethasone implant and anti-vascular endothelial growth factor drugs, being aflibercept one of the most commonly used them. However, there is no consensus about which treatment constitute the best alternative. METHODS We searched in Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others. We extracted data from the systematic reviews, reanalyzed data of primary studies, conducted a meta-analysis and generated a summary of findings table using the GRADE approach. RESULTS AND CONCLUSIONS We identified two systematic reviews that included four primary studies overall, all randomized trials. We concluded that it is not possible to establish whether aflibercept is superior to dexamethasone in terms of improvement of visual acuity and safety, because the certainty of the existing evidence has been evaluated as very low.

Efficacy of aflibercept on exudative age-related macular degeneration in patients exhibiting complete ranibizumab resistance and tachyphylaxis / Eficácia do aflibercept em pacientes portadores de degeneração macular relacionada à idade exsudativa com resistência completa e taquifilaxia ao ranibizumab

ABSTRACT Purpose: The present study compared the efficacy of aflibercept for neovascular age-related macular degeneration (NV-AMD) in patients with complete ranibizumab resistance and tachyphylaxis. Methods: Forty-four eyes of 38 neovascular age-related macular degeneration patients were evaluated. Eyes were divided into a complete resistance group (n=23 eyes) and tachyphylaxis group (n=21 eyes). Results: After three injections, eight (38.1%) patients in the tachyphylaxis group and nine (39.1%) in the complete resistance group presented with macular dryness. After the first injection of aflibercept, the mean visual acuity improved significantly in the tachyphylaxis group (p=0.018) but remained unchanged in the complete resistance group (p=0.37). There was a non-significant trend towards improved mean visual acuity in both groups after the second and third injections relative to the acuity at the final visit for ranibizumab treatment. In the tachyphylaxis group, the presence of subfoveal pigmented epithelium detachment (PED) decreased significantly after intravitreal aflibercept treatment. Conclusions: Although treatment with aflibercept yielded generally positive anatomical results in both groups, no significant increase in visual acuity was achieved.

RESUMO Objetivo: O presente estudo comparou a eficácia do aflibercept na degeneração macular neovascular relacionada à idade (NV-AMD) com de resistência completa ao ranibizumab e taquifilaxia ao ranibizumab. Método: Quarenta e quatro olhos de 38 pacientes com degeneração macular neovascular relacionada à idade foram inscritos. Eles foram divididos em dois grupos: grupo de resistência completa (n=23 olhos) e grupo taquifilaxia (n=21 olhos). Resultados: Depois de três injeções, 8 (38,1%) olhos no grupo de taquifilaxia e 9 (39,1%) olhos no grupo de resistência completa, apresentaram mácula seca. Após a primeira injeção de aflibercept, a acuidade visual média melhorou significativamente no grupo taquifilaxia (p=0,018) e manteve-se inalterada no grupo de resistência completa (p=0,37). Houve uma tendência de melhora da acuidade visual média em ambos os grupos após a segunda e terceira injeções em comparação com a última visita do tratamento com ranibizumab, mas isso não foi estatisticamente significativo. A presença de descolamento do epitélio pimentado subfoveal (PED) em olhos com taquifilaxia ao ranibizumab diminuiu significativamente após o tratamento aflibercept intravítreo. Conclusões: Embora o tratamento com aflibercept tenha mostrado resultados anatômicos positivas em ambos os grupos, não foi obtida melhora significativa da acuidade visual.

Sterile Inflammation after Intravitreal Injection of Aflibercept in a Korean Population

PURPOSE: To report the frequency and clinical features of sterile inflammation after intravitreal aflibercept injection in a Korean population. METHODS: A single-center, retrospective study was performed in patients who received intravitreal aflibercept from July 2013 through January 2015. RESULTS: A total of four cases of post-injection sterile inflammation were identified from 723 aflibercept injections in 233 patients. Patients presented 1 to 13 days after intravitreal aflibercept injection (mean, 5 days). The mean baseline visual acuity was 20 / 60, which decreased to 20 / 112 at diagnosis but ultimately recovered to 20 / 60. Three cases had inflammatory cells in the anterior chamber (mean, 2.25+; range, 0 to 4+), and all cases had vitritis (mean, 3+; range, 2+ to 4+). No patients had pain. Only one patient underwent anterior chamber sampling (culture negative) and injection of antibiotics. Three of four patients were treated with a topical steroid, and all experienced improvement in their symptoms and signs of inflammation. CONCLUSIONS: The overall incidence of sterile inflammation after intravitreal aflibercept injection in a Korean population was 4 of 723 injections (0.55%), or 4 of 233 patients (1.79%). Sterile inflammation after intravitreal aflibercept injection typically presents without pain, and the visual outcomes are generally favorable.

Aflibercept Treatment for Neovascular Age-related Macular Degeneration and Polypoidal Choroidal Vasculopathy Refractory to Anti-vascular Endothelial Growth Factor

PURPOSE: To report the results of switching treatment to vascular endothelial growth factor (VEGF) Trap-Eye (aflibercept) in neovascular age-related macular degeneration (AMD) and polypoidal choroidal vasculopathy (PCV) refractory to anti-VEGF (ranibizumab and bevacizumab). METHODS: This is a retrospective study involving 32 eyes from 29 patients; 18 were cases of neovascular AMD and 14 were cases of PCV. The best-corrected visual acuity (BCVA) and central macular thickness (CMT) of spectral-domain optical coherence tomography were evaluated. RESULTS: BCVA and CMT improved from 0.58 to 0.55 (p = 0.005) and from 404 to 321 microm (p < 0.001), respectively, after switching to aflibercept. The 14 eyes that received 6 or more aflibercept injections remained stable at 0.81 to 0.81 and 321 to 327 microm (p = 1.0, 0.29), respectively, after 3 aflibercept injections. The 10 eyes that received 3 or more bevacizumab injections after 3 or more aflibercept injections worsened, from 0.44 to 0.47 and from 332 to 346 microm (p = 0.06, 0.05), respectively. The results showed similar improvement of BCVA and CMT in neovascular AMD and PCV. CONCLUSIONS: Aflibercept seems to be effective for improvement and maintenance of BCVA and CMT for neovascular AMD and PCV refractory to anti-VEGF. Switching from aflibercept back to bevacizumab treatment may not be a proper strategy.

Combined blockade of HER2 and VEGF exerts greater growth inhibition of HER2-overexpressing gastric cancer xenografts than individual blockade

Gastric cancer overexpressing the human epidermal growth factor 2 (HER2) protein has a poor outcome, although a combination of chemotherapy and the anti-HER2 antibody trastuzumab has been approved for the treatment of advanced gastric cancer. Vascular endothelial growth factor (VEGF) expression in gastric cancer is correlated with recurrence and poor prognosis; however, the anti-VEGF antibody bevacizumab has shown limited efficacy against gastric cancer in clinical trials. In this study, we evaluated the antitumor effects of trastuzumab; VEGF-Trap binding to VEGF-A, VEGF-B and placental growth factor (PlGF); and a combination of trastuzumab and VEGF-Trap in a gastric cancer xenograft model. Although trastuzumab and VEGF-Trap each moderately inhibited tumor growth, the combination of these agents exerted greater inhibition compared with either agent alone. Immunohistochemical analyses indicated that the reduction in tumor growth was associated with decreased proliferation and increased apoptosis of tumor cells and decreased tumor vascular density. The combined treatment resulted in fewer proliferating tumor cells, more apoptotic cells and reduced tumor vascular density compared with treatment with trastuzumab or VEGF-Trap alone, indicating that trastuzumab and VEGF-Trap had additive inhibitory effects on the tumor growth and angiogenesis of the gastric cancer xenografts. These data suggest that trastuzumab in combination with VEGF-Trap may represent an effective approach to treating HER2-overexpressing gastric cancer.

Protective effects of transduced Tat-DJ-1 protein against oxidative stress and ischemic brain injury

Reactive oxygen species (ROS) contribute to the development of a number of neuronal diseases including ischemia. DJ-1, also known to PARK7, plays an important role in transcriptional regulation, acting as molecular chaperone and antioxidant. In the present study, we investigated whether DJ-1 protein shows a protective effect against oxidative stress-induced neuronal cell death in vitro and in ischemic animal models in vivo. To explore DJ-1 protein's potential role in protecting against ischemic cell death, we constructed cell permeable Tat-DJ-1 fusion proteins. Tat-DJ-1 protein efficiently transduced into neuronal cells in a dose- and time-dependent manner. Transduced Tat-DJ-1 protein increased cell survival against hydrogen peroxide (H2O2) toxicity and also reduced intracellular ROS. In addition, Tat-DJ-1 protein inhibited DNA fragmentation induced by H2O2. Furthermore, in animal models, immunohistochemical analysis revealed that Tat-DJ-1 protein prevented neuronal cell death induced by transient forebrain ischemia in the CA1 region of the hippocampus. These results demonstrate that transduced Tat-DJ-1 protein protects against cell death in vitro and in vivo, suggesting that the transduction of Tat-DJ-1 may be useful as a therapeutic agent for ischemic injuries related to oxidative stress.

Angiopoietin-1 variant, COMP-Ang1 attenuates hydrogen peroxide-induced acute lung injury

Reactive oxygen species (ROS) play a crucial role in acute lung injury. Tissue inflammation, the increased vascular permeability, and plasma exudation are cardinal features of acute lung injury. Angiopoietin-1 (Ang1) has potential therapeutic applications in preventing vascular leakage and also has beneficial effects in several inflammatory disorders. Recently developed COMP-Ang1 is more potent than native Ang1 in phosphorylating tyrosine kinase with immunoglobulin and EGF homology domain 2 receptor in endothelial cells. However, there are no data on effects and related molecular mechanisms of COMP- Ang1 on ROS-induced acute lung injury. We used hydrogen peroxide (H2O2)-inhaled mice to evaluate the effect of COMP-Ang1 on pulmonary inflammation, bronchial hyper-responsiveness, and vascular leakage in acute lung injury. The results have revealed that VEGF expression, the levels of IL-4, TNF-alpha, IL-1 beta, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1 in lungs, the levels of hypoxia-inducible factor-1alpha (HIF-1 alpha) and NF-kappa B in nuclear protein extracts, phosphorylation of Akt, and vascular permeability were increased after inhalation of H2O2 and that the administration of COMP-Ang1 markedly reduced airway hyper-responsiveness, pulmonary inflammation, plasma extravasation, and the increases of cytokines, adhesion molecules, and VEGF in lungs treated with H2O2. We have also found that the activation of HIF-1a and NF-kappa B and the increase of phosphoinositide 3-kinase activity in lung tissues after H2O2 inhalation were decreased by the administration of COMP-Ang1. These results suggest that COMP-Ang1 ameliorates ROS-induced acute lung injury through attenuating vascular leakage and modulating inflammatory mediators.

Retiro precoz de esteroides en la inmunosupresión del trasplante renal pediátrico / Early steroid withdrawal in pediatric renal transplantation

Background: Cardiovascular risk, growth failure and the new immunosuppressive drugs, have encouraged steroid withdrawal or total avoidance with promising results in renal transplant (Tx) immunosuppression. Aim: To evaluate a new immunosuppressor protocol with early withdrawal of steroids in pediatric kidney transplant. Patients and methods: Prospective study in pediatric patients older than 1 year and low immunological risk. Group A (n =28): steroids in decreasing doses until day 7 post Tx, tacrolimus (FK) and micophenolate mofetil (MMF). Group B (n =28) control: steroids, cyclosporine and azathioprine or steroids, FK and MMF. In both groups the induction therapy included basiliximab. Anthropometric and biochemical variables (renal function, lipid profile, hematological, blood glucose and acid-base equilibrium), acute rejection and CMV infection, were evaluated. Mean values and variations for continuous variables were calculated at months 1, 6, 12 and 18. Results: Two children were withdrawn before month 2, one had an untreatable diarrhea and the second died due to Aspergillus septicemia. Mean values at months 1, 6, 12 and 18 for groups A and B: Creatinine clearence (ml/min): 85.4 vs 89; 79.9 vs 83; 89 vs 80; 79.8 vs 80.6 (p: ns); hematocrit ( percent): 28.8 vs 30.4; 31.7 vs 34.4; 34.4; 32.4 vs 34.8; 34.4 vs 35.5 (p: ns). Total cholesterol (mg/dl): 151 vs 206; 139 vs 174; 138 vs 186; 140 vs 180 (p <0.05). Mean delta height/age Z score at the first year: 0.5 vs 0.15; 0.7 vs 0.22; 0.97 vs 0.25 (p <0.05). Mean systolic blood pressure Z score: 0.9 vs 1.5; 0.5 vs 0.9; -0.3 vs 0.8; 0.1 vs 1.0 (p <0.05). The height/age Z score was significantly superior in patients without steroids. A normalization of growth patterns at month 18 was observed (< 0.05). Both groups presented a negative variation of creatinine clearance during the follow-up, but it was minor in the study group (p <0.05). Two acute rejections were found in each group, and no difference in CMV infections...

Sensibilidad a IGF-I en niños pequeños para la edad gestacional / IGF-I sensitivity in small for gestational age children

Background: The lack of catch up growth (CUG) in small for gestational age (SGA) children may be related to a reduced sensitivity to insulin growth factor 1 (IGF-I). Aim: To assess the sensitivity to IGF-I in small for gestational age children, measuring basal and post IGF-I nocturnal profile of growth hormone (GH). Patients and methods: We studied 34 prepubertal SGA children aged 4 to 11 years. Twenty three had CUG and 11 did not have CUG. As an IGF-I sensitivity test, nocturnal GH levels were measured every 20 minutes from 23:00 h to 07:00 h, both under baseline conditions and after the administration of a subcutaneous bolus of 1 mg/kg/body weight of the IGF-I + IGFBP-3 complex (Somatokine®). Results: At the time of the study, the Z scores for height among children with and without CUG were -1.55 ± 0.22 and -3.24 ± 0.28, respectively (p <0.0001). There were no statistical differences between CUG + vs CUG- patients in mean basal GH (6.6 ± 0.5 and 5.6 ± 0.6 ng/ml, respectively). After Somatokine® administration, mean GH, and the mean GH area under the curve (AUC) decreased significantly in both groups. However, mean overnight GH AUC decreased in all SGA children with CUG, after Somatokine® administration, whereas 3 out of 11 SGA children without CUG had an increase in their mean GH AUC in response to Somatokine®. Conclusions: These findings suggest that pituitary sensitivity to IGF-I may be decreased in some SGA children without CUG.

Cytotoxicity of anthrax lethal factor microinjected into macrophage cells through Sendai virus envelopes.

Lethal toxin (LT) secreted by Bacillus anthracis consists of two proteins, protective antigen (PA) and lethal factor (LF). LT causes lysis of macrophages and derived cell lines at low concentrations. PA binds to the cell surface receptors and mediates translocation of LF into cytosol of mammalian cells. Internalization of LF into cytosol by osmotic lysis of pinocytic vesicles requires high concentration of LF for cell lysis. To examine the possible cell lysis by LF at low concentration, we introduced LF directly into cytosol of J774A.1 cells through reconstituted Sendai virus envelopes. The introduction of LF lysed J774A.1 cells in a concentration dependent manner. Internalization of PA alone through virosome had no toxic effect on J774A.1 cells. In the process of cytotoxicity LF was not cleaved by cellular proteases. Unlike many protein toxins, golgi was not involved in the expression of lethal toxin activity. These results indicate that LF is the toxic component of anthrax lethal toxin and prior proteolytic processing or trafficking through golgi is not required for its activity.