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• W2025375706 abstract "Purpose: To evaluate the effect of different bevacizumab concentrations on retinal endothelial cell proliferation, retinal structures and apoptotic activity after intravitreal injection in a retinopathy of prematurity (ROP) mouse model. Methods: A total of 35 of C57BL/J6 mice were exposed to 75 ± 2% oxygen from postnatal day 7 to postnatal day 12. On day 12, 10 mice (group C) were injected with 2.5 μg intravitreal bevacizumab (IVB), 11 mice (group D) were injected with 1.25 μg IVB, and 14 mice (group E) were injected with 0.625 μg IVB in one eye. The contralateral eyes were injected with isotonic saline (control group = group B). Four nonexposed mice served as negative controls (group A). Neovascularization was quantified by counting the endothelial cell proliferation on the vitreal side of the inner limiting membrane of the retina. Histological and ultrastructural changes were examined by light and electron microscopy. Terminal deoxynucleotidyl transferase deoxy-UTP-nick end labelling (TUNEL) was used to detect apoptosis. Results: The endothelial cell count per histological section was lower in groups C (p < 0.0001), D (p < 0.0001) and E (p < 0.0001) compared with the control group B. Histological evaluation showed no retinal toxicity in any group. Electron microscopy revealed hyperoxia-induced mitochondrial dysmorphology in group B. Mitochondrial dysmorphology displayed dose-dependent gradual increase in IVB-injected eyes. Intravitreal bevacizumab induced no significant increase in apoptotic cell death. Conclusion: Bevacizumab suppresses endothelial cell proliferation in a ROP mouse model. In addition to hyperoxia-induced mitochondrial dysmorphology of C57BL/J6 retina, morphological findings implicate further mitochondrial vulnerability because of bevacizumab without increase in apoptotic cell death. Bevacizumab is a complete humanized murine monoclonal antibody against all isoforms of human vascular endothelial growth factor (VEGF). It has been approved by the Food and Drug Administration for treatment of metastatic colorectal cancer. Intravitreal bevacizumab, in off-label use, is also of benefit in the treatment of many retinal diseases with intraocular vascular proliferation in patients with corneal neovascularization, ischaemic retinopathy, such as diabetic retinopathy, retinopathy of prematurity (ROP) and retinal vein occlusion (Stolk et al. 1995; Mitchell et al. 1998; Mintz-Hittner & Kuffel 2008; Arevalo et al. 2009; Leydolt et al. 2009; Bonnin et al. 2009; Habot-Wilner et al. 2009). Vascular endothelial growth factor has been implicated as the major angiogenic stimulus responsible for the formation of intraocular neovascularization in these diseases, and drugs that inhibit the biological activity of VEGF represent a new paradigm in the treatment of intraocular neovascular diseases (Gragoudas et al. 2004). Currently used anti-VEGF drugs are pegaptanib, ranibizumab and bevacizumab. Pegaptanib is a ribonucleic acid aptamer that targets only the VEGF-165 isoform, ranibizumab and bevacizumab are recombinant antibodies with a pan-VEGF-A blocking activity (Mordenti et al. 1999; Ferrara et al. 2004; Gragoudas et al. 2004). There are limited data indicating structural and ultrastructural effect of intravitreally administered bevacizumab on retinal cells and organelles (Bakri et al. 2006; Manzano et al. 2006; Inan et al. 2007; Peters et al. 2007; Avci et al. 2009; Kim et al. 2008; Sharma & Chalam 2009). The aim of our study was to investigate the effect of intravitreal-injected bevacizumab in different concentrations on retinal structures by light and electron microscopy (EM) and to investigate the apoptotic cell death in an oxygen-induced retinopathy (OIR) of prematurity mouse model using C57BL/J6 mouse. The OIR in the mouse, with vascular development similar to the human, with reproducible and quantifiable proliferative retinal neovascularization, is useful for study of pathogenesis of retinal neovascularization as well as for the study of medical intervention for ROP and other retinal vasculopathies (Smith et al. 1994). All experimental procedures were approved by the local animal care committee of Baskent University and were carried out in accordance with the Association of Research in Vision and Ophthalmology’s Statement for the Use of Animals in Ophthalmic and Vision Research. The murine hyperoxia–normoxia-induced ROP model established by Smith et al. was used in this study. Briefly, newborn C57BL/J6 mice were exposed to a mean of 75 ± 2% oxygen from postnatal day 7 to postnatal day 12, with their nursing mothers. At postnatal day 12, the animals were returned to room air (21% oxygen). A commercially available formulation of bevacizumab (Avastin; Roche Pharma AG, Grenzach, Germany) was used. For the ROP mouse model, we used doses of 2.5, 1.25 and 0.625 μg bevacizumab, whereas 1.25 μg bevacizumab as being almost representative of the equivalent dosage of 1.25 mg bevacizumab given intravitreally in humans. For a 2.5 μg injection, 1 μl of the original suspension was injected. For 1.25 μg injection, 1 ml of the original suspension was diluted with 1 ml sterile saline and resuspended, whereupon 1 μl of the new suspension was immediately injected into the vitreous. For 0.625 μg injection, 1 ml of the original bevacizumab suspension was diluted two times with 1 ml sterile saline and 1 μl of the new suspension was injected into the vitreous. One microliter of bevacizumab was intravitreally injected with a 32-gauge needle and a Hamilton syringe under direct observation with a stereoscopic microscope, at the corneascleral junction, at the 6 o’clock position. The mice were deeply anaesthetized by means of intraperitoneal injection of ketamine hydrochloride (40 mg/kg) and xylazine hydrochloride (5 mg/ml). Additionally, the eye was desensitized by a drop of 0.5% proparacaine hydrochloride. Intravitreal injections were performed on postnatal day 12 by delivering of 1 μl bevacizumab into the vitreous cavity of the right eye. The contralateral eye received an intravitreal injection of 1 μl isotonic saline (NaCl) in the same position. Four mice of the same age that had been kept in room air without exposure to high levels of oxygen were used as negative controls. On postnatal day 17, the mice were killed using an intraperitoneal injection of ketamine hydrochloride (100 mg/kg) and xylazine hydrochloride (5 mg/ml), and the eyes were enucleated. A total of 35 of C57BL/J6 mice were exposed to 75 ± 2% oxygen from postnatal day 7 to postnatal day 12. On day 12, 10 mice (group C, n = 10 eyes) were injected with 2.5 μg intravitreal bevacizumab (IVB), 11 mice (group D, n = 11 eyes) were injected with 1.25 μg IVB, and 14 mice (group E, n = 14 eyes) were injected with 0.625 μg IVB in one eye. The contralateral eyes were injected with isotonic saline (control group = group B, n = 35 eyes). Four age-matched mice, maintained in room air, were used as negative controls (negative control = group A, n = 8 eyes). Enucleated eyes were examined on light microscopy (LM) (in groups A, B, C, D and E, 5, 32, 7, 8 and 11 eyes, respectively) and EM (three eyes in each group). The extent of apoptosis was investigated using terminal deoxynucleotidyl transferase-mediated nick end labelling (TUNEL) technique. Terminal deoxynucleotidyl transferase-mediated nick end labelling staining was performed using paraffin sections, which were used for LM (in group A five eyes, in groups B, C, D and E, seven eyes for each group). Enucleated eyes were fixed with 4% formalin and embedded in paraffin for light microscopic evaluation. Serial sections of the retina (6 μm thick) were obtained, starting from the optic disc. The second or third sections after the optic disc were taken for evaluation. One section per eye was evaluated. For quantitative assessment of retinal neovascularization, periodic acid-Schiff (PAS)- and haematoxylin-stained serial sections were used. Neovascularizations were quantified by counting the endothelial cell proliferation on the vitreal side of the inner limiting membrane (ILM) per histological section of the retina. In the morphological analysis of retinal layers, findings as cystic degeneration, hypocellularity or loss of the nuclear layer was investigated specifically in each group. Slides were examined using LM (OLYMPUS BX51, Germany). For quantitative assessment of retinal neovascularization, results are shown as the mean (± standard deviation [SD]) count of the endothelial cell nuclei. For electron microscopic examination, all tissues were fixed in phosphate buffer containing 2.5% gluteraldehyde for 2–3 hr; then they were postfixed in 1% osmium tetraoxide (OsO4) and dehydrated in a series of graded alcohols. After passing through propylene oxide, the specimens were embedded in Araldyte CY 212, 2-dodecenyl succinic anhydride (DDSA), benzyldimethyl amine (BDMA) and dibutylpytalate. Semithin sections were cut and stained with 1% toluidine blue and examined with a light microscope. Ultrathin sections were stained with uranyl acetate and lead citrate and examined with LEO 906E EM transmission electron microscope (TEM). Evaluation of ultrastructural morphology especially of inner and outer photoreceptor layers was performed in each group using EM. The EM and LM assessment of retinal tissues were done by two independent observers in blinded fashion. Enucleated globes were fixed in 4% paraformaldehyde and embedded in paraffin. Serial sections of the retina (6 μm thick) were obtained, starting from the optic disc. The third or fourth sections after the optic disc were taken for evaluation and stained with haematoxylin–eosin. One section per eye was evaluated. Terminal deoxynucleotidyl transferase-mediated nick end labelling staining was performed with a kit (In Situ Cell Death Detection Kit, AP, Roche Diagnostics GmbH, Mannheim, Germany), according to the manufacturer’s instructions. Two independent observers used in blinded fashion LM (OLYMPUS BX51, Germany) to look for TUNEL-positive cells in randomly selected fields on each slide at 100× magnification (oil immersion). Apoptotic TUNEL-positive cells were measured in 10 randomly selected fields on each slide. Statistical analyses were performed using PASW Statistics 17 (SPSS Inc., Chicago, IL, USA). One-way anova and Student’s paired t-test was used to determine the significance of difference between the groups. p values <0.05 were considered statistically significant. The degree of hyperoxia-induced neovascularization was quantified in serial paraffin sections by counting the endothelial cell nuclei on the vitreal side of the ILM. In group A (negative control group), there were no endothelial cell nuclei detected on the vitreal side of the ILM of the retina. In group B (control group), the retina contained multiple neovascular tufts extending into the vitreous (Fig. 1A). These tufts originated from the retinal vessels, forming clusters of immature endothelial cells. In this group, the mean ± SD number of endothelial nuclei anterior to the ILM was 19.3 ± 1.3 per histological section. Figure 1B is an electron micrograph of a similar area in Fig. 1A. Endothelial cell nuclei counts were 0.6 ± 0.7 in group C (2.5 μg IVB), 1.3 ± 0.9 in group D (1.25 μg IVB) and 6.4 ± 1.1 in group E (0.625 μg IVB). Regarding endothelial cell nuclei counts groups C, D and E displayed significant differences compared with group B, the control group (p < 0.0001). There was also significant difference between groups D and E (p < 0.0001). Significant differences were obtained, when group A was compared with groups B (p < 0.0001), D (p = 0.009) and E (p < 0.0001), respectively. However, no significant difference was found between groups C and D (p = 0.6) and between groups A and C (p = 0.6), respectively (Fig. 2). Compared with the control group (group B), endothelial cell nuclei counts were reduced by 97% in group C (2.5 μg IVB), 93% in group D (1.25 μg IVB) and 67% in group E (0.625 μg IVB). (A) Light micrographs of C57BL/J6 mouse retina. Isotonic saline-injected eye, exposed to hyperoxia from postnatal days 7–12 (group B, control group); arrows indicate neovascular tufts extending into the vitreous (original magnification ×20). (B) Electron micrograph: (group B, control group); arrow indicates neovascular tuft extending into the vitreous (original magnification ×1000). Histogram showing the count of neovascular cells [mean (SD)] on the vitreal surface of the inner limiting membrane of the retina with an experimental model of retinopathy of prematurity with C57BL/J6 mouse in different study groups. Morphological analysis of retinal layers using LM, neither IVB-injected groups (groups C, D and E) nor the control group (group B) and the negative control group (group A) did not reveal signs of cystic degeneration, hypocellularity or loss of the nuclear layer (Fig. 3). Light micrographs of C57BL/J6 mouse retina. Sections were taken from almost the same region of the retina in all groups. (A) Mouse retina exposed to room air (group A, negative control group). (B) Isotonic saline-injected eye, exposed to hyperoxia from postnatal days 7–12 (group B, control group); the arrow indicates endothelial cell proliferation. (C) Eye injected with 2.5 μg intravitreal bevacizumab (IVB) (group C). (D) Eye injected with 1.25 μg IVB (group D). (E) Eye injected with 0.625 μg IVB (group E). Original magnification ×20. Evaluation of ultrastructural morphology was performed in each group using EM. The evaluation of the ultrathin sections revealed no distinguishable sign of morphological changes in the negative control group (group A) including mitochondria in the inner segment of the photoreceptors (Fig. 4). In the control group (group B), there were some changes in the morphology of mitochondria seen as mottled matrix and electron-dense bodies in the central region of cristae surrounded by lytic matrix and extensive cristalysis in the inner segment of the photoreceptors (Fig. 5). These ultrastructural changes were apparent also in the IVB-injected groups C, D and E. To quantify the mitochondrial dysmorphology in the groups, we defined an atypical mitochondrion with mottled matrix and electron-dense bodies in the central region of cristae surrounded by lytic matrix and extensive cristalysis and counted the numbers of these in the fields of view using the same magnification (×3250) for each sample in given area in each group. The results are shown in Fig. 6. Regarding atypical mitochondria counts, groups C, D and E displayed significant differences (p = 0.001, p = 0.01 and p = 0.008, respectively) compared with group B, the control group. Significant differences were obtained, when group A was compared with groups B (p < 0.0001), C (p < 0.0001), D (p < 0.0001) and E (p < 0.0001), respectively. There was significant difference between groups C and D as well as groups C and E (p = 0.04, p = 0.003, respectively). There was no significant difference between groups D and E (p = 0.16). Electron micrograph: a section through the inner segments of photoreceptors cells belonging to the negative control group (group A). Mitochondria reflect the usual fine structural characteristics, with double membrane, tubular transversely oriented cristae and few small dense matrix granules. Electron micrograph: Group B. Changes in the mitochondrial morphology as mottled matrix and electron-dense bodies in the central region of cristae surroundet by lytic matrix and extensive cristalysis. Histogram showing the number of atypical mitochondria [mean (SD)] in different study groups in the retina of C57BL/J6 mouse using an experimental model of retinopathy of prematurity. For each sample, the number of TUNEL-positive cells was determined. In the negative control group (group A), control group (group B) and in the intravitreal-injected groups (groups C, D, and E), we detected apoptotic TUNEL-positive cells in the outer nuclear layer (ONL) and in the inner nuclear layer (INL) without significant difference between the groups (7, 8). No significant differences were obtained, when group A was compared with groups B (p = 0.70), C (p = 0.60), D (p = 0.60) and E (p = 1.0), respectively. There was no significant difference, when group B was compared with groups C (p = 0.87), D (p = 0.87) and E (p = 0.74), respectively. There was no significant difference between groups C, D and E, respectively (p = 1.0, p = 0.65, respectively). Furthermore, there was no difference between groups D and E (p = 0.65). Light micrographs of C57BL/J6 mouse retina showing assessed apoptotic cells using TUNEL assay. Each slide represents one of five independent experiments in group A–E. Apoptotic cells appear distinct deep pigmented (arrow) in the outer nuclear layer and inner nuclear layer in each group (original magnification ×100, oil immersion). Histogram showing the count of detected apoptotic cells [mean (SD)] in different study groups in the retina of C57BL/J6 mouse using an experimental model of retinopathy of prematurity. In the present study, using a well-established oxygen-induced ROP model with C57BL/J6 mice, we observed the effect of intravitreal-injected bevacizumab on retinal endothelial cell proliferation, furthermore the effect on retinal structures and apoptosis. Comparing the retinal endothelial cell nuclei count, we demonstrated a decrease in retinal endothelial cell count with increasing concentration of intravitreal-injected bevacizumab. These findings suggest that bevacizumab may have a dose-dependent antiangiogenic effect on retinal endothelial cell proliferation, whereas this effect is not linear. Previous investigators observed a dose-dependent reduction in choroidal endothelial cell proliferation to about 65% during exposure of pig choroidal endothelial cells to bevacizumab (Spitzer et al. 2006). Ameri et al. (2007) evaluated the effect of intravitreous bevacizumab (1.25 mg) after single injection in the pigmented rabbit retinal neovascularization model and demonstrated suppression of endothelial cell growth and reduction in vascular permeability. Zhang et al. (2009) described significantly reduced neovascularization, which was assessed by counting the endothelial cell nuclei in the nerve fibre layer and ganglion cell layer in the C57BL/J6 mouse retina in OIR model after intravitreal injection of bevacizumab. A single intraocular injection of bevacizumab is limited by the reduction in effective vitreous drug levels over time. In addition, it must be considered that bevacizumab targets only VEGF and has no direct effect on other mediators like FGF or TGF. Consequently, and the fact that the therapy of ocular neovascular diseases with bevacizumab is symptomatic rather than causative, a single injection may not be sufficient, and in view of this point safe concentrations of bevacizumab have to be evaluated (Rich et al. 2006; Mintz-Hittner & Kuffel 2008). It is well demonstrated that bevacizumab binds to murine VEGF, although much weaker than to human VEGF (Bock et al. 2007). Heiduschka et al. (2008) demonstrated that bevacizumab binds to endogenous VEGF in mouse retina. They also detected bevacizumab after intravitreal injection immunohistochemically in the retina of C57BL/6 mouse. This finding is in accordance with the results found by Shahar et al. (2006), who injected bevacizumab intravitreally in albino rabbits. Heiduschka et al. (2007) demonstrated full retinal penetration of bevacizumab after intravitreal injection in monkeys. Based on electrophysiological findings, bevacizumab was found to be nontoxic to the retina of rabbits and on the mouse retina and had no harm on retinal function (Shahar et al. 2006; Heiduschka et al. 2008). Manzano et al. (2006) also did not observe significant changes in the electroretinograms of albino rabbits or signs of retinal toxicity after intravitreal administration of bevacizumab at concentrations ranging from 0.025 to 2.5 mg/ml. Kim et al. (2008) observed no definite histological abnormalities after IVB injection at concentration 2.5 mg/ml in C57BL/6 mouse. Inan et al. (2007) reported normal retinal function and structure in electrophysiological investigation and in LM in rabbits after intravitreally injected bevacizumab at doses of 1.25 and 3.0 mg. Spitzer et al. (2006) reported that bevacizumab at higher concentrations (2.5 mg/ml) may be harmful to the retinal pigment epithelium cells. It is known that melanin granules have an affinity for lipophilic drugs (Dayhaw-Barker 2002). It would therefore be advisable to use pigmented tissue to demonstrate any possible drug toxicity to the human eye. In our study, bevacizumab did not cause morphological changes in LM in layers of the retina in eyes with pigmented tissue in C57BL/J6 mice in ROP model treated with 0.625, 1.25 and 2.5 μg IVB. Dorfman et al. (2006) described cytoarchitectural retinal changes in an oxygen-induced ROP model in albino rats in terms of gradual thinning of the outer plexiform layer and reduction in the number of horizontal cells. Natoli et al. exposed 3-month-old adult C57BL/J6 mice to 75% oxygen for 0, 3, 7, 14 and 35 days. They described hyperoxia caused photoreceptor-specific cell death in the C57BL/J6 retina. The retinal response was biphasic. In the C57BL/J6 mouse, the acute phase lasts less than 1 week. Data at 7 days appear to be transitional; by 14 days, the pattern of gene expression has changed and photoreceptor death has begun (Natoli et al. 2008). In our study, we exposed the C57BL/J6 juvenile mouse from postnatal day 7–12 to hyperoxia (75% oxygen). From postnatal day 12 to 17, the mice were returned to room air (21% oxygen), and on postnatal day 17 enucleation was realized. Compared to Natoli et al., we used newborn mice and exposed the mice to hyperoxia for 5 days. Furthermore, it is well known that in OIR hyperoxia deprivation induce relative hypoxia in the tissue (Pierce et al. 1996), and this provoke swelling, fragmentation of the cristae, condensation of the matrix and fading of the outer and inner membranes of the mitochondria (Benninghof & Dreckhahn 2008; Natoli et al. 2008). In accordance with literature, in our control group (group B), which represents the OIR group without bevacizumab, in ultrastructural morphological investigation using EM, there were mottled matrix and electron-dense bodies in the central region of cristae surrounded by lytic matrix and extensive cristalysis, maintaining the mitochondrial configuration in outer borders in the inner segment of the photoreceptors. These findings, visible in the hyperoxia-exposed control group, indicate hyperoxia vulnerability of C57BL/J6 retina. Peters et al. (2007) observed changes after intravitreal injection of 1.25 mg bevacizumab in cynomolgus monkey’s eye and described ultrastructural changes in the choriocapillaris as significant reduction in choriocapillaris endothelial cell fenestration. Inan et al. (2007) found in retina layers of rabbits ultrastructural morphological changes of mitochondria in the photoreceptor inner segment after intravitreal injection of bevacizumab of 1.25 and 3.0 mg. Swelling and disruption in the mitochondria and destruction in the cristae were described. Several reports have demonstrated that VEGF works as a survival factor protecting cells (Liu et al. 2000; Harmey & Bouchier-Hayes 2002). In our study, withdrawal of VEGF by bevacizumab may induce the advanced morphological mitochondrial changes in the study groups with increasing intravitreal-injected bevacizumab concentrations from 0.625 to 2.5 μg. The internal structure of mitochondria can change in response to their physiological state and reaction to a stress signal like exposure to hyper- or hypoxia, therapeutic drugs, growth factor withdrawal and ultraviolet radiation (Benitez-Bribiesca et al. 2000). The level of stress seems to be determining the morphological and functional change in mitochondria. These changes can induce survival of the cell or lead to apoptosis (Detmer & Chan 2007). To evaluate apoptotic cell death, we performed TUNEL staining. We detected apoptosis in the negative control group, in the control group and in the bevacizumab-injected groups, without significant increase in apoptotic cell death in bevacizumab-injected eyes. These results indicate that increased mitochondrial dysmorphology in the bevacizumab-injected groups may be a sign of reversible cell injury (Robins & Cotran 2005) without resulting in increased apoptosis. Actually, apoptosis occurs normally in many physiological processes and serves to eliminate harmful or unnecessary cells. Death by apoptosis is also responsible for loss of cells in a variety of pathologic states like hypoxia or cytotoxic agents (Robins & Cotran 2005). In our study, we detected physiological apoptotic process and no toxic effect of IVB in contractions from 0.625 to 2.5 μg in a ROP mouse model as examined by TUNEL staining. Avci et al. (2009) described increased apoptotic activity at higher bevacizumab doses after intravitreal injection of bevacizumab in rabbit. Inan et al. (2007) showed in immunhistochemical staining apoptotic expression in outer plexiform, outer nuclear and photoreceptor layers because of caspase-3, caspase-9 and bax protein expression in these layers in the rabbit eye. However, Kim et al. (2008) reported no significant increase in apoptotic cell death in the C57BL/6 mouse even after intravitreal injection of 25 mg/ml, 1 μl bevacizumab on P56. This study describes the results in the C57BL/J6 mouse in a ROP mouse model after IVB injection. Remtulla & Hallett (1985) investigated the optics of mouse eye from C57BL/J6 mouse with 20–23 weeks and described the mean axial length with 3.379 mm and vitreous volume nearly 5.3 μl. Schmucker & Schaeffel (2004) described the mean axial length of C57Bl/6 mouse on P22 with approximately 3.0 mm and with 3.34 mm on P100. Zhou et al. (2008) investigated the development of the refractive status and ocular growth in C57BL/6 mouse and described the mean axial length on P22 with 2.859 ± 0.040 mm. In our study, we measured on P17, day of the enucleation, the mean axial length of approximately 2.8 mm (data not shown). The human vitreous volume is nearly 5.200 μl (Oyster 1999). For the ROP mouse model, we used doses of 2.5, 1.25 and 0.625 μg, whereas 1.25 μg bevacizumab as being almost representative of the equivalent dosage of 1.25 mg bevacizumab given intravitreally in humans. We injected 1 μl of suspension into the vitreous. The main difficulty was to overcome the very limited vitreous space. We were not able to monitor intraocular pressure (IOP) during or after our injections. The fact that the vitreous bulges rather than leaks means that there is scope for normalization of IOP through the normal control mechanism. Furthermore, after the intravitreal injection, it may develop picayune reflux from the entry site as in human after the intravitreal injection. In conclusion, our study demonstrated dose-dependent suppression of retinal endothelial cell proliferation after single intravitreal injection of 2.5, 1.25 and 0.625 μg bevacizumab, respectively, in oxygen-induced ROP mouse model using C57BL/J6 mouse. Light microscopy did not show retinal toxicity in any group. Ultrastructural observation revealed acceleration of mitochondrial damage in the inner segment of the photoreceptors in increasing bevacizumab concentrations. There was no increasing apoptotic cell death in the IVB-injected groups. Further immunohistochemical and functional studies are necessary to determine toxic effects of intravitreal-injected bevacizumab, especially in different doses and after repeated injections. Testing of bevacizumab in the context of randomized experimental and clinical trials are warranted before definitive statements can be made on the safety and efficacy of bevacizumab in intraocular neovascular diseases. We are indebted to Tufan H, MD, PhD, Department of Pharmacology, Baskent University, Faculty of Medicine, Ankara-Turkey for critical review of the manuscript; and Bacanli D, DVM, PhD, Breeding Center, Baskent University, Faculty of Medicine, Ankara-Turkey for ongoing and enthusiastic support. Supported by the Research Fund of the Baskent University, Ankara, Turkey. Abstract of the article has been presented in part at EVER-2009, Portoroz-Slovenia. The authors have no conflict of interest." @default.
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• W2025375706 title "Structural consequences after intravitreal bevacizumab injection without increasing apoptotic cell death in a retinopathy of prematurity mouse model" @default.
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