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Buenos Aires, Argentina

Buitrago E.,University of Buenos Aires | Del Sole M.J.,CONICET | Torbidoni A.,Service of Hematology Oncology | Fandino A.,Service of Ophthalmology | And 5 more authors.
Experimental Eye Research | Year: 2013

Treatment of intraocular retinoblastoma with vitreous seeding is a challenge. Different routes of chemotherapy administration have been explored in order to attaining pharmacological concentrations into the posterior chamber. Intravitreal drug injection is a promissing route for maximum bioavailability to the vitreous but it requires a well defined dose for achieving tumor control while limited toxicity to the retina. Topotecan proved to be a promising agent for retinoblastoma treatment due to its pharmacological activity and limited toxicity. High and prolonged concentrations were achieved in the rabbit vitreous after 5 μg of intravitreal topotecan. However, whether a lower dose could achieve potentially therapeutic levels remained to be determined. Thus, we here study the pharmacokinetics of topotecan after 0.5 μg and the toxicity profile of intravitreal topotecan in the rabbit eye as a potential treatment of retinoblastoma. A cohort of rabbits was used to study topotecan disposition in the vitreous after a single dose of 0.5 μg of intravitreal topotecan. In addition, an independent cohort of non-tumor bearing rabbits was employed to evaluate the clinical and retinal toxicity after four weekly injections of two different doses of intravitreal topotecan (Group A, 5 μg/dose; Group B, 0.5 μg/dose) to the right eye of each animal. The same volume (0.1 ml) of normal saline was administered to the left eye as control. A third group of rabbits (Group C) served as double control (both eyes injected with normal saline). Animals were weekly evaluated for clinical and hematologic values and ocular evaluations were performed with an inverse ophthalmoscope to establish potential topotecan toxicity. Weekly controls included topotecan quantitation in plasma of all rabbits. Electroretinograms (ERGs) were recorded before and after topotecan doses. One week after the last injection, topotecan concentrations were measured in vitreous of all eyes and samples for retinal histology were obtained. Our results indicate that topotecan shows non linear pharmacokinetics after a single intravitreal dose in the range of 0.5-5 μg in the rabbit. Vitreous concentration of lactone topotecan was close to the concentration assumed to be therapeutically active after 5 h of 0.5 μg intravitreal administration. Eyes injected with four weekly doses of topotecan (0.5 or 5 μg/dose) showed no significant differences in their ERG wave amplitudes and implicit times in comparison with control (p > 0.05). Animals showed no weight, hair loss or significant changes in hematologic values during the study period. There were no significant histologic damage of the retinas exposed to topotecan treatments. After intravitreal administration no topotecan could be detected in plasma during the follow-up period nor in the vitreous of treated and control animals after 1 week of the last injection. The present data shows that four weekly intravitreal injection of 5 μg of topotecan is safe for the rabbit eye. Despite multiple injections of 0.5 μg of topotecan are also safe to the rabbit eye, lactone topotecan vitreous concentrations were potentially active only after 5 h of the administration. We postulate promising translation to clinics for retinoblastoma treatment. © 2013 Elsevier Ltd. Source

Borras E.,Molecular Genetics Unit | de Sousa Dias M.,Molecular Genetics Unit | Hernan I.,Molecular Genetics Unit | Pascual B.,Molecular Genetics Unit | And 4 more authors.
Clinical Genetics | Year: 2013

We explored an approach to detect disease-causing sequence variants in 448 candidate genes from five index cases of autosomal dominant retinitis pigmentosa (adRP) by sequence DNA capture and next-generation DNA sequencing (NGS). Detection of sequence variants was carried out by sequence capture NimbleGen and NGS in a SOLiD platform. After filtering out variants previously reported in genomic databases, novel potential adRP-causing variants were validated by dideoxy capillary electrophoresis (Sanger) sequencing and co-segregation in the families. A total of 55 novel sequence variants in the coding or splicing regions of adRP candidate genes were detected, 49 of which were confirmed by Sanger sequencing. Segregation of these variants in the corresponding adRP families showed three variants present in all the RP-affected members of the family. A novel mutation, p.L270R in IMPDH1, was found to be disease causing in one family. In another family a variant, p.M96T in the NRL gene was detected; this variant was previously reported as probably causing adRP. However, the previously reported p.A76V mutation in NRL as a cause of RP was excluded by co-segregation in the family. We discuss the benefits and limitations of our approach in the context of mutation detection in adRP patients. © 2013 John Wiley & Sons A/S. Source

Bouledjfane B.,Annaba University | Bennacer L.,Annaba University | Kahli M.S.,Service of Ophthalmology
2013 8th International Workshop on Systems, Signal Processing and Their Applications, WoSSPA 2013 | Year: 2013

Image sharpening is the essential preprocessing step when improving the angiographies retinal image quality. It is helpful for the vessel retinal analysis and for improving the quality of their. For this reason, we propose a new technique for image sharpening based on Unsharp Masking (UM), and Bidimensional Empirical Mode Decomposition (BEMD). Firstly, the image is decomposed into a set of bidimensional intrinsic mode functions (BIMFs) and the residual image. Afterward, a weighting mask is achieved from an edge map multiplied by a compensation factor. Then, we apply the weighting mask to the first mode. Finally, we perform the reconstruction of the sharpened image by summing the compensated BIMF1 with the rest of the other modes and the residual image. The proposed scheme is enhanced by means of deringing's step to overcome the overshooting introduced during image sharpening. The obtained results proved that the proposed approach is effective to sharpen retinal images. © 2013 IEEE. Source

Chantada G.L.,Service of Hematology Oncology | Sampor C.,Service of Hematology Oncology | Bosaleh A.,Service of Pathology | Solernou V.,Service of Pathology | And 2 more authors.
JAMA Ophthalmology | Year: 2013

IMPORTANCE Different staging systems for extraocular retinoblastoma have been published, but to date they have not been validated in large cohorts. OBJECTIVE To review 533 patients (and pathology slides) with retinoblastoma included in 4 protocols (January 1, 1988, to December 31, 2009) who received uniform treatment. DESIGN AND SETTING Retrospective review in a hospital setting. A critical analysis for detecting inconsistencies and omissions was performed. PARTICIPANTS Patients were reclassified according to the modified St Jude Children's Research Hospital staging system, Grabowski-Abramson staging system, International Retinoblastoma Staging System (IRSS), and American Joint Committee on Cancer TNM staging system. MAINOUTCOMEAND MEASURE The main outcome measure was disease-free survival (DFS), considering only extraocular relapse as an event. RESULTS In the IRSS and the St Jude system, higher stages correlated with poorer DFS. For intraocular disease, only the TNM system and the IRSS included pathological definitions, and all systems except for the IRSS included substages without differences in DFS. Omissions of factors significantly associated with lower DFS included scleral invasion by the TNM system and massive choroidal invasion by the Grabowski-Abramson system. The St Jude system omits postlaminar optic nerve involvement, but this omission did not correlate significantly with lower DFS because these patients received intensive therapy. No differences in DFS were observed among substages for metastatic disease except for the presence of central nervous system involvement. All staging systems had inconsistencies in definitions of extent of disease. No system provides guidelines for imaging. CONCLUSIONS AND RELEVANCE Only the IRSS and the St Jude system allowed for grouping of patients with increasing risk of extraocular relapse. For lower stages, only the IRSS considers all unequivocal pathological prognostic factors. For higher stages, all systems had redundant information, resulting in an excess of substages. Source

De La Cruz J.P.,Laboratorio Of Investigaciones Antitromboticas E Isquemia Tisular Liait | Del Rio S.,Service of Ophthalmology | Lopez-Villodres J.A.,Laboratorio Of Investigaciones Antitromboticas E Isquemia Tisular Liait | Villalobos M.A.,University of Malaga | And 2 more authors.
British Journal of Nutrition | Year: 2010

The aim of the present study is to evaluate the possible influence of virgin olive oil (VOO) on the effect of acetylsalicylic acid (ASA) in platelet aggregation, prostanoid and NO production and retinal vascular pattern in rats with experimental type 1-like diabetes. We used 100 male Wistar rats that were distributed into five groups: (1) non-diabetic rats (NDR); (2) untreated diabetic rats (DR); (3) DR treated with ASA (2mg/kg per d per os (p.o.);(5) DR treated with VOO (05ml/kg per d p.o.); (5) DR treated with ASA plus VOO. The duration of diabetes was 3 months, and each treatment was administered from the first day of diabetes. Variables that were quantified were platelet aggregation (Imax), thromboxane B2 (TxB2), aortic prostacyclin (6-keto-PGF1) and NO, and the percentage of retina with horseradish peroxidase-permeable vessels (HRP-PV). Diabetic rats showed a higher Imax (35%) and TxB2 (63%) than NDR, and a lower 6-keto-PGF11α, NO and HRP-PV than NDR (746%). ASA and VOO administration reduced these differences and prevented the percentage of HRP-PV (597% with ASA and 467% with VOO). The administration of ASA plus VOO showed a strong platelet inhibition (802 v. 234% for VOO and 506% for ASA+VOO, P<00001), and reduced HRP-PV differences to 316% (P<0001 with respect to DR and P<00001 with respect to DR treated with ASA). In conclusion, the administration of VOO to rats with type 1-like diabetes mellitus improves the pharmacodynamic profile of ASA, and increases its retinal anti-ischaemic effect. Copyright © The Authors 2010. Source

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