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Schultes, Klaus. "Ultrastructural characterization of ultraviolet induced corneal disease : an animal model." Master's thesis, University of Cape Town, 1994. http://hdl.handle.net/11427/27046.
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The majority of ancient people worshipped the sun and viewed it as a health - bringing deity. During the eighteenth and nineteenth century therapeutic benefits of sunlight exposure were beginning to be understood and by the end of the nineteenth century the importance of ultraviolet radiation was being realized. Danish physician Niels Finsen, whom many regard as the father of ultraviolet phototherapy, also stressed that it was ultraviolet radiation in the solar spectrum which cause sunburn. We now recognize that the small portion of ultraviolet radiation which reaches the earth's surface is not necessarily therapeutic, but in fact could be harmful to humans. There are numerous accounts of the harmful effects of UV radiation to the skin and the eye as a whole. These effects may be caused by either acute or chronic exposure to UV radiation. For example, some acute effects of UV-B radiation include conjunctivitis and photokeratitis. "Snow blindness" and "arc welders eye" are further examples of acute ultraviolet damage specifically to the surface of the cornea. On the other hand, chronic exposure to ultraviolet radiation is thought to be responsible for pterygia, climatic droplet keratopathy Hill and Maske (1989), cancers of the external eye, cataracts and various types of retinal diseases. The present study is an extension of ongoing studies on ultraviolet radiation damage to the cornea in the Department of Ophthalmology, University of Cape Town and Groote Schuur Hospital. Their specific interest lies in the causes and treatment of climatic droplet keratopathy. The aims of the present study are: 1) Establish a possible role of ultraviolet B radiation in human corneal diseases such as climatic droplet keratopathy and pterygium using the rabbit as an animal model. 2) Determine by means of SEM the initial effects and subsequent recovery of the epithelium after a 3-hour dose of ultraviolet B radiation. We refer to this study as "acute" response to ultraviolet B radiation. 3) To try and confirm the effects observed by SEM with ultrastructural studies using TEM. 4) In addition, we are also looking at the possible effects after exposing rabbit cornea to a daily dose of low level ultraviolet B radiation, over a long period of time. We refer to this as chronic exposure to ultraviolet B radiation. It is hoped that by exposing rabbits to ultraviolet light, principally ultraviolet B radiation, diseases similar to those found in humans could be simulated and disease progression studied. People are generally exposed to substantial amounts of UV radiation for a very long time. Since people generally live longer they will be exposed to an ever-increasing amount of solar UV radiation and subsequently, there is an increasing risk of developing corneal diseases. The possible threat to the ozone is also a real possibility and could lead to increased levels of ultraviolet radiation reaching the earth's surface. This will require a greater understanding of the very nature of corneal damage due to acute and chronic exposure. This study focusses mainly on the acute response to UV-B radiation since most studies have investigated effects of prolonged exposure to UV light. Accordingly, much less is known about acute exposure. Many people suffering from acute UV B radiation effects probably never visit the ophthalmologist or wait for a couple of days. This could also contribute to the fact that effects of short-term damage is not well documented.
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Yang, Juan. "Universal corneal epithelial-like cells derived from human embryonic stem cells in a defined, xeno-free, and albumin-free condition for cellularization of a corneal scaffold." Thesis, University of Macau, 2018. http://umaclib3.umac.mo/record=b3953938.
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Hammar, Björn. "Two New Corneal Diseases Characterized by Recurrent Erosions." Doctoral thesis, Linköpings universitet, Oftalmologi, 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-17490.
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Recurrent corneal erosions are a common complication of superficial corneal wounds. They most commonly arise following a trauma, in association with various corneal dystrophies, or are idiopathic. The main aim of this thesis was to investigate two hereditary corneal diseases with recurrent erosions in order to find out if they had been described before, and more specifically to describe the clinical picture and the morphological changes, differentiate them from other known autosomal dominant corneal dystrophies with a clinical resemblance, and to exclude genetic linkage to known corneal dystrophies with autosomal-dominant inheritance and a clinical resemblance. The thesis is based on two families of subjects belonging to different phenotypes. The subjects from Småland (Dystrophia Smolandiensis) belonged to a six-generation family, which included 171 individuals of whom 44 were affected individuals, and the family from Hälsingland (Dystrophia Helsinglandica) included sevengenerations of 342 individuals, of whom 84 were affected. The individuals in both families were investigated by collection of medical history through medical records and questionnaires assessing different aspects of the diseases, pedigree analysis, and from clinical examination. Haplotype analysis was used to exclude genetic linkage of both diseases to known autosomal-dominant corneal dystrophies with a clinical resemblance. The morphological changes in Dystrophia Smolandiensis were investigated by examining affected individuals with in-vivo confocal microscopy and/or slit-lamp biomicroscopy, and examining corneal tissue samples using histopathology and immunohistochemistry. In Dystrophia Helsinglandica, the morphological changes were described using in-vivo confocal microscopy and/or slit-lamp biomicroscopy, but also using videokeratography and corneal sensitivity measurement. The main results were the findings of two new corneal disorders with autosomal dominant inheritance, characterized by recurrent corneal erosions. In Dystrophia Smolandiensis the symptoms often started within the first year of life. The number of recurrences per year was highest from the onset and for about 30-40 years, and the duration of recurrence could stretch up to 21 days. The frequency of recurrences was variable in the disease from continuous symptoms to once a year and tended to decrease later in life. The risk of having recurrences did not disappear completely with age. Typical precipitating factors of recurrence were draught and a common cold. About two thirds of the affected individuals responded well to oral vitamin B treatment, but no other therapy has so far been successful. In Dystrophia Smolandiensis development of corneal opacifications or secondary scarring of varying type and degree was seen in about half of the subjects. Opacifications were first noted at the age of about 7 years, but usually first seen at the age of 20-40 years. Corneal grafting was performed in nine individuals, and recurrences were seen in all grafts. The corneal buttons showed epithelial hyperplasia, partial or total loss of Bowman’s layer, and subepithelial fibrosis in the light microscope. The deeper stroma, Descement’s membrane, and endothelium were normal. Confocal microscopy confirmed loss of Bowman’s layer and revealed that the corneal nerves either were normal in their sub-basal plexa or showed signs of regeneration. None of the morphological findings were specific. We believe that the opacifications are reactive corneal changes to repeated erosive events. The onset in Dystrophia Helsinglandica was usually at the age of 4-7 years and late-developing subepithelial fibrosis not significantly affecting visual acuity was seen in all affected individuals over the age of 37 years. The number of recurrences per year was highest from the onset and for about 20-30 years, and the duration of recurrence was usually up to about a week. The frequency of recurrences tended to decrease in the disease with increasing age, but did not cease completely. The precipitating factor of recurrence was typically a minor trauma. No therapy has so far been successful in the family. The corneal changes of affected individuals were classified into different stages from a nearly normal cornea to progressive fairly discrete subepithelial fibrosis of the central cornea. Discrete localized Subepithelial fibrosis in the periphery or mid-periphery (stage I) was the sole finding in 12% of the individuals. A more widespread subepithelial fibrosis, mainly in the mid-periphery, was found in 31% of the individuals (stage II). In stage III, the subepithelial fibrosis engaged the central cornea but did not affect the vision to a significant degree. In late phases of stage III small jellylike corneal irregularities could be seen. We believe that the opacifications are reactive changes to repeated erosive events. In conclusion this thesis describes two new corneal disorders – Dystrophia Smolandiensis and Dystrophia Helsinglandica.
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Alzubaidi, Rania S. M. "Fully automated computer system for diagnosis of corneal diseases. Development of image processing technologies for the diagnosis of Acanthamoeba and Fusarium diseases in confocal microscopy images." Thesis, University of Bradford, 2017. http://hdl.handle.net/10454/17142.
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Confocal microscopy demonstrated its value in the diagnosis of Acanthamoeba and fungal keratitis which considered sight-threatening corneal diseases. However, it can be difficult to find and train confocal microscopy graders to accurately detect Acanthamoeba cysts and fungal filaments in the images. Use of an automated system could overcome this problem and help to start the correct treatment more quickly. Also, response to treatment can be difficult to assess in infectious keratitis using clinical examination alone, but there is evidence that the morphology of filaments and cysts may change over time with the use of correct treatment. An automated system to analyse confocal microscopy images for such changes would also assist clinicians in determining whether the ulcer is improving, or whether a change of treatment is needed.
This research proposes a fully automated novel system with GUI to detect cysts and hyphae (filaments) and measure useful quantitative parameters for them through many stages; Image enhancement, image segmentation, quantitative analysis for detected cysts and hyphae, and registration and tracking of ordered sequence of images.
The performance of the proposed segmentation procedure is evaluated by comparing between the manual and the automated traced images of the dataset that was provided by the Manchester Royal Eye Hospital. The positive predictive values rate of cysts for Acanthamoeba images was 76%. For detected hyphae in Fusarium images, many standard measurements were computed. The accuracy of their values was quantified by calculating the percent error rate for each measurement and which ranged from 23% to 49%.
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Frida, Jonsson. "Underlying genetic mechanisms of hereditary dystrophies in retina and cornea." Doctoral thesis, Umeå universitet, Institutionen för medicinsk biovetenskap, 2017. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-130538.
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Inherited retinal and corneal dystrophies represent a group of disorders with great genetic heterogeneity. Over 250 genes are associated with retinal diseases and 16 genes are causative of corneal dystrophies. This thesis is focused on finding the genetic causes of corneal dystrophy, Leber congenital amaurosis (LCA), Stargardt disease and retinitis pigmentosa in families from northern Sweden. By whole exome sequencing a novel mutation, c.2816C>T, p.Thr939Ile, in Collagen Type XVII, Alpha 1 chain, COL17A1, gene was identified in several families with epithelial recurrent erosion dystrophy (ERED). We showed that the COL17A1 protein is expressed in the basement membrane of the cornea, explaining the mutation involvement in the corneal symptoms. We could link all the families in this study to a couple born in the late 1700s confirming a founder mutation in northern Sweden. Our finding highlights role of COL17A1 in ERED and suggests screening of this gene in patients with similar phenotype worldwide. Furthermore the genetic causes in several retinal degenerations were identified. In one family with two recessive disorders, LCA and Stargardt disease, a novel stop mutation, c.2557C>T, p.Gln853Stop, was detected in all LCA patients. In the Stargardt patients two intronic variants, the novel c.4773+3A>G and c.5461-10T>C, were detected in the ABCA4 gene. One individual was homozygous for the known variant c.5461-10T>C and the other one was compound heterozygote with both variants present. Both variants, c.4773+3A>G and c.5461-10T>C caused exon skipping in HEK293T cells demonstrated by in vitro splice assay, proving their pathogenicity in Stargardt disease. Finally, in recessive retinitis pigmentosa, Bothnia Dystrophy (BD), we identified a second mutation in the RLBP1 gene, c.677T>A, p.Met226Lys. Thus, BD is caused not only by common c.700C>T variant but also by homozygosity of c.677T>A or compound heterozygosity. Notably, known variant, c.40C>T, p.R14W in the CAIV gene associated with a dominant retinal dystrophy RP17 was detected in one of the compound BD heterozygote and his unaffected mother. This variant appears to be a benign variant in the population of northern Sweden. In conclusion, novel genetic causes of retinal dystrophies in northern Sweden were found demonstrating the heterogeneity and complexity of retinal diseases. Identification of the genetic defect in COL17A1 in the corneal dystrophy contributes to understanding ERED pathogenesis and encourages refinement of IC3D classification. Our results provide valuable information for future molecular testing and genetic counselling of the families.
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Zderic, Vesna. "Ultrasound-enhanced ocular drug delivery /." Thesis, Connect to this title online; UW restricted, 2004. http://hdl.handle.net/1773/8085.
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Hamilton, Kirsten School of Optometry & vVsion Science UNSW. "Corneal hydration and the accuracy of Goldmann tonometry." Awarded by:University of New South Wales. School of Optometry and vVsion Science, 2006. http://handle.unsw.edu.au/1959.4/30468.
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The purpose of this thesis was to investigate the effect of corneal swelling on the accuracy of Goldmann tonometry estimates of intraocular pressure (IOP). In the first experiment, central corneal thickness (CCT, ultrasonic pachymetry), IOP (Goldmann tonometry) and corneal curvature (keratometry) was measured in one eye of 25 subjects every two hours for 24 hours, except for 8 hours overnight (no measurements taken), and for the first two hours after awakening (measurement frequency 20 minutes). CCT (+20.1??10.9 pm) and IOP (+3.1??2.4 mmHg) peaked on eye opening, and then decreased at a similar rate (r=0.967, p<0.001) for the next two hours. Corneal swelling may have influenced the accuracy of Goldmann IOP measurements during this time. In the second and third studies, the CCT, IOP and corneal curvature were measured in both eyes of two groups of 25 subjects before and after the induction of corneal swelling, resulting from two hours of monocular closed eye contact lens wear. The increase in IOP was correlated to the increase in CCT at a rate of 0.33 to 0.48 mmHg per 10 pm, which signified an overestimation error in Goldmann IOP measurement. However, the change in IOP could not be accounted for solely by the change in CCT. In the fourth study, CCT, IOP and corneal curvature were used in conjunction with the Orssengo-Pye algorithm to determine the range of Young's modulus in the normal population, which was 0.29??0.06 MPa. Physiological variations in Young's modulus had a similar effect on Goldmann tonometry to CCT. In the fifth study, the data collected for studies 2 and 3 was used to calculate the Young's modulus changes associated with corneal swelling, again with the assistance of the Orssengo-Pye algorithm. No systematic change in Young's modulus was recorded after contact lens wear, but the model suggested that corneal biomechanical changes were responsible for the remainder of the change in IOP. All experimental results were combined to develop a model to calculate the diurnal variation of Goldmann IOP errors. The likely error in IOP due to overnight corneal swelling was 0.6 to 1.4 mmHg, which may explain as much as 45% (1.4 mmHg) of the 3.1 mmHg diurnal variation of IOP. In summary, small amounts of corneal swelling were shown to have a clinically significant impact on the accuracy of Goldmann tonometry. This may interfere with the measurement of the diurnal variation of IOP, particularly if measurements are taken prior to the resolution of overnight corneal swelling.
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Barbosa, Virginia Tessarine. "Emprego do etil-cianoacrilato ou do octil-cianoacrilato no preenchimento de lesões corneais, após ceratectomia lamelar em coelhos /." Jaboticabal : [s.n.], 2007. http://hdl.handle.net/11449/89026.
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Orientador: José Luiz LausBanca: Duvaldo Eurides
Banca: Márcia Rita Fernandes Machado
Resumo: São diversas as indicações para o emprego de adesivos derivados do cianoacrilato na área médica. Em oftalmologia humana, há décadas, estes biomateriais são utilizados com resultados satisfatórios. Entretanto, em veterinária, ainda são escassos o conhecimento de suas propriedades e a sua aplicação. Considerando o interesse em se avaliar o comportamento do etil-cianoacrilato, comparativamente ao octil-cianoacrilato, clínica e histopatologicamente, em córneas de coelhos, empregaramse 36 animais, nos quais, após ceratectomia lemelar de 3 mm de diâmetro, os adesivos foram aplicados e recobertos por uma fina película acelular. No pós-operatório, foram realizadas avaliações gerais (dias 1 a 10), exames oftálmicos (dias 0, 1, 3, 5, 7, 10, 14, 21, 30, 44 e 60) e estudos histopatológicos (períodos 3, 7, 14, 21, 30 e 60). Consideraram-se, ainda, os custos e disponibilidade dos adesivos. Clinicamente, houve diferença significativa para as variáveis, consumo de água, atitude, blefarite, edema corneal, teste da fluoresceína e tempo de permanência dos adesivos. À histopatologia, para o etil-cianoacrilato, já nos primeiros períodos de avaliação, observou-se epitelização corneal, organização do colágeno e moderada reação inflamatória. Para o octil-cianoacrilato, constatou-se a permanência do adesivo até as fases mais tardias, sob o qual, mais lentamente os eventos de reepitelização e organização do colágeno ocorreram com reação inflamatória discreta. Os custos e disponibilidade de aquisição do etil-cianoacrilato foram mais acessíveis do que os do octil-cianoacrilato.
Abstract: There are several indications for the employment of adhesives derived from the cyanoacrylate in the medical area. In human ophthalmology, from decades, the cyanoacrylates have been used with satisfactory results. However, in veterinary medicine, there is a scarcity of knowledge of its properties and applications. Considering the objective of evaluating the behavior of the ethyl-cyanoacrylate, comparatively to octhyl-cyanoacrylate, clinically and histopatologically, in rabbit corneas, there were used 36 animals. After lamellar keratectomy with 3 mm of diameter the adhesives was applied and recovered with a fine pellicle. In the post operative period general (days 1 to 10), ophthalmic (days 0, 1, 3, 5, 7, 14, 21, 30, 44 and 60) and hystopathologic (periods 3, 7, 14, 21, 30 and 60) exams was performed. There was also considered the costs and accessibility of the adhesives. Clinically, there were significant differences for the variables water consumption, attitude, blepharitis, corneal edema, fluorescein test and adhesive permanence time. With respect to the histopathological evaluation, for the treatment with ethyl-cyanoacrylate, there was observed already in the very first periods of evaluation, corneal epitelization, collagen organization and moderate inflammatory reaction. For the octhyl-cyanoacrylate treatment, there was observed the adhesive permanence until later phases, under which more vagarously the events of reepithelization and collagen organization occurred with a discrete inflammatory reaction. The ethyl-cyanoacrylate presented minor costs and more facility to acquire.
Mestre
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Costa, Dacio Carvalho. "Uso de triancinologia subconjuntival no tratamento da rejeição endotelial do transplante de cornea." [s.n.], 2009. http://repositorio.unicamp.br/jspui/handle/REPOSIP/311490.
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Orientador: Newton Kara-JoseTese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas
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Resumo: Objetivo: Comparar a eficácia da injeção subconjuntival de 20 mg de triancinolona associada a prednisolona 1% tópica com a injeção intravenosa de 500 mg de metilprednisolona associada a prednisolona 1% tópica no tratamento da rejeição endotelial de transplante de córnea. Métodos: Estudo caso-controle realizado no Hospital das Clínicas da UNICAMP. Os pacientes submetidos a transplante penetrante de córnea que apresentaram primeiro episódio de rejeição endotelial com até 15 dias do início dos sintomas durante o período de novembro de 2005 a outubro de 2006 foram tratados com injeção subconjuntival de 20 mg de acetonido de triancinolona associado a acetato de prednisolona 1% tópico. Estes pacientes foram pareados por idade e diagnóstico com pacientes submetidos a tratamento com injeção intravenosa de 500 mg de succinato sódico de metilprednisolona associado a acetato de prednisolona 1% tópico e analisados quanto à capacidade de reversão do episódio de rejeição, pressão intraocular aos 30 dias e acuidade visual ao final de 1 ano. Resultados: 16 pacientes foram tratados com 20 mg de triancinolona subconjuntival e prednisolona 1% tópica durante o período de recrutamento e foram pareados com 16 pacientes tratados com 500 mg de metilprednisolona intravenosa e prednisolona 1% tópica. Ao final de 1 ano, o grupo tratado com triancinolona obteve melhores resultados do que o grupo tratado com metilprednisolona (p=0,025), obtendo 15 pacientes com córnea transparente enquanto o grupo tratado com metilprednisolona obteve 10 pacientes. 3 pacientes do grupo tratado com triancinolona apresentaram segundo episódio de rejeição durante o seguimento e foram retratados com sucesso enquanto no grupo da metilprednisolona, 4 pacientes apresentaram segunda rejeição, com 2 pacientes apresentando falência com o retratamento e 2 obtendo sucesso. A pressão intraocular subiu nos dois grupos (p=0,002) após 30 dias, porém não houve diferença entre os grupos (p=0,433). A acuidade visual melhorou após 1 ano em ambos os grupos (p=0,049) e o grupo tratado com triancinolona obteve melhor acuidade visual (p=0,002). Conclusão: A injeção subconjuntival de 20 mg de triancinolona combinada com prednisolona 1% tópica mostrou-se mais eficaz em reverter episódios de rejeição de transplante de córnea neste estudo caso-controle do que a aplicação intravenosa de 500 mg de metilprednisolona. Estudos adicionais necessitam ser realizados para verificar a segurança e eficácia deste tratamento em grandes populações
Abstract: Purpose: To compare the efficacy of 20 mg subconjunctival triamcinolone in association with topical prednisolone 1% to 500 mg intravenous methylprednisolone in association with topical prednisolone 1% in the treatment of cornea endothelial graft rejection. Methods: Case-control study carried out at State University of Campinas Hospital. Patients submitted to penetrating keratoplasty that presented first episode of corneal endothelial rejection within 15 days of symptoms onset between November 2005 and October 2006 were treated with 20 mg subconjunctival injection of triamcinolone acetate in association with topical prednisolone acetate 1%. These patients were matched for age and diagnosis to patients that were submitted to a single 500 mg intravenous injection of methylprednisolone sodium succinate in association with topical prednisolone acetate 1% and analyzed regarding the reversion of the rejection episode, intraocular pressure at day 30 and visual acuity at the end of 1 year. Results: 16 patients were treated with 20 mg subconjunctival triamcinolone and topical prednisolone 1% during the period of recruitment and were matched to 16 patients treated with 500 mg intravenous methylprednisolone and topical prednisolone 1%. At the end of 1 year, the group treated with triamcinolone had a better outcome than the group treated with methylprednisolone (p=0.025), having 15 patients with clear grafts as the group treated with methylprednisolone had 10 patients. 3 patients from the group treated with triamcinolone had new rejection episodes during follow-up and were retreated successfully as in the group treated with methylprednisolone 4 patients had a new rejection episode, with 2 progressing to failure and 2 to success with retreatment. Intraocular pressure rose in both groups (p=0.002) at day 30 but there were no statistically significant differences between the groups (p=0.433). Visual acuity improved after 1 year in both groups (p=0.049) and the group treated with triamcinolone had better visual acuities (p=0.002). Conclusions: 20 mg subconjunctival injection of triamcinolone acetonide associated with topical prednisolone acetate 1% showed to be more effective than 500 mg intravenous methylprednisolone associated with prednisolone acetate 1% in this case-control study. Further studies need to be accomplished to verify its safety and effectiveness in larger populations
Doutorado
Oftalmologia
Doutor em Ciências Médicas
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Lima, Mário Henrique Camargos de. "Avaliação da função visual de pacientes submetidos a transplante de córnea lamelar anterior profundo utilizando dissecção com fio." Universidade de São Paulo, 2015. http://www.teses.usp.br/teses/disponiveis/5/5149/tde-05012016-154155/.
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Objetivo: Avaliar a função visual de pacientes submetidos a transplante lamelar anterior profundo (DALK) utilizando a dissecção com tunelizador manual e fio. Métodos: Foram incluídos 33 pacientes com ceratocone que apresentavam BCVA <= 0,60 LogMar, miopia e astigmatismo entre 8,00 e 10,00D, K central médio > 53,00D, ausência de cicatrizes, espessura corneana mínima entre 300 e 400 um. Foi feita avaliação oftalmológica completa no pré e no pós-operatório de 6 a 8 meses. Estas avaliações foram complementadas com exame topográfico da córnea, microscopia especular para avaliação da densidade das células endoteliais corneanas, aberrometria corneana e exame de tomografia de coerência óptica do segmento anterior. As variáveis BCVA, UCBA e os valores totais das aberrações corneanas de alta ordem foram correlacionadas com a espessura do leito estromal residual. Resultados: Os pacientes submetidos à DALK apresentaram BCVA de 0,68 ± 0,27 LogMar o que representa BCVA superior a 20/40 em 60% da amostra analisada. Não foram observadas micro ou macroperfurações. Houve diminuição na contagem endotelial de 2702,87 ± 548,87 células por mm2 para 2282,10 ± 525,66 células por mm2 . A dissecção do estroma profundo com o fio facilitou a remoção de tecido estromal posterior, fato corroborado com o achado de que o leito residual estromal aferido foi de 49,18 ± 18,36 ?m na região central e foi inferior a 80 ?m em grande parte dos pacientes estudados. No que se refere à regularidade da dissecção, observou-se tendência a valores mais elevados de espessura residual na periferia (60,09 ± 17,70 ?m). Não houve correlação da BCVA, UCVA e do total de aberrações de alta ordem da córnea com a espessura do leito estromal residual. Conclusão: A apreciação dos resultados desse estudo mostrou que com a técnica utilizada para realização de DALK em portadores de ceratocone obteve-se resultados topográficos e funcionais semelhantes a outras técnicas consagradas pela literatura. A facilidade na dissecção do estroma profundo, a regularidade da dissecção e a presença de baixíssimo índice de conversão para transplantes penetrantes são encorajadoresObjective: Evaluate the visual function of patients undergoing deep anterior lamellar keratoplasty (DALK) using a manual spatula and a wire dissection. Methods: Thirty three keratoconus patients were included, meeting the following inclusion criteria: BCVA logMAR <=0,60, myopia and astigmatism between 8.00 and 10,00D, K central average > 53.00D, no corneal scars and minimal corneal thickness between 300 and 400 um. Complete ocular evaluation was performed preoperatively and postoperatively in 6-8 months. These assessments were supplemented by topographical survey of the cornea, specular microscopy to evaluate the density of corneal endothelial cells, corneal wavefront analysis and examination of optical coherence tomography of the anterior segment (Visante). The BCVA variables, UCVA and the total amounts of corneal higher-order aberrations were correlated with the the residual stromal bed thickness. Results: Patients that undergone to DALK with the described technique presented a BCVA of 0.68 ± 0.27 logMAR which represents a BCVA of more than 20/40 at 60% of the analyzed sample. There were no micro or macroperforations. We observed a small decrease in the endothelial cell count from 2702.87 ± 548.87 cells per mm2 to 2282.10 ± 525.66 cells per mm2. The dissection of the deep stroma with a wire facilitated the posterior stromal tissue removal, thus the measured stromal bed thickness was 49.18 ± 18.36 ?m in the central region and less than 80 ?m in the majority of the studied patients. As regards the dissection regularity, we showed a tendency to higher values of residual thickness at the periphery (60.09 ± 17.70 ?m). There was no correlation of the BCVA, UCVA and total corneal higher-order aberrations with the residual stromal bed thickness. Conclusion: The assessment of the study data showed that the described technique achieved a topographical and functional result similar to other techniques consecrated by literature. The shallow learning curve, the ease to perform the dissection of the deep stroma, the postoperative stromal regularity and the presence of very low conversion rate for penetrating keratoplasty are encouraging
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Fonzar, Joice Furtado [UNESP]. "Uso subconjuntival de lipossomas com rapamicina e tacrolimus tópico no tratamento de ceratoconjuntivite seca em cães." Universidade Estadual Paulista (UNESP), 2014. http://hdl.handle.net/11449/123280.
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Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
O presente estudo teve por objetivo avaliar o emprego da associação de Tacrolimus tópico com lipossomas contendo Rapamicina, em cães com ceratoconjuntivite seca grave, sem resposta a tratamentos convencionais. Foram estudados 29 olhos com valor de teste lacrimal de Schirmer menor que 5 mm/minuto. Os cães receberam, a cada 15 dias, durante dois meses, injeção subconjuntival de lipossomas com Rapamicina na dose de 0,4mg/ml, sendo mantida a medicação tópica com colírio de Tacrolimus 0,03%. Avaliação ocular completa, utilizando-se do protocolo de McDonald e Shadduck modificado, bem como testes de produção lacrimal Schirmer I e II e tempo de ruptura do filme lacrimal, foram realizados a cada 15 dias. O tratamento empregado não gerou efeitos adversos oculares em nenhum animal estudado. A associação de Tacrolimus tópico com lipossomas contendo Rapamicina foi eficaz na atenuação dos sinais clínicos de ceratoconjuntivite seca em cães, bem como incrementou a produção lacrimal e a qualidade da lágrima dos animais tratados
The present study aimed to evaluate the use of the association of topical Tacrolimus with liposomes containing Rapamycin in dogs with severe keratoconjunctivitis sicca, non-responsive to conventional treatments. Were studied 29 eyes with Schirmer tear test value of less than 5 mm/min. The dogs received every 15 days a subconjunctival injection of liposomes with Rapamycin at a dose of 0.4 mg/ml for two months. Topical eye drop medication was maintained with 0.03% Tacrolimus. Complete ophthalmologic evaluation using a modified McDonald-Shadduck protocol, as well as Schirmer tear tests I and II and tear film break up time were made every 15 days. The treatment used did not cause ocular side effects in any animal studied. The association of topical Tacrolimus with liposomes containing Rapamycin was effective in alleviating the clinical signs of keratoconjunctivitis sicca in dogs, as well as increased tear production and tear film quality of the studied animals
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Fonzar, Joice Furtado. "Uso subconjuntival de lipossomas com rapamicina e tacrolimus tópico no tratamento de ceratoconjuntivite seca em cães /." Botucatu, 2014. http://hdl.handle.net/11449/123280.
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Orientador: José Joaquim Titton RanzaniBanca: Cláudia Valéria Seuller Brandão
Banca: Geórgia Nadalini Rodrigues
Banca: Daniela Nogueira Cremonini
Banca: Maria Guadalupe Sereno
Resumo: O presente estudo teve por objetivo avaliar o emprego da associação de Tacrolimus tópico com lipossomas contendo Rapamicina, em cães com ceratoconjuntivite seca grave, sem resposta a tratamentos convencionais. Foram estudados 29 olhos com valor de teste lacrimal de Schirmer menor que 5 mm/minuto. Os cães receberam, a cada 15 dias, durante dois meses, injeção subconjuntival de lipossomas com Rapamicina na dose de 0,4mg/ml, sendo mantida a medicação tópica com colírio de Tacrolimus 0,03%. Avaliação ocular completa, utilizando-se do protocolo de McDonald e Shadduck modificado, bem como testes de produção lacrimal Schirmer I e II e tempo de ruptura do filme lacrimal, foram realizados a cada 15 dias. O tratamento empregado não gerou efeitos adversos oculares em nenhum animal estudado. A associação de Tacrolimus tópico com lipossomas contendo Rapamicina foi eficaz na atenuação dos sinais clínicos de ceratoconjuntivite seca em cães, bem como incrementou a produção lacrimal e a qualidade da lágrima dos animais tratados
Abstract: The present study aimed to evaluate the use of the association of topical Tacrolimus with liposomes containing Rapamycin in dogs with severe keratoconjunctivitis sicca, non-responsive to conventional treatments. Were studied 29 eyes with Schirmer tear test value of less than 5 mm/min. The dogs received every 15 days a subconjunctival injection of liposomes with Rapamycin at a dose of 0.4 mg/ml for two months. Topical eye drop medication was maintained with 0.03% Tacrolimus. Complete ophthalmologic evaluation using a modified McDonald-Shadduck protocol, as well as Schirmer tear tests I and II and tear film break up time were made every 15 days. The treatment used did not cause ocular side effects in any animal studied. The association of topical Tacrolimus with liposomes containing Rapamycin was effective in alleviating the clinical signs of keratoconjunctivitis sicca in dogs, as well as increased tear production and tear film quality of the studied animals
Doutor
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Lewis, David. "Proteoglycans in normal and diseased cornea." Thesis, Lancaster University, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.250553.
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Lee, Graham Andrew. "Advances in anterior segment disease / Graham A. Lee." [St. Lucia, Qld.], 2003. http://www.library.uq.edu.au/pdfserve.php?image=thesisabs/absthe18442.pdf.
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Hammar, Björn. "Two new corneal diseases characterized by recurrent erosions /." Linköping : Department of Clinical and Experimental Medicine, Linköping University, 2009. http://www.bibl.liu.se/liupubl/disp/disp2009/med1114s.pdf.
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Mwaikambo, Bupe Rose. "Emerging roles for the CD36 scavenger receptor in neovascular ocular disease." Thesis, McGill University, 2008. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=115899.
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Ocular neovascularization (NV) associated with corneal NV, ischemic retinopathies and age-related macular degeneration is a leading cause of severe vision loss. While numerous contributing factors have been identified, the potential role of the CD36 scavenger receptor has been largely overlooked notwithstanding its crucial involvement in normal retinal function. Accordingly, the central aim of this work was to elucidate the contribution and regulation of CD36 during ocular NV using the cornea as a model.Initial work investigating the role of CD36 10 maintaining corneal avascularity, an important feature of the normal cornea, revealed that genetic ablation of CD36 elicits age-related corneal NV. Subsequent studies using a pathophysiologically relevant model of inflammatory corneal NV showed constitutive expression of CD36 in the normal cornea with marked induction in the neovascularized cornea. Importantly, activation of CD36 suppressed and induced regression of corneal NV, effects that proceeded via concerted inhibition of VEGFA, JNK-1, and cJun.
Because hypoxia is a fundamental stimulus for angiogenesis, it was pertinent to explore the role and regulation of CD36 during hypoxia. We demonstrate that CD36 expression was significantly elevated in hypoxia-exposed corneal and retinal tissue and in hypoxic retinal pigment epithelial cells. Essential contributions of hypoxia-inducible factor (HIF)-1 and reactive oxygen species were also established. Functional consequences were depicted by augmentations in CD36 phagocytic and anti-angiogenic activities.
Collectively, data disclose CD36 as an important modulator of corneal avascularity and inflammatory corneal NV; this imparts several interesting avenues for future research on the involvement of CD36 in neovascular diseases of the eye. Novel data further identify CD36 as a hypoxia and HIF-1 regulated gene thus creating a framework for future elucidation of the regulatory aspects of this receptor.
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Bhattacharya, Pradipta. "The corneal epithelium in health and disease." Thesis, Queensland University of Technology, 2022.
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The cornea is the anterior transparent layer of the eye, and understanding corneal epithelial morphology is valuable in monitoring ocular surface diseases. A meta-analysis showed that central corneal basal cell density and nerve parameters were reduced in diseases affecting the ocular surface including limbal stem cell deficiency. Using newly developed image analysis techniques it was observed that epithelial cell density was highest at the corneal nerve whorl region. A decrease in epithelial cell density was observed in eyes with conjunctival ultraviolet autofluorescence, i.e. with sunlight-induced UV damage.
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Basche, M. D. A. "Gene therapy approaches to disease of the cornea and anterior chamber." Thesis, University College London (University of London), 2014. http://discovery.ucl.ac.uk/1451385/.
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The field of ocular gene therapy has become one of the most developed areas within the wider gene therapy field, however most work to date has focused upon the retina with the cornea, by comparison, having seen relatively little application of gene therapy. This thesis describes a program of work to further develop viral gene therapy approaches to the three cellular layers of the cornea, with particular emphasis upon the application of novel vector technologies and overcoming the various challenges presented by each layer. Gene therapy of the corneal endothelium has to date largely aimed to increase or maintain endothelial cell density to improve the quality of donor corneas for engraftment. Such a strategy however carries an inherent risk of oncogenesis and this study has therefore aimed to improve the safety profile of endothelial gene delivery methods. The transduction profile of various AAV serotypes within the corneal stroma was also investigated, and the most promising results applied in an augmentation gene therapy approach to prevent corneal neovascularisation. The selected methodology is shown to mediate high level transgene expression and, when delivering the antiangiogenic factor sFlt1, was highly effective in preventing haem (but not lymph) angiogenesis in a murine model of induced corneal neovascularisation. If long term gene delivery to the corneal epithelium is to be achieved it must be targeted to the limbal epithelial stem cells (LESCs) responsible for the continuous regeneration of the layer. This study has convincingly demonstrated gene delivery to these cells in vivo for the first time, with the methodology developed leading to a lasting transgene expression throughout the LESC daughter cell lineages that comprise the epithelium. In addition to potential application in the treatment of congenital epithelial dystrophies this technique may also provide new insights into LESC biology and the cellular dynamics of epithelial renewal.
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Durham, Steven Edward. "Age and disease related changes of the mitochondria in human ocular tissues." Thesis, University of Newcastle Upon Tyne, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.366638.
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Jones, Frances E. "The corneal endothelium in development, disease and surgery." Thesis, Cardiff University, 2013. http://orca.cf.ac.uk/49911/.
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Aims: The cornea is a tough, transparent tissue providing the primary refractive element of the eye. The stroma consists of specially arranged collagen required for corneal transparency. Correct stromal hydration is important in the maintenance of transparency, a feature controlled by the endothelial cells on the posterior surface of the cornea. The aims of this research were firstly to investigate the morphology of corneal endothelial cells and their expression of the sodium bicarbonate cotransporter during avian embryonic development and secondly, to clarify the effect of disease, surgery and drugs on the posterior cornea including in particular the corneal endothelium. Methods: The corneal endothelial cell morphology and posterior stroma were examined using transmission electron microscopy to determine the ultrastructure of the cells and collagen fibril arrangement in the stroma in all results chapters. Immunohistochemistry and A-scan ultrasonography were employed to identify the presence of the Na+HCO3- cotransporter and to determine the thickness changes in embryonic chick cornea, respectively. Electron tomography was also used to determine the collagen arrangement in Descemet’s membrane. Results: The expression of the Na+HCO3- cotransporter was identified in the endothelial layer of the embryonic chicks at all stages imaged. Central corneal thickness increased in the initial stages of development before a plateau between the E12-E15 developmental period followed by a steady thickness decrease. The ultrastructure of Descemet’s membrane was determined using electron tomography of transverse and en face resin embedded sections from which a model was produced. Polygonal and elongated structures were observed with proteoglycans present at the intermodal regions of the collagenous structures. The polygonal lattice visualised in en face sections appeared to be composed of stacked globular domains which were integrated into the collagen type VIII model. Predominant changes in the Col8a2 knock-in mouse models were observed in the posterior cornea. Differences included increased proteoglycans at the Descemet’s endothelial interface, dilated rough endoplasmic reticulum and focal posterior oedema. This animal model exhibits features similar to those seen in the human form of early-onset Fuchs’ endothelial corneal dystrophy, unlike previous models reported. The final chapter is concerned with regeneration of the corneal endothelial cells. Tissue from posterior corneal surgery examined using electron microscopy revealed the presence of the host endothelial cells and fibrous tissue at the interface in non-Descemet’s membrane stripping automated endothelial keratoplasty and interface haze in Descemet’s membrane stripping automated endothelial keratoplasty. However, these features did not appear to interfere with the adhesion of the graft nor the clarity. Finally, ultrastructural analysis of Rho-kinase inhibited cells showed cells with typical morphology when compared with the untreated group Conclusions: 1) The Na+HCO3- cotransporter is present in the embryonic cornea. It is possible that the cotransporter is involved in the developmental stages and probably the thickness changes we observe during this period. 2) The ultrastructure of Descemet’s membrane appears to be composed of stacked globular domains arranged in a polygonal lattice alongside more elongated structures interspersed with proteoglycans within the internodal regions. 3) Our studies have helped validate Col4a2 mice as a promising Fuchs’ endothelial corneal dystrophy model. 4) Our investigation into posterior corneal surgery revealed ultrastructural changes that occur post-surgery at the graft interface.
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Porter, Louise. "Brittle cornea syndrome : molecular characterisation of a multisystem disorder." Thesis, University of Manchester, 2015. https://www.research.manchester.ac.uk/portal/en/theses/brittle-cornea-syndrome-molecular-characterisation-of-a-multisystem-disorder(6a34fd5d-14ac-40cc-9206-1caf06c9ef51).html.
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Brittle cornea syndrome (BCS) is an autosomal recessive, multisystemic connective tissue disorder characterised by extreme corneal thinning and fragility. Mutations in transcription factors ZNF469 and PRDM5 cause BCS types 1 and 2, respectively. Both genes are believed to regulate the transcription of extracellular matrix (ECM) components, particularly fibrillar collagens, and are suggested to act on a common pathway. Molecular diagnosis is available for affected patients, and those at risk of being heterozygous carriers. Chapter 3 presents the identification of mutations in ZNF469 in 14 families with BCS, and evidence for the downregulation of ECM-associated transcripts in skin fibroblasts from patients with ZNF469-associated disease by Q-PCR.Chapters 4 and 5 focus on PRDM5-associated disease. Chapter 4 highlights previously undescribed and potentially phenotype-related aspects of PRDM5- associated BCS. In chapter 4, a potential role for PRDM5 in development of Bruch’s membrane is suggested, by the observation of significantly reduced expression of major components of Bruch’s membrane, including collagens types I, III, and IV in patients with PRDM5-associated disease using immunohistochemistry. A first description of PRDM5 expression in the human eye is also presented in chapter 4. In chapter 5, a potential role for PRDM5 in retinal vasculogenesis is suggested. PRDM5-related disease also offers an in vivo opportunity to observe a subset of epigenetic regulatory mechanisms in an inherited eye disease, providing mechanistic insights, presented in chapter 5. Examination of PRDM5 interaction partners by pull-down and mass spectrometry reveals the diminished interaction of a PRDM5 construct carrying a BCS-associated mutation with repressive complexes, and, through studies on fibroblasts and retinal tissue from patients, we suggest a role for dysregulation of the repressive histone mark H3K9 di- methylation in vivo. These findings suggest a role for a molecular network surrounding dysregulated H3K9 di-methylation in PRDM5-associated disease. Finally, chapter 6 expands the study of a rare disease into more common diseases investigating the role of genetic variations in ZNF469 and PRDM5 in keratoconus, an ocular disorder resulting in progressive corneal thinning. I identified enrichment of rare potentially pathogenic alleles in ZNF469 in 12.5% of keratoconus patients, highlighting ZNF469 as the most significant genetic factor responsible for keratoconus identified to date. In conclusion, this study of a rare disease, BCS, has provided translational research insights (chapter 3), functional insights (chapter 4) mechanistic insights (chapter 5) and has expanded into other, less rare, diseases (chapter 6).
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Brantman, Karen Renee. "Tear Film VEGF in Dogs with Vascularizing Corneal Disease." Thesis, Virginia Tech, 2013. http://hdl.handle.net/10919/23166.
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This body of work encompasses two studies: the collection of canine tears via a novel polyesterrod and the comparison of VEGF-A concentrations in tears from dogs with normal and
vascularized corneas. The first study used polyester rods for tear collection in dogs. Fluid volume and VEGF recovery characteristics, as well as potential binding of VEGF to the rod, were determined. Tears were harvested from normal dogs using rods and glass capillary tubes. Tears were assayed for tear film VEGF using a commercial canine VEGF sandwich ELISA kit. Dilutions of VEGF standard were wicked into the rods or drawn into capillary tubes, eluted, and assayed. Percent volume recovery is adequate for polyester rods as is percent VEGF recovery. VEGF is detectable in normal canine tears.The second study harvested tear samples from eyes of dogs with vascularizing corneal disease, as well as the contralateral unaffected eye of unilaterally diseased dogs, and normal dogs. Vascularization scores were assigned to diseased eyes and tear film VEGF concentration was assayed as above. Mean tear film VEGF concentration of diseased eyes did not differ from control eyes, and was not correlated with disease process, extent of vascularization, or other parameters. Tear film VEGF in unaffected eyes was significantly higher than control and vascularized eyes. Canine tear film VEGF exceeds biologically active concentrations, but does not correlate with state of corneal vascularization. VEGF-related control of corneal vascularization may be mediated by other proangiogenic factors.
Master of Science
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McPherson, Nicole A. "Public health implications of the 1540 nm laser on the cornea /." Download the dissertation in PDF, 2007. http://www.lrc.usuhs.mil/dissertations/pdf/NMcPherson2007.pdf.
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Williams, David Leonard. "Canine chronic superficial keratitis : histochemical characterisation and clinical management." Thesis, Royal Veterinary College (University of London), 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.307438.
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Segarra, López Sergi. "Estudios de escalada de dosis sobre los efectos del cloruro de benzalconio intracameral en conejos: un modelo animal de enfermedad endotelial corneal." Doctoral thesis, Universitat Autònoma de Barcelona, 2016. http://hdl.handle.net/10803/393871.
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Objetivo: Hallar una dosis de cloruro de benzalconio (BAC) que, inyectada por vía intracameral en conejos, provoque daño selectivo sobre el endotelio corneal, sin afectar al resto de estructuras intraoculares, creando un modelo animal repetible y reproducible de enfermedad endotelial corneal.
Materiales y métodos: Estudio ex vivo inicial con 40 ojos de conejo obtenidos post-mortem, que se dividieron en 8 grupos en función del compuesto inyectado por vía intracameral: control (sin inyección), BSS (solución salina balanceada), y concentraciones crecientes de BAC (0,005%, 0,01%, 0,025%, 0,05%, 0,1% y 0,2%). Estudio in vivo con 24 conejos, que fueron divididos en 4 grupos: BSS (grupo control) y BAC al 0,025%, 0,05% y 0,1%. Solamente se emplearon conejos sanos y ojos sin alteraciones. Las inyecciones intracamerales se efectuaron en el limbo esclerocorneal utilizando una aguja de 27G. con la ayuda de gafas lupa. En ambos estudios, se realizaron evaluaciones de exploración oftalmológica, paquimetría y microscopía especular (a las 0, 6, 24 y 48 horas en el estudio ex vivo; y a los 0, 2, 7 y 14 días en el estudio in vivo). A los 14 días, los conejos del estudio in vivo fueron eutanasiados. Al final de cada estudio, se realizaron tinciones vitales de las córneas para evaluar la morfología y viabilidad de las células endoteliales corneales (CECs). En el estudio in vivo también se hizo histopatología de los globos oculares.
Resultados: Estudio ex vivo: Comparado con BSS, la densidad de las CECs comenzó a disminuir de manera significativa a la concentración de BAC 0,025%, mientras que la superficie de las CECs, el grado de edema corneal y el espesor corneal aumentaron de forma significativa con BAC al 0,05%, 0,005% y 0,1%, respectivamente. Concentraciones de BAC al 0,05% y superiores ocasionaron aumentos significativos en la mortalidad y el pleomorfismo de las CECs, en comparación con el control y BSS. Estudio in vivo: Comparado con el BSS, concentraciones de BAC al 0,025% y superiores provocaron aumento significativo en el grado de edema y espesor corneales, y en la superficie y el polimegatismo de las CECs. La mortalidad de las CECs fue significativamente mayor a partir de BAC 0,05%. La densidad y hexagonalidad de las CECs disminuyeron significativamente en todos los grupos de BAC. BAC al 0,1% ocasionó mayor número de casos de congestión conjuntival y úlceras corneales. La histopatología no reveló alteraciones significativas que afectasen al resto de las estructuras oculares tras la inyección de BAC.
Conclusiones: La inyección intracameral de 0,1 ml de BAC al 0,05% en conejos provoca daño selectivo sobre el endotelio corneal, sin afectar al resto de estructuras intraoculares. Esta técnica, desarrollada y validada en un estudio ex vivo y otro in vivo, puede utilizarse para inducir un modelo animal repetible y reproducible de enfermedad endotelial corneal en conejos.Objective: Find a dose of benzalkonium chloride (BAC) which, injected into the anterior chamber in rabbits, causes a selective damage on the corneal endothelium, without affecting the rest of intraocular structures and thus can be used to induce a repeatable and reproducible animal model of corneal endothelial disease. Material and Methods: First, an ex vivo study was performed using 40 rabbit eyes obtained postmortem, which were classified into 8 groups depending on the injected compound: Control (no injection), Balance salt solution (BSS), and increasing concentrations of BAC (0.005%, 0.01%, 0.025%, 0.05%, 0.1% and 0.2%). Secondly, an in vivo study was performed using 24 New Zealand White rabbits, which were classified into 4 groups: BSS (control group); and 0.025%, 0.05% and 0.1% BAC. Only healthy rabbits and eyes without abnormalities were used. The intracameral injections were made at the corneoscleral limbus using a 27G needle and magnifying loupes. In both studies, follow-up assessments of ophthalmological examination, pachymetry and specular microscopy were performed (at 0, 6, 24 and 48 hours in the ex vivo study; and at 0, 2, 7 and 14 days in the in vivo study). Fourteen days after injection, the rabbits from the in vivo study were euthanized. At the end of each study, corneas were vital-stained and evaluated under the light microscope in order to assess the morphology and viability of the corneal endothelial cells (CECs). In the in vivo study, histopathology of the eye globes was also performed. Results: Ex vivo study: Compared to BSS, the CECs density began to decrease significantly with 0.025% BAC, while the CECs area, the degree of corneal edema and the corneal thickness increased significantly with 0.05%, 0.005% and 0.1% BAC, respectively. BAC concentrations of 0.05% and above caused significant increases in CECs mortality and pleomorphism, compared to control and BSS. In vivo study: Compared to BSS, concentrations of 0.025% BAC and above caused a significant increase in the degree of corneal edema and corneal thickness, and in CECs area and polymeghetism. CECs mortality was significantly higher with 0.05% BAC and above concentrations. The CECs density and hexagonality decreased significantly in all BAC groups. A concentration of 0.1% BAC resulted in a higher number of cases presenting with conjunctival congestion and corneal ulcers. Histopathology revealed no significant alterations affecting the rest of the ocular structures after BAC injection. Conclusions: Intracameral injection of 0.1 ml 0.05% BAC in rabbits causes a selective damage on the corneal endothelium, without affecting the rest of intraocular structures. This technique, developed and validated in an ex vivo and an in vivo study, could be used to induce a repeatable and reproducible animal model of endothelial corneal disease in rabbits.
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Cordes, Steffen [Verfasser]. "Endothelial dysfunction during Graft-versus-Host Disease / Steffen Cordes." Berlin : Freie Universität Berlin, 2018. http://d-nb.info/1155420799/34.
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Väisänen, T. (Timo). "Cellular localisation of type XIII collagen, and its induced expression in human neoplasias and corneal diseases." Doctoral thesis, University of Oulu, 2005. http://urn.fi/urn:isbn:9514279107.
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Abstract
Type XIII collagen belongs to the group of transmembrane collagens. In this thesis the plasma membrane localisation and function of type XIII collagen have been studied using cell biological methods.
Type XIII collagen was found to reside in focal adhesions. It appeared in these structures at a very early stage of their assembly and disappeared from them concurrently with focal adhesion proteins talin and vinculin. Insect cells expressing type XIII collagen showed an enhanced adhesion to certain matrix components. These localisation and adhesion data suggested that the function of type XIII collagen is related to cell adhesion. Supporting this, in tissues type XIII collagen was found to localise to cell-matrix and cell-cell adhesion structures.
Type XIII collagen was found to be partly present in cholesterol-enriched membrane microdomains. With other membrane proteins this localisation has been shown to be linked to ectodomain shedding. The connection between the membrane microdomain localisation and the ectodomain shedding of type XIII collagen was also characterised, and it was demonstrated that manipulation of the cellular cholesterol level affected the efficiency of the ectodomain shedding. Additionally, insights into intracellular shedding of type XIII collagen in the Golgi apparatus were obtained.
The study of type XIII collagen expression in human cancers revealed that it was enhanced especially in the desmoplastic cancer stroma. Since the increased expression of type XIII collagen was detected during the dysplastic stages, type XIII collagen may be involved in the early pathogenesis of cancer. The result indicated that type XIII collagen is involved in the matrix remodelling. In support of this, the cell culture experiments showed that the soluble type XIII collagen ectodomain altered the vitronectin-rich matrix unfavourable for cell adhesion and spreading. This may enhance cancer metastasis.
Type XIII collagen expression was also induced in the remodelled stroma of keratoconus and corneal wounds. Data suggested that myofibroblasts were responsible for the increased expression of type XIII collagen in these situations. Therefore both in cancer and in the corneal pathologies studied, type XIII collagen expression was induced by the activated stromal cells.
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Byström, Berit. "Laminins and alpha11 integrin in the human eye : importance in development and disease." Doctoral thesis, Umeå universitet, Oftalmiatrik, 2008. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-1950.
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The extracellular matrix (ECM) offers a protective shelter for cells and provides signaling paths important for cell to cell communication. ECM consists of basement membranes (BM) and interstitial matrix. BMs provide mechanical support for parenchymal cells, influence cell proliferation, survival, migration and differentiation. They are also important for tissue integrity. Laminins (LM) are the major non-collagenous component of BMs. Cell-ECM interactions, mediated by receptors, are indispensable during embryonic development, wound healing, remodeling and homeostasis of tissues. The integrins are the major cell-adhesion receptors. The expression of alpha11 integrin chain in the cornea is of great interest, as it is part of the alpha11beta1 integrin receptor for collagen type I, the predominant component of the corneal stroma. The aims were to thoroughly characterize the ECM in the developing and adult human eye, with particular focus on the cornea, LM and alpha11 integrin chains, and to examine alpha11 integrin chain in an animal model of corneal wound healing and remodeling. Human fetal eyes, 9-20 weeks of gestation (wg), and adult human corneas with different diagnosis were treated for immunohistochemistry with specific antibodies against LM and alpha11 integrin chains. Normal and knockout (ko) mice were treated with laser surgery to create a deep wound in the corneal stroma. The wound healing process was followed at different time points. The cellular source of alpha11 integrin chain was studied in cell cultures. In the fetal eyes, the BM of the corneal epithelium, the Descemet’s membrane (DM) and the Bruch’s membrane each had their specific combinations of LM chains and time line of development, whereas the lens capsule and the internal limiting membrane showed constant LM chain patterns. The epithelial BMs of normal and diseased adult corneas contained similar LM chains. The normal morphology of the epithelial BM was altered in the different diseases, particularly when scarring was present. In the scarred keratoconus corneas there were excessive LM chains. The majority of keratoconus corneas also expressed extra LM chains in the DM. At 10-17 wg alpha11 integrin chain was present in the human corneal stroma, especially in the anterior portion, but it was scarce at 20 wg, in normal adult corneas and in Fuchs’ endothelial dystrophy. In contrast, it was increased in the anterior portion of the stroma in keratoconus corneas with scarring. Alpha11 integrin ko mice had a defective healing with subsequent thinner corneas. Alpha11 integrin expression correlated to the presence of alpha-smooth muscle actin in vivo as well as in vitro. The distinct spatial and temporal patterns of distribution for alpha11 integrin and each of the LM chains suggest that they play an important role in human ocular differentiation. The selectively affected LM composition and the novel expression of alpha11 integrin chain in scarred keratoconus corneas as well as the pathologic healing in ko mice, indicate that alpha11 integrin and LM chains also play an important role in the process of corneal healing, remodeling and scarring and might participate in the pathogenesis of corneal disease. This knowledge is of practical importance for future topical therapeutic agents capable of modulating the corneal wound healing processes.
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MIKOU, ABDELOUAHHAB. "Contribution a l'etude de l'interaction lumiere-cornee : application a la decoupe de la cornee par le laser co 2." Université Louis Pasteur (Strasbourg) (1971-2008), 1987. http://www.theses.fr/1987STR13029.
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White, Tomas. "Structural studies of the corneal stroma with focus on the elastic fibre network in health and disease." Thesis, Cardiff University, 2016. http://orca.cf.ac.uk/97157/.
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The optical and biomechanical properties of the cornea are largely governed by the collagen-rich stroma, a layer that represents approximately 90% of the total thickness. It has been postulated that a novel corneal layer exists in the posterior stroma, immediately above Descemet’s membrane, termed ‘pre-Descemet’s layer’. The main aim of this thesis was to determine if this region has different structural properties to the overlying stroma. A second aim was to examine the elastic fibre distribution throughout the depth of the stroma in healthy and diseased corneas, with focus on pre-Descemet’s layer. Techniques used include serial block face scanning electron microscopy, transmission electron microscopy, and X-ray diffraction, amongst various other imaging techniques. Depth analysis revealed that centre-to-centre interfibrillar spacing was significantly lower in the first ~10µm of stroma distal to Descemet’s membrane compared to overlying regions in central cornea. Three-dimensional analysis revealed the presence of long elastic fibres running throughout the stroma, parallel to the surface of the cornea, which were concentrated in pre-Descemet’s layer. This elastic material seemed to originate from the limbus as fenestrated sheets before travelling radially into the cornea as small fibres. This data provides evidence for pre-Descemet’s layer containing altered biomechanical properties that may contribute to the formation of a variable cleavage plane observed during pneumodissection. Additionally, the elastic fibre network is likely to play an important role in the deformation and recovery of the cornea. Furthermore, the presence of elastic fibres in foetal cornea suggests a potential role in development. The distribution of elastic fibres was very different in keratoconic buttons. No fibres were located above Descemet’s membrane, whereas the elastic fibres appeared concentrated below the epithelium in thinned coned regions, potentially as a biomechanical response to prevent rupture. Attempts were made to elucidate a functional role for elastic fibres by studying the corneas from a mouse model for Marfan syndrome, where there was a ~50% reduction in elastic fibre quantity. These corneas were significantly thinner and flatter than wild types suggesting that elastic fibres play a role in maintaining the shape of the cornea. Overall, this thesis has characterised pre-Descemet’s layer, demonstrating that structural differences are present. It is likely that the network of elastic fibres described in this thesis play a multi-functional role in the cornea.
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Cherubini, Marta. "Study of mitochondrial dysfunction mechanisms in Huntington's disease striatal degeneration." Doctoral thesis, Universitat de Barcelona, 2016. http://hdl.handle.net/10803/398895.
Full textAbstract:
Huntington's disease (HD) is an autosomal-dominant inherited neurodegenerative disorder, characterized by progressive behavioral, motor and cognitive deficits (HDCRG, 1993; Ross & Margolis, 2001). The predominant neuropathological hallmark of HD is the selective loss of medium spiny neurons within the striatum that extends to other brain regions with the progression of the disease (Martin & Gusella, 1986). Although mutant huntingtin (mHtt) represents a key factor in the pathogenesis of the disease, the molecular mechanisms underlying the preferential vulnerability of the striatum to mHtt toxicity remain unclear. Compelling evidence suggest that mitochondrial defects may play a crucial role in the disease, however, it is still debated whether mitochondrial dysfunction represents just an epiphenomenon of the cellular degeneration or it has an actual pathogenic role. In this Thesis, the general purpose was to identify possible mitochondrial impaired mechanisms and to investigate their role in the selective striatal vulnerability of HD, in order to provide important insights for the development of new therapeutic strategies. The first aim was to clarify whether mitochondrial injuries perpetrate the dopaminergic neurotoxicity in HD striatal degeneration. Since Cdk5 has been proposed as a critical regulator of mitochondrial fission (Meuer et al., 2007) and as a deleterious player in the striatal vulnerability upon dopamine signalling (Paoletti et al., 2008), we hypothesize a new detrimental role for Cdk5 in HD pathology by mediating dopaminergic neurotoxicity through deregulation of mitochondrial dynamic processes. On the other hand, several studies have proposed mitochondrial Ca mishandling as a component of Ca controversial and a conclusive cause remains uncertain. We propose that the propensity of mitochondria to undergo fragmentation in HD could result in the disruption of ER-mitochondria contacts, which are essential for the proper buffering of Ca whether defects in ER-mitochondria associated membranes could be responsible for the alteration of mitochondrial Ca handling in HD. dyshomeostasis in HD. However, the results appear 2+ 2+ by mitochondria. Therefore, the second aim of this study was to investigate.La enfermedad de Huntington (EH) es un trastorno neurodegenerativo de herencia autosómica dominante, causado por la expansión del trinucleótido CAG en el gen IT15 que codifica para la proteína huntingtina (htt) (HDCRG, 1993). Los pacientes con EH desarrollan alteraciones neurológicas tales como trastornos psiquiátricos, motores y cognitivos (Ross & Margolis, 2001). El sello neuropatológico más característico de este trastorno es la atrofia del cuerpo estriado que se extiende a otras regiones del cerebro con la progresión de la enfermedad (Martin & Gusella, 1986). Aunque la huntingtina mutada (mHtt) representa un factor clave en la patogénesis de la enfermedad, los mecanismos implicados en la selectiva degeneración estriatal todavía se desconocen. Estudios previos de nuestro grupo de investigación han demostrado que el aumento de la vulnerabilidad de las células estriatales a la mHtt tras activación dopaminérgica implica la actividad aberrante de Cdk5 (Paoletti et al., 2008). Por otra parte, estudios recientes han involucrado también Cdk5 en la regulación de la fisión mitocondrial (Meuer et al., 2007). En este escenario hemos planteado la hipótesis de que la desregulación de Cdk5 inducida por la mHtt podría contribuir a la patología estriatal en la EH. Por ello el primer objetivo de esta Tesis ha sido definir si el aumento de la actividad de Cdk5 inducida por la mHtt incrementa la vulnerabilidad estriatal a insultos excitotóxicos mediante la alteración de la dinámica mitocondrial. Por otra parte, estudios recientes identifican una defectuosa captación del calcio mitocondrial como otro mecanismo responsable de la patogénesis y progresión de la EH (Giacomello et al., 2011). Un excesiva fragmentación mitocondrial podría alterar la dispersión de los orgánulos en el espacio intracelular alterando su capacidad de captación del Ca endoplásmico (RE). Por lo tanto, el segundo objetivo de esta Tesis fue investigar el papel de los sitios de contacto entre mitocondria y RE en la alteración de la señalización del Ca y la interacción con otras membranas, tales como las del retículo 2+ que caracteriza la EH.
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Hayes, Sally. "Structural organisation of collagen in the corneas of primates and other mammals and the stromal changes associated with the disease keratoconus." Thesis, Cardiff University, 2005. http://orca.cf.ac.uk/56112/.
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X-ray diffraction was used to determine the ultrastructural arrangement of collagen in the normal human, monkey and bovine cornea. Using the same technique, the ultrastructural organisation of collagen in human keratoconus corneal buttons and in the corneas of mice with a murine specific keratopathy (SKC), in which the males develop a cone shaped cornea, was also examined. Collagen fibrils were found to be most closely packed in the prepupillary region of the normal human cornea, suggesting an optimisation of tissue strength and transparency in the main optical zone. In humans and marmoset monkeys, fibril size and interfibrillar spacing increased rapidly at the limbus to provide additional tensile strength at the point where the cornea meets the less curved sclera. A difference in the preferred orientation of collagen fibrils was observed between human and bovine corneas. Throughout the human corneal stroma, (and predominantly in the posterior stroma), collagen fibrils are preferentially aligned in the superior-inferior and nasal-temporal directions this alignment coincides with the insertion points of the rectus muscles. The proportion of aligned collagen mass (relative to the total collagen mass), which increases in all four quadrants of the peripheral human cornea, is highest in the superior-nasal and inferior-temporal regions, revealing a symmetry between the left and right cornea in terms of collagen mass distribution. Abnormalities in collagen orientation and mass distribution were seen in the majority of keratoconus corneal buttons examined. A relationship between the size and shape of the cone and the extent of the structural alterations was seen in some cases however a large variation existed between corneas. These results are consistent with a theoretical mechanism of keratoconus progression which involves enzyme action and inter-fibrillar and inter-lamellar slippage. Examination of the structural organisation of collagen in SKC mice corneas, revealed the strain to be an unsuitable model for studying human keratoconus.
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Huang, Lan. "Endothelial Colony Forming Cells (ECFCs): Identification, Specification and Modulation in Cardiovascular Diseases." Thesis, Connect to resource online, 2009. http://hdl.handle.net/1805/2063.
Full textAbstract:
Thesis (Ph.D.)--Indiana University, 2009.Title from screen (viewed on February 2, 2010). Department of Biochemistry and Molecular Biology, Indiana University-Purdue University Indianapolis (IUPUI). Advisor(s): Mervin C. Yoder, Jr., David A. Ingram, Jr., Lawrence A. Quilliam, Mark D. Pescovitz. Includes vitae. Includes bibliographical references (leaves 171-194).
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Martín, Flores Núria. "Study of the mTOR pathway in neurodegenerative diseases: from synapses to genes." Doctoral thesis, Universitat de Barcelona, 2018. http://hdl.handle.net/10803/665330.
Full textAbstract:
Huntington's disease (HD) and Parkinson's disease (PD) are devastating neurodegenerative diseases that progress with the death of selective neuronal subpopulations. Neuronal dysfunction and death are consequence of multiple pathogenic processes which alter signalling cascades. The identification of such molecular pathways is crucial to understand the cellular processes that triggers the symptomatology of diseases. One of the common affected pathways in neurodegeneration is the mTOR pathway. It regulates multiple cellular processes to preserve cellular viability and function. Consequently, to maintain a proper function mTOR activity needs to be fine-tuned. RTP801 is an mTOR negative regulator whose action over this pathway plays a significant role in neurodegeneration. RTP801 protein is induced in an attempt to cope cellular stress. However a sustained RTP801 increase leads to neuronal death by sequentially inactivating first mTOR and then Akt pro-survival kinase. RTP801 pathological increase has been involved in neurodegenerative diseases such as PD. Therefore, identifying RTP801 as a possible new therapeutic target in HD would be highly valuable in designing new pharmacological therapies that block, or at least delay, the neurodegeneration and changes in synaptic plasticity associated with it.
Our results show that the overexpression of pathogenic N-terminal htt increases RTP801 levels by both lengthening the protein half-life and up-regulating its gene expression. Blockade of RTP801 expression prevents mhtt-induced cell death in HD cellular models. Importantly, RTP801 is elevated in HD-iPSC and putamen, caudate nucleus and cerebellum of human HD post-mortem brain. Although total RTP801 levels in the striatum of HD murine models are not altered, RTP801 is increased in the synaptic compartment which contributes to motor learning deficits in the R6/1 model. Downregulation of striatal RTP801 preserves motor learning skills in R6/1 mice. Hence, RTP801 is identified as a novel downstream effector of mhtt which mediates its toxicity.
Recently, exosomes have emerged as a key mechanism to maintain trophic support between neural cells and as vehicle for the clearance of toxic proteins from neurons. Since RTP801 is upregulated under stressful conditions, its propagation by exosomes may allow the neuron-to-neuron spreading of RTP801 toxicity through the modulation of mTOR/Akt pathway.
Our results have elucidated a novel function of RTP801 as an exosomal protein. We demonstrate that both ectopic and endogenous RTP801 can be found in exosomes derived from HEK293 cells. In cortical neurons, exosomal RTP801 elevation is sensitive to PD mimetic 6-OHDA (6-hydroxydopamine) but not to potassium depolarization. Consequently, 6-OHDA exposure induces the loading of RTP801 into exosomes released from cortical neurons. Intriguingly, mhtt does not elevate RTP801 in exosomes obtained from a cellular model. In addition, we demonstrate that exosomes have a protective role promoting the activation of both mTOR complex 1 and 2 in recipient neurons, but increased RTP801 counteracts exosomal mTOR pathway activation suggesting that RTP801 negatively modulates pro-survival signals transneuronally.
Altered protein functions of the mTOR pathway are a common hallmark in many neurodegenerative diseases. However, little is known about the contribution of genetic variants or single nucleotide polymorphisms (SNPs) that belong to the mTOR pathway. As a multifactorial disease, we studied the association of SNPs in genes encoding mTOR pathway protein components with the susceptibility PD and the response to levodopa (L-DOPA) treatment.
The data found indicate that polymorphisms in genetic markers of the mTOR pathway contribute to the susceptibility to PD and the response to L-DOPA treatment in PD patients. We show that these SNPs influence the outcome individually or interacting epistatically with other genetic markers.
Taken together, our findings indicate that deregulation of the mTOR signalling pathway plays an important role in the pathogenesis associated with PE and HD and its regulation is crucial to maintain adequate neuronal function and viability.La enfermedad de Huntington (EH) y la enfermedad de Parkinson (EP) son enfermedades neurodegenerativas devastadoras caracterizadas por la muerte de subpoblaciones neuronales selectivas. La disfunción neuronal y la muerte son consecuencia de múltiples procesos patogénicos que llevan a la alteración de cascadas de señalización. Una de las vías afectadas de forma común en los procesos neurodegenerativos es la vía mTOR. Como modulador de numerosos procesos celulares, la vía de mTOR está regulada para mantener la supervivencia neuronal y la plasticidad sináptica. Una de las proteínas que modula esta cascada de señalización es RTP801. RTP801 se induce en respuesta a factores de estrés celular y su aumento desencadena la muerte neuronal al regular negativamente la vía mTOR/Akt. La implicación de RTP801 en la EP ha sido ampliamente estudiada, sin embargo, su contribución a la patogénesis de la EH nunca antes había sido explorada. Específicamente, nuestros resultados han identificado a RTP801 como un mediador de la toxicidad inducida por huntingtina mutada. El aumento de RTP801 medía la muerte celular inducida por huntingtina mutada y contribuye a la disfunción del aprendizaje motor en el modelo murino R6/1. El silenciamiento de RTP801 en el estriado de los ratones R6/1 contribuye a preservar la plasticidad sináptica de la vía corticoestriatal, y por tanto del aprendizaje motor. Por otra parte, mostramos que los exosomas secretados por neuronas activan la vía de supervivencia mTOR/Akt en neuronas recipientes. Sin embargo, ante un estrés celular, la toxicidad de RTP801 es propagada a través de exosomas que contrarrestan la activación trófica de la vía mTOR/Akt. Finalmente, demostramos que variaciones genéticas en los componentes de la vía de mTOR modulan la susceptibilidad y la edad de inicio de la EP y, contribuyen a la aparición y severidad de la discinesia inducida por levodopa. En conjunto, nuestros hallazgos indican que la desregulación de la vía de mTOR desempeña un papel importante en la patogénesis asociada a la EP y la EH y, su correcta regulación es crucial para mantener la viabilidad y función neuronal.
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Mergler, Stefan [Verfasser]. "Functional expression of temperature-sensitive transient receptor potential channels (TRPs) in cultured human corneal and conjunctival cells : Relevance in the pathophysiology of ocular surface diseases / Stefan Mergler." Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2015. http://d-nb.info/1078505403/34.
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Alvarez, Periel Elena. "Dual role of CDK5 on cognitive deficits and striatal vulnerability in Huntington’s disease." Doctoral thesis, Universitat de Barcelona, 2018. http://hdl.handle.net/10803/663831.
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Huntington’s disease (HD) is a neurodegenerative disorder caused by an autosomic mutation on the Huntingtin (HTT) coding gene. HD is mainly characterized by the appearance of motor symptoms or choreas, which are associated to the selective degeneration of striatal neurons, and by the presence of cognitive disturbances, which are attributed to alterations in corticostriatal connectivity and to hippocampal dysfunction. For this reason, finding targets involved both on striatal vulnerability and cognitive disturbances, might result in therapeutic strategies able to act simultaneously on HD’s motor and cognitive symptoms. In this Thesis we have focused on Cyclin-dependent kinase 5 (Cdk5) as one of these putative targets. Cdk5 acts mainly in the central nervous system, where its activator p35 is expressed, and it plays a major role on synaptic plasticity regulation. In addition, altered Cdk5 activity has been described in several neurodegenerative disorders, including HD, where Cdk5 deregulation has been associated to increased striatal vulnerability to excitotoxicity. Moreover, alteration of Cdk5 activity and/or subcellular distribution has also been linked to neuronal cell cycle re-entry, which has been proposed as a possible mechanism leading to neuronal dysfunction and eventual death in several neurodegenerative conditions.
Therefore, on one hand, we aimed to study Cdk5 involvement in cognitive deficits and synaptic plasticity alterations in HD. To this end, we generated a new double mutant mice model which expresses one copy of mutant HTT (mHTT) (knock-in or KI), and is conditionally heterozygous for Cdk5 (Cdk5+/). We described that double mutant mice (KI:Cdk5+/-) presented restored corticostriatal and hippocampal cognitive function when compared to their KI littermates. We also observed that preserved corticostriatal function correlated with recovery of corticostriatal NR2B surface levels, which were reduced in KI mice. Moreover, recovery of NR2B surface levels was associated to normalization of NR2B total levels and of the pSrc/pNR2B pathway in the cortex of KI:Cdk5+/- mice. On the other hand, preserved hippocampal cognitive function correlated with recovery of CA1 dendritic spine density, as well as, with increased Rac1 activity in KI:Cdk5+/- mice. Restoration of dendritic spine density was also observed in layer V cortical neurons, in a Rac1-independent manner. Finally, we described that KI mice showed reduced physiological p35 plasma membrane levels in the cortex, which was recovered in KI:Cdk5+/- mice, correlating with preferential alteration of Cdk5 substrates phosphorylation levels in this brain region. In sum, our results demonstrate Cdk5 complex and brain region-specific involvement in cognitive deficits appearance and in synaptic alterations in HD.
On the other hand, we also assessed whether Cdk5 deregulation might cause cell cycle re-entry of striatal neurons in HD. Cdk5 forms a nuclear complex with p27 and E2F1 in differentiated neurons, thus preventing E2F1 from binding to its coactivator DP1 and from activating transcription of cell cycle progression genes. For this reason, we analysed nuclear levels of Cdk5 and p27, and we observed that KI mice showed reduced Cdk5 and p27 nuclear levels, which could induce neuronal cell cycle re-entry. In agreement, we also observed increased levels of CyclinD1 in the striatum of KI mice since early symptomatic stages, and increased Cdk4 levels at late disease stages. Finally, we observed that NMDA treatment of striatal primary cultures caused a general reduction of cell cycle proteins neuronal expression, and importantly, it altered their subcellular distribution, reducing nuclear localization of the cell cycle inhibitor p27 and inducing nuclear presence of cell cycle progression proteins, E2F1 and Cdk4. Our results also suggested that presence of mHTT might further potentiate NMDA-induced subcellular distribution alteration of cell cycle proteins. Therefore, we suggest that reduction of Cdk5 nuclear levels might induce cell cycle re-entry of striatal neurons, a process which could be favoured by alterations in NMDA receptors activation, present in HD.La malaltia de Huntington (MH) és un desordre neurodegeneratiu causat per una mutació al gen que codifica per la proteïna Huntingtina (HTT), i que consisteix principalment en l’aparició de dèficits motors, associats a la degeneració selectiva de l’estriat; i en l’aparició de dèficits cognitius, associats a una alteració en la connectivitat corticoestriatal i a una disfunció hipocampal. En aquesta Tesi, hem analitzat la implicació de la cinasa Cdk5, per una banda, en l’aparició dels dèficits cognitius; i per l’altre banda, en la reentrada neuronal al cicle cel·lular com a un possible mecanisme de susceptibilitat a la vulnerabilitat estriatal en la MH. Els nostres resultats han mostrat que la reducció genètica de Cdk5 en un model murí de la MH (KI), prevé l’aparició dels dèficits cognitius corticoestriatal i hipocampals. Aquesta millora cognitiva està associada a la recuperació dels nivells de membrana de NR2B a nivell corticoestriatal, i a la restauració de la densitat d’espines dendrítiques a l’hipocamp i a l’escorça, indicant una implicació de Cdk5, complexa i específica de regió cerebral, en les alteracions sinàptiques i l’aparició dels dèficits cognitius en la MH. D’altre banda, hem observat que els nivells nuclears de Cdk5 estan disminuïts a l’estriat dels ratolins KI, cosa que podria alterar la seva funció com a inhibidor de la progressió del cicle cel·lular en neurones diferenciades. En concordança amb aquesta hipòtesi, diferents proteïnes del cicle cel·lular presenten una alteració en els seus nivells proteics, tant en ratolins KI, com en mostres de pacients humans. A més, l’activació dels receptors NMDA en neurones estriatals porta a una alteració de la distribució subcel·lular de les proteïnes del cicle cel·lular prèviament analitzades, un efecte que podria ser potenciat per la presència de la HTT mutada. En conclusió, els resultats d’aquesta Tesi, mostren la complexa implicació de Cdk5 en l’aparició dels dèficits cognitius en la MH, i suggereixen que l’alteració de la localització nuclear de Cdk5 podria portar a la desregulació de diferents proteïnes del cicle cel·lular, un mecanisme que es podria veure afavorit per alteracions en l’activació dels receptors NMDA, presents en la MH.
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Lutz, Elizabeth Anne. "Effects of Modified Cyclosporine A on Posterior Capsule Opacification Formation and Corneal Endothelial Cell Viability in an Ex Vivo Model." The Ohio State University, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=osu1371477702.
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Rué, Cabré Laura. "Characterization of the mechanisms underlying alterations in macroautophagy and survival signalling in Huntington’s disease." Doctoral thesis, Universitat de Barcelona, 2012. http://hdl.handle.net/10803/109154.
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La malaltia de Huntington és un trastorn neurodegeneratiu progressiu causat per una expansió de repeticions del triplet CAG (més de 37) en l’exó 1 del gen de la huntingtina que genera una proteïna aberrant. Aquesta proteïna modificada és tòxica i provoca una pèrdua selectiva de neurones GABAèrgiques de projecció en el nucli estriat, tot i que també s’han detectat alteracions i degeneració en altres àrees de l’encèfal, generant una simptomatologia complexa que engloba alteracions motores, cognitives i emocionals. Un marcador de la patologia és la formació d’agregats proteics, principalment compostos per fragments N-terminals de la huntingtina mutada que es generen per l’acció de proteases. Un dels processos que condueix a la mort selectiva de les neurones és l’activació de l’apoptosi. L’equilibri entre vies pro-apoptòtiques i vies de supervivència no només és el que regula el destí de la cèl•lula, sinó que també podria participar en la regulació de l’aparició dels primers símptomes de la patologia en un individu afectat. En aquesta Tesi es descriuen tres possibles mecanismes cel•lulars activats en un model murí de malaltia de Huntington, que podrien participar en compensar la toxicitat que genera la huntingtina mutada i així retardar-ne la patologia: (1) la sobreactivació de l’autofàgia selectiva a estadis inicials de la patologia, important per la degradació de la huntingtina mutada; (2) la sobreactivació de la via de senyalització mTOR-AKT, que participa en mecanismes de supervivència cel•lular; i (3) la inhibició de la via de senyalització de la PKCδ, que quan es troba activada genera apoptosis cel•lular en cèl•lules que expressen la huntingtina mutada. Potenciar des d’edats primerenques qualsevol d’aquests tres mecanismes, doncs, podria ser una bona estratègia terapèutica per a la malaltia de Huntington.Huntington’s disease (HD) is a neurodegenerative disorder caused by a CAG expansion (more than 37 repeats) in the exon 1 of the huntingtin gene, which results in the synthesis of a mutant protein that is toxic for some neuronal types. The striatum is the most affected brain region, although other brain areas, such as the cerebral cortex or hippocampus are also affected. Aggregates are a pathological hallmark of the disease, which are mainly composed by N-terminal mutant huntingtin fragments and are present within the cells in both cytoplasm and nucleus. Apoptotic activation is one of the mechansims by which neurodegeneration occurs. Thus, whether a neuron lives or dies in pathological condition is the result of a complex balance between anti- and pro-apoptotic signals, which is crucial to determine cell fate. Moreover, this balance might strongly regulate the onset of the disease. Here, we have characterized three putative compensatory pro-survival processes that are altered in Huntington’s disease and could be involved in delaying the pathology progression. First, we have studied selective autophagy, a mechanism that degrades toxic mutant huntingtin species. To this end, we analyzed protein levels and intracellular localization of p62 and NBR1 (two selective autophagy receptors that specifically recognize cell components that need to be removed by means of autophagy) in the R6/1 mouse model of HD along the progression of the disease.,. We have observed that at early stages of the disease, p62 and NBR1 protein levels are reduced, indicating increased autophagic activity that could play a role in degrading mutant huntingtin. However, at later stages of the disease protein levels of both proteins have a different pattern depending on the cerebral region analyzed. In the cortex protein levels of both proteins are still reduced, indicating that selective autophagy is overactivated until later stages of the disease. However, in the striatum and in the hippocampus they accumulate due to distinct factors. p62 is sequestered by nuclear mutant huntingtin aggregates, while NBR1 is still in the cytoplasm, thus still taking part in the autophagy process. Its accumulatiion could be due to an inefficient selective autophagy that could get worst with age. We have also studied whether different intracellular signalling pathways, involved in cell survival or apoptosis, are altered by mutant huntingtin expression. We have observed that the mTOR signalling pathway, through the mTORC2 but not mTORC1 complex, is over-activated in the striatum of R6/1 mice, and we think that this overactivation could play a role in the previous reported increased phosphorylation of the pro-survival kinase AKT in the same HD mouse model. An increase in the activity of the mTORC2 complex, could be due to an increase in Rictor protein levels that have been found specifically in the striatum of R6/1 mice and in the putamen of HD patients. Finally, we also analyzed the PKC signalling pathway, since PKCs regulate different processes important for neuronal survival and plasticity. We have observed that protein levels of different PKC isoforms, PKCα, PKCβII and PKCδ, are reduced in the striatum, cortex and hippocampus of R6/1 mice. The most important reduction was observed for the proapototic PKC isoform PKCδ, which started already at early stages of the disease. This suggests that neurons could try to block this signalling pathway in order to reduce mutant huntingtin toxicity. We have obsereved that striatal cells that express mutant huntingtin, but not wild-type huntingtin, are more vulnerable to undergo apoptosis when they overexpress PKCδ. The present Thesis describes the up-regulation of several compensatory prosurvival mechanisms in HD to counteract the mutant huntingtin-induced toxicity. The potentiation of such prosurvival mechanisms could be a good therapeutical approach in HD.
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Anglada, Huguet Marta. "Characterization of mechanisms underlying neuronal survival and plasticity in Huntington's disease." Doctoral thesis, Universitat de Barcelona, 2013. http://hdl.handle.net/10803/125774.
Full textAbstract:
Huntington’s disease is a progressive neurodegenerative disorder caused by the expansion of a CAG tract in the exon-1 of the huntingtin gene. Mutant huntingtin induces a large amount of toxic effects that trigger cell dysfunction and consequently, behavioral alterations such as motor dysfunction, cognitive decline and psychological disturbances. However, before the onset of symptoms individuals are healthy. Thus, it is plausible that compensatory mechanisms may be activated to regulate a balance between cell death and survival. This compensatory mechanism might modulate the progression of Huntington’s disease. Understanding altered mechanisms due to mutant huntingtin expression in order to find new therapeutic targets to reduce neuronal dysfunction/death in Huntington’s disease must be a priority. It is believed that there is a balance between positive signaling for cell survives or dies. Many of the pathways involved in these processes are controlled at the level of phosphorylation and transcription. In this thesis we have studied mechanisms of transcription and protein activation, which are considered one of the main causes that trigger to mutant huntingtin-induced neuronal dysfunction. We have identified two targets, the protein kinase p90Rsk and the transcription factor Elk-1, that are activated during the progression of Huntington’s disease in order to protect striatal cells against mutant huntingtin-induced cell death. These two proteins are tightly related to neuronal survival and transcription regulation. p90Rsk is a kinase that phosphorylates substrates in the cytoplasm inhibiting their pro-apoptotic activity and phosphorylate transcription factors in the nucleus promoting their pro-survival activity. Likewise, Elk-1 promotes the transcription of many immediate early genes related to synaptic plasticity and neuronal survival. We observed an up-regulation of these to proteins during the progression of Huntington’s disease in different mouse models. This up-regulation was necessary to protect striatal cells from mutant-huntingtin.
The prevention of cell death is an important point for neurodegenerative diseases; even so, it is unlikely that cellular machinery works well until the death of the cells. In many neurodegenerative diseases, such as Huntington’s disease, neuronal and synaptic dysfunction precedes cell death and occurs long before, or sometimes in absence of cell death. Recent studies suggest that targeting early pathophysiological disturbances in models of Huntignton’s disease can reverse neuronal dysfunction and delay progression to neurodegeneration. In this thesis, we also point out for the first time the modulation of Prostaglandin E2 (PGE2) EP receptors, namely EP1 and EP2, as a therapeutic targets in Huntington’s disease. The activation of EP1 receptor produces an increase in intracellular levels of calcium, while EP2 receptor activation increases cAMP; therefore, the activation of different EP receptors can have opposite effects. Whereas the blockade of EP2-EP4 receptors can aggravate neurodegeneration, antagonizing EP1 receptor has neuroprotective effects. We observed that pharmacological inhibition of EP1 receptor improves motor coordination and reduces memory decline in R6/1mice model of Huntington’s disease. Moreover, EP1 antagonism increases the expression of specific synaptic markers in the striatum and the hippocampus of these mice and also improves the long-term potentiation in the hippocampus. Finally, EP1 receptor antagonism reduces the presence of striatal and hippocampal mutant huntingtin nuclear aggregates in the striatum and the hippocampus of treated-R6/1 mice. Contrary to EP1 receptor, EP2 receptor plays a neuroprotective role in Huntington’s disease. We observe that EP2 receptor activation improves long-term memory in R6/1 mice. Moreover, EP2 activator increases dendritic branching in a BDNF-dependent manner, increases the protein levels of BDNF and the total number of PSD-95+ spines in the hippocampus of these mice. In conclusion, we propose the modulation of PGE2 receptors as a new therapeutic strategy in Huntington’s disease.La malaltia de Huntington és un trastorn neurodegeneratiu progressiu caracteritzat per la presencia d’alteracions motores i dèficits cognitius. Aquesta malaltia està causada per l’expansió anòmala del triplet CAG en l’exó 1 del gen que codifica per la proteïna huntingtina. La huntingtina mutada indueix gran quantitat d’efectes tòxics que desencadenen la disfunció cel•lular i, en conseqüència, les alteracions en la conducta característiques d’aquesta malaltia. Tot i així, abans de l’aparició del símptomes, els individus són sans. Per tant, és plausible pensar que es produeix una activació de mecanismes compensatoris per a regular l’equilibri entre la mort i la supervivència cel•lular. En aquesta tesis, ens hem centrat en dos objectius principals: (1) l’estudi dels mecanismes compensatoris activats en la presencia de la huntingtina mutada per tal de millorar la supervivència cel•lular i (2) la identificació de dianes moleculars per a reduir els dèficits motors i cognitius, així com per a millorar la plasticitat sinàptica en models murins de la malaltia de Huntington. Específicament, els nostres resultats han ajudat a entendre el paper de la proteïna cinasa p90Rsk i del factor de transcripció Elk-1 en la susceptibilitat de les neurones estriatals a la mort induïda per la huntingtina mutada. Per altre banda, mostrem per primera vegada el potencial terapèutic dels receptors de la prostaglandina E2, EP1 i Ep2, per al tractament dels símptomes clínics y histopatològics en la malaltia de Huntington.
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Dantas, Paulo Elias Corrêa. "Alterações topográficas da córnea em pacientes com cérato-conjuntivite vernal." Universidade de São Paulo, 2002. http://www.teses.usp.br/teses/disponiveis/5/5149/tde-07032002-002915/.
Full textAbstract:
Doença alérgica ocular acomete cerca de ¼ da população mundial. Dentro do espectro da doença alérgica ocular, a cérato-conjuntivite vernal, que afeta principalmente crianças, pode apresentar-se sob forma severa e persistente, levando a dano do tecido corneal e comprometimento da função visual. Traumatismo epitelial crônico, induzido pelo ato de coçar os olhos, associado ao intenso prurido ocular tem sido apontado como fator de risco importante na patogênese do ceratocone. Pode estimular a apoptose prematura dos ceratócitos, provocando mudanças estruturais do estroma da córnea. A associação de cérato-conjuntivite vernal e ceratocone tem sido apontada como freqüente na literatura oftalmológica através de estudos descritivos e qualitativos, que, entretanto, não auxiliam na detecção precoce da doença ectásica corneal, prejudicando sua análise epidemiológica, seu estudo genético e a definição de sua patogênese. Propôs-se estudo clínico caso-controle de pacientes com cérato-conjuntivite vernal do Ambulatório de Alergia Ocular do Departamento de Oftalmologia da Santa Casa de São Paulo, com finalidade de obter-se, por meio da análise topográfica computadorizada de córnea utilizando-se de descritor quantitativo da superfície anterior da córnea (sumário diagnóstico de Holladay), informações sobre as alterações topográficas da superfície anterior da córnea, que pudessem determinar a freqüência da associação entre cérato-conjuntivite vernal e ceratocone, além de seus efeitos sobre o desempenho da visão destes pacientes. Os resultados obtidos neste estudo mostram alta freqüência de ceratocone em pacientes com cérato-conjuntivite vernal. A performance visual destes pacientes é influenciada pelas aberrações provocadas por alterações da asfericidade corneal e de outras variáveis topográficas.Allergic ocular disease affects ¼ of the world population. Inside the spectrum of the allergic ocular disease, vernal keratoconjunctivitis, that affects mostly children, may present as severe and persistent form, leading to corneal tissue damage and disturbing visual function. Chronic epithelial trauma, provoked by eye rubbing due to intense ocular itching, has been postulated as an important risk factor in the pathogenesis of keratoconus. It may induce early keratocyte apoptosis that results in structural changes to the corneal stroma. The association of keratoconus with vernal keratoconjunctivitis has been observed to be frequent in the ophthalmological literature by descriptive and qualitative studies, unable to detect earlier forms of this ectatic corneal disease, weakening epidemiological analysis, genetic studies and the definition of its pathogenesis. We proposed a case-control clinical study of patients with vernal keratoconjunctivitis from the Ambulatory of Ocular Allergy of the Department of Ophthalmology of Santa Casa of São Paulo, aiming for information on the anterior corneal curvature and visual performance, using a quantitative descriptor analyzer (Holladay Diagnostic Summary). The results suggest high frequency of the keratoconus in patients with vernal keratoconjunctivitis. The visual performance is affected by the induced aberration caused by changed corneal asphericity and other topographic variables.
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Suelves, Caballol Núria. "Evaluation of therapeutic targets for the treatment of behavioral alterations and neuropathology in Huntington’s disease. The role of histone deacetylase 3 and p75 neurotrophin receptor." Doctoral thesis, Universitat de Barcelona, 2018. http://hdl.handle.net/10803/663911.
Full textAbstract:
Huntington’s disease (HD) is a rare genetic disorder caused by an aberrant expansion of a CAG trinucleotide in the huntingtin gene (Htt). The neuropathology of the disease is characterized by progressive neuronal dysfunction and degeneration in specific regions within the central nervous system, which causes a triad of symptoms including motor, cognitive and psychiatric features. Current treatments only alleviate some of these symptoms without preventing the inevitable neuropathological progression and, therefore, there is great need for finding new therapies that act at the root of the illness. Transcriptional dysregulation, somatic CAG repeat instability and neurotrophic signaling alterations appear early in HD and have been considered important underlying pathogenic mechanisms. Additionally, it has been recently suggested that HDAC3 and p75NTR could participate in some of these processes. Accordingly, the main aim of this thesis was to evaluate the potential therapeutic benefits of the pharmacological inhibition of HDAC3 and the genetic reduction of p75NTR in a knock-in mouse model of HD, termed HdhQ7/Q111. Our results have demonstrated that the selective inhibition of HDAC3 ameliorates cognitive deficits (motor learning and long-term memory alterations) in HdhQ7/Q111 mice by restoring the neuronal activity- dependent transcription of important memory-related genes, such as Arc and Nr4a2. This effect could be due to an increase in histone acetylation, leading to a relaxed DNA configuration, as well as an increase in CBP acetylation, potentially promoting its transcriptional activity. Besides, we have observed that chronic HDAC3 inhibition suppresses somatic CAG repeat expansions in Htt gene. Results of this thesis have shown that HDAC3 inhibition increases Msh2 acetylation at lysine 73, probably altering its DNA repair activity, which has been involved in promoting somatic CAG repeat length increases. Finally, our results have shown that p75NTR levels are increased in HdhQ7/Q111 mice from symptomatic stages. Interestingly, p75NTR normalization delays the onset of motor coordination alterations, several neuropathological HD hallmarks and the overall neurotrophic signaling imbalance in HdhQ7/Q111 mice, which comprise a reduction of the neurotrophin BDNF, a reduction and disrupted activation of its specific receptor, TrkB, and an overactivation of the p75NTR-dependent JNK signaling pathway. However, normalization of p75NTR levels at late disease stages is not able to prevent the loss of striatal integrity and motor coordination in KI mice. This might be the result of the unstoppable advance of other pathological mechanisms that do not depend on p75NTR expression. Therefore, a pharmacological strategy aimed to reduce the expression or activity of p75NTR in HD could provide some benefits at early stages of the disease but, as the pathogenic process progresses, the benefits would be limited. Collectively, our results have provided further insight into the contribution of transcriptional dysregulation, somatic CAG instability and neurotrophin signaling disturbances to HD neuropathological progression and highlight HDAC3 and p75NTR as promising therapeutic targets to correct these pathogenic mechanisms and ameliorate cognitive and motor behavioral impairments in HD.La malaltia de Huntington (MH) és un trastorn neurodegeneratiu i hereditari que es caracteritza per la presència d’alteracions motrius, cognitives i psiquiàtriques. Actualment no existeix cap tractament que aconsegueixi frenar la progressió d’aquesta patologia, de manera que l’avaluació de dianes terapèutiques esdevé de vital importància. La desregulació transcripcional, l’expansió somàtica del triplet CAG i l’alteració de la senyalització neurotròfica s’han descrit com importants mecanismes subjacents i s’ha determinat que les proteïnes HDAC3 i p75NTR podrien promoure alguns d’aquests processos. Per això, en aquesta tesi hem avaluat els possibles beneficis resultants de la inhibició farmacològica de la HDAC3 o de la reducció genètica del receptor p75NTR en un model de ratolí de la MH, anomenat HdhQ7/Q111. Els nostres resultats han demostrat que la inhibició de la HDAC3 en ratolins HdhQ7/Q111 aporta millores cognitives degut a la prevenció de les alteracions transcripcionals. Aquest efecte podria ser conseqüència d’un increment de l’acetilació d’histones, promovent una conformació més relaxada de l’ADN, i d’un increment de l’acetilació de la proteïna CBP, estimulant la seva activitat transcripcional. A més, hem demostrat que la inhibició de la HDAC3 suprimeix l’expansió somàtica del triplet CAG en el gen mutat de la proteïna huntingtina, possiblement degut a que s’incrementen els nivells d’acetilació de la proteïna Msh2 en un residu que podria alterar la seva activitat, la qual s’ha vist recentment implicada en l’allargament del tram CAG. Per últim, els nostres resultats han determinat que la normalització del receptor p75NTR en els ratolins HdhQ7/Q111 endarrereix l’aparició de les alteracions en coordinació motora, coincidint amb una millora de diferents característiques neuropatològiques de la MH i amb una recuperació de l’alterada senyalització neurotròfica. No obstant, en etapes avançades de la malaltia, l’efecte d’altres mecanismes patogènics que ocorren de forma progressiva en la MH acaben anul·lant els efectes positius de la reducció en els nivells de p75NTR. Les evidències experimentals recopilades permeten concloure que les proteïnes HDAC3 i p75NTR participen en l’aparició de mecanismes patològics clau per a la correcta funció neuronal en diferents regions cerebrals i, per tant, representen prometedores dianes terapèutiques per tractar la simptomatologia motora i cognitiva de la MH.
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Puigdellívol, Cañadell Maria del Mar. "Description and Validation of New Therapeutical Targets to Prevent Neurodegenertlion and Cognitive Deficits in Huntington's Disease." Doctoral thesis, Universitat de Barcelona, 2014. http://hdl.handle.net/10803/291444.
Full textAbstract:
Understanding the molecular underpinnings of neuronal dysfunction and degeneration involved in Huntington’s disease is a goal of increasing urgency for society and scientific community. In this Thesis we have studied different proteins and signaling pathways, specifically altered by the presence of mutant huntingtin, as new potential candidates to develop pharmacological strategies to treat or delay motor and cognitive deficits in Huntington’s disease.
AIM 1. To study the contribution of CBP/CREB pathway in the cognitive deficits present in Huntington’s disease.
AIM 2. To study the molecular mechanisms involved in neurotrophic support dysfunction in Huntington’s disease.
2.1. To analyze the role of p75NTR/TrkB receptors in the major striatal vulnerability in Huntington’s disease.
2.2. To study the role of p75NTR in cognitive deficits in Huntington’s disease.
AIM 3. To study the molecular mechanisms involved in corticostriatal dysfunction in Huntington’s disease.
3.1. To characterize corticostriatal deficits in HD mouse models and analyze the role of Kalirin-7 in the alteration of corticostriatal excitatory synapses in HD.
AIM 4. To study the role of Cdk5 in cognitive deficits in Huntington’s disease.
AIM 5. To study the role of D1R-H3R heteromers in neuronal cell death and cognitive deficits in Huntington’s disease.La malaltia de Huntington (MH) és un desordre neurodegeneratiu caracteritzat per la disfunció i mort neuronal de regions específiques del cervell. La regió més afectada és l’estriat (nuclis caudat i putamen en humans), tot i que en estadis més avançats de la malaltia s’ha descrit una atròfia i pèrdua neuronal del còrtex cerebral i hipocamp (Vonsattel et al., 1985;Vonsattel and DiFiglia, 1998). La temprana disfuncionalitat de les neurones hipocampals i corticals es creu crítica per restablir les deficiències cognitives i de memòria en aquesta patologia. La malaltia s’hereta de forma autosòmica dominant i és causada per la mutació del gen IT15, localitzat en el braç curt del cromosoma 4 (4p.16.3), que codifica per la proteïna anomenada huntingtina (htt). Aquesta mutació va ser identificada l’any 1993 com una expansió de repeticions del triplet CAG que codifiquen per una regió poliglutamínica (poliQ) a l’extrem N-terminal de la proteïna htt (350KDa) (HDCRG, 1993). En individus sans, el nombre de repeticions oscil·la de 6 a 35; quan el nombre de repeticions d’aquest triplet és superior a 40, l’individu desenvoluparà la malaltia. Les primeres manifestacions de la malaltia solen produir-se als 35 anys d’edat conduint a la mort 15-20 anys després de l’aparició dels símptomes (Bates, 2003;Martin and Gusella, 1986). La simptomatologia inclou disfunció motora, associada majoritàriament a l’atròfia estriatal, acompanyada de trastorns cognitius i emocionals associats a l’afectació corticoestriatal i hipocampal que son de manifestació primerenca, fins i tot prèvia a la simptomatologia motora. Aquestes alteracions cognitives i emocionals constitueixen un dels pilars discapacitants en aquesta patologia, per això al llarg d’aquesta Tesi doctoral proposem un estudi dual que ens permeti definir diverses estratègies terapèutiques dirigides al tractament d’ambdues simptomatologies: motora i cognitiva. Si bé es coneix que aquesta mutació és la causant de la malaltia, avui en dia no es coneixen els mecanismes cel·lulars i moleculars responsables de la disfunció i mort neuronal en la MH. Diversos estudis han postulat que la pèrdua de funció de la proteïna wild-type i/o el guany de funció de la proteïna mutada (mhtt) juguen un paper clau en el desenvolupament de la malaltia. Així s’ha descrit que l’expressió de la proteïna huntingtina mutada resulta en l’alteració de diversos processos cel·lulars i moleculars, tals com l’agregació proteica, alteracions en el sistema ubiqüitinaproteosoma, desregulació en la maquinària transcripcional així com en la remodelació de la cromatina, alteracions en la síntesi proteica, reducció del suport tròfic, alteracions en les vies de senyalització intracel·lulars, alteració en la homeòstasis del calci, dany mitocondrial, excitotoxicitat, activació de caspases, alteracions en les interaccions proteïna-proteïna i alteració en la circuiteria neuronal (Cattaneo et al., 2005;Zuccato and Cattaneo, 2009). En aquesta Tesis ens hem centrat en estudiar alguns dels mecanismes moleculars implicats en la mort neuronal, així com en els dèficits cognitius i alteracions en la plasticitat sinàptica produïda per la presència de la huntingtina mutada, mitjançant l’estudi de les alteracions produïdes en: 1) maquinària transcripcional, 2) suport neurotròfic, 3) canvis estructurals en les sinapsis excitadores, 4) senyalització de proteïnes cinasa i fosfatasa i 5) formació d’heteròmers entre receptors acoblats a proteïnes G.
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Mira, Alexandra Sofia Schonburg Carrillo de. "Utilização do PCR real-time na detecção de herpesvírus felino-1 e Chlamydophila felis em gatos com manifestações oculares." Bachelor's thesis, Universidade Técnica de Lisboa. Faculdade de Medicina Veterinária, 2010. http://hdl.handle.net/10400.5/2904.
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Dissertação de Mestrado Integrado em Medicina VeterináriaA coriza felina, um problema de apresentação frequente na prática clínica, afecta principalmente os animais mais jovens, mostrando-se por regra auto-limitante. Em alguns indivíduos, porém, os sinais clínicos tornam-se crónicos ou recorrentes. No presente trabalho avaliou-se por PCR real-time a presença de herpesvírus felino-1 (HVF-1) e de Chlamydophila felis, os agentes mais importantes no desenvolvimento das manifestações oculares de coriza, em 24 gatos com e sem sinais oculares compatíveis com esta síndrome. O HVF-1 apresentou uma prevalência global de 87,5%, enquanto a C. felis apenas se detectou em 4,17% dos casos. Não foi possível encontrar uma associação estatisticamente significativa entre a quantidade de vírus existente nas amostras e a presença de sinais oculares, ou entre a quantidade de vírus e a gravidade desses sinais. Observou-se, no entanto, uma correlação negativa entre a classe etária dos 2 aos 6 meses e a carga viral no olho esquerdo, entre a idade e a presença de simbléfaro, entre a presença de conjuntivite e a carga viral orofaríngica e entre a presença de corrimento ocular purulento ou mucopurulento e a carga viral orofaríngica. O PCR real-time permitiu detectar o HVF-1 num maior número de amostras do que o PCR convencional, mostrando assim, aparentemente, uma maior sensibilidade, o que poderá justificar a sua preferência em relação à modalidade clássica. Contudo, devemos encarar estes resultados com precaução, uma vez que a amostra utilizada apresentava uma dimensão reduzida.
ABSTRACT - Detection of feline herpesvirus-1 and Chlamydophila felis by real-time PCR in cats with ocular signs - Feline infectious respiratory disease is commonly seen in clinical practice, especially among young animals, and it is usually self-limiting. Some cats, however, develop chronic or recurring signs. In the present study we tested 24 cats with and without ocular signs of feline infectious respiratory disease for the presence of feline herpesvirus-1 (FHV-1) and Chlamydophila felis, which are the most important causes of these manifestations, using real-time PCR. FHV-1 had a prevalence of 87,5%, whereas C. felis was only detected in 4,17% of the animals. There wasn’t a significant correlation between the viral load found in our samples and the presence of ocular signs, nor between viral load and the severity of those signs. There was, however, a negative correlation between the 2 to 6 months age group and the viral load in conjuntival swabs of the left eye. We also found a negative correlation between age and the presence of symblepharon, between conjunctivitis and the viral load found in oropharyngeal swabs and between purulent or mucopurulent ocular discharge and the viral load in oropharyngeal swabs. FHV-1 was detected more often by real-time than by conventional PCR, which suggests a greater sensibility of the former technique, justifying its preference. These results must be interpreted with caution, due to the small size of the populational sample.
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Schweitzer, Cédric. "Analyse épidémiologique du glaucome dans une population âgée : l'étude ALIENOR (Antioxydants, Lipides Essentiels, Nutrition et maladies Occulaires)." Thesis, Bordeaux, 2016. http://www.theses.fr/2016BORD0186/document.
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Le glaucome est une maladie neurodégénérative qui se définit par une perte progressive en fibres nerveuses rétiniennes et un rétrécissement du champ visuel. Il s’agit de la première cause de cécité irréversible dans le monde et le principal facteur de risque est la pression intraoculaire (PIO). L’étude ALIENOR (Antioxydants, Lipides Essentiels, Nutrition et maladies OculaiRes) est une étude épidémiologique qui a pour but de déterminer l’incidence des différentes pathologies oculaires liées à l’âge avec les facteurs nutritionnels, démographiques ou environnementaux dans une population représentative de la région de Bordeaux. En 2009-2010, 624 sujets âgés de plus de 74 ans ont bénéficié d’un examen ophtalmologique complet incluant un examen du nerf optique en rétinophotographie et en tomographie à cohérence optique spectral-domain (SD-OCT), d’une mesure la PIO au tonomètre à air et d’une évaluation des propriétés biomécaniques de la cornée. Une mesure de l’accumulation cutanée de produits de glycation avancée a été réalisée par autofluorescence. Le diagnostic de glaucome a été réalisé en utilisant les critères de la classification ISGEO (International Society for Epidemiologic and Geographical Ophthalmology). Les paramètres biomécaniques de la cornée étaient modifiés avec l’âge et chez les sujets ayant une histoire résidentielle à des latitudes plus exposées aux ultraviolets ambiants. L’épaisseur de cornée était plus élevée chez les sujets anciennement fumeurs. L’autofluorescence cutanée ≥ 2.7 UA (Unité Arbitraire) était indépendamment associée au glaucome. Les paramètres d’épaisseur en fibres nerveuses rétiniennes du SD-OCT présentaient de bonnes performances diagnostiques pour discriminer les sujets glaucomateux des témoins et la base normative présentait de bonnes performances discriminatives lorsqu’au moins un des paramètres était considéré comme anormal. Notre étude apporte des résultats originaux en termes de facteurs de risque de glaucome ou de déterminants des facteurs de risque de glaucome. De plus les performances diagnostiques du SD-OCT pourraient fournir des informations utiles pour optimiser les stratégies de dépistage du glaucome dans une population générale âgéeGlaucoma is a neurodegenerative disease defined by a progressive loss of optic nerve axons and retinal ganglion cells resulting in a characteristic enlargement of the optic nerve head cup and associated visual field defects. It remains the first cause of irreversible blindness worldwide and intraocular pressure (IOP) is the main risk factor. The ALIENOR (Antioxydants, Lipides Essentiels, Nutrition et maladies OculaiRes) study is a population-based study. It aims to assess the associations of age-related eye diseases with nutritional, demographic and environmental factors in a representative population of the Bordeaux area. In 2009-2010, 624 subjects, aged 74 years or more, underwent a complete eye examination, including an optic nerve head evaluation using retinophotography and a spectral-domain optical coherence tomography (SD-OCT), an IOP measurement using air-puff tonometry and an evaluation of biomechanical properties of the cornea. A measurement of skin accumulation of advanced glycation end-products was performed using an autofluorescence reader. Glaucoma diagnosis was made using ISGEO (International Society for Epidemiologic and Geographical Ophthalmology) criteria. Biomechanical properties of the cornea were modified by increasing age and in subjects having a higher lifetime ambient ultraviolet exposure. Central corneal thickness was thicker in former smokers. Skin autofluorescence values ≥ 2.7 AU (Arbitrary Unit) were independently associated with glaucoma. SD-OCT retinal nerve fiber layer thickness parameters had good diagnostic performances for discriminating glaucoma and control subjects and the normative database had good diagnostic performances if at least one parameter was considered abnormal by the machine. Our study provides new insights on glaucoma risk factors and determinants of glaucoma risk factors. Furthermore diagnostic performances of SD-OCT may provide valuable information in a screening strategy to optimize glaucoma detection in a general population of elderly people
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Assis, Bruno Moraes. "Histomorfometria, microtomografia bidimensional e tridimensional, teste de nanodureza e composição bioquímica do estojo córneo de bubalinos." Universidade Federal de Goiás, 2015. http://repositorio.bc.ufg.br/tede/handle/tede/5132.
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Conselho Nacional de Pesquisa e Desenvolvimento Científico e Tecnológico - CNPq
Despite not being a common subject of studies about buffalo, the incidence of hulls diseases has important scientific aspects as these animals, as they are breeded in adverse conditions, have different resistance for the occurrence of podais diseases when compared to cattle, especially dairy cattle. The knowledge about microstructural structures of buffalo’s hoof generated important information for understanding of the intrinsic resistance of buffaloes foot diseases. This study aimed to investigate the microstructure of adult Jafarabadi buffaloes, through histomorphometric ratings, two-dimensional microtomography, three-dimensional, nanohardness test and biochemical composition. Histomorphometric ratings revealed important features not yet investigated by other researchers, highlighting the structural behavior of epidermal papillae in different regions of corneal layer, the morphology and disposition of the horn tubules, the architecture of extratubular and intratubular keratin and even organization of melanosomes . It was observed that the average length of buds, thickness and spacing in pelvic and thoracic digit did not show statistically significant differences. However, an increase in thickness of the laminar corium papillae of the wall and spacing was observed when comparing the average of the coronary corium and wall and sole laminar corium. When compared to the findings of other researchers, this study have shown that the epidermal papillae on the hulls of these animals are presented larger than the epidermal papillae of Holstein and Gir animals, suggesting that the buffalo’s has greater keratin production and better epidermis and horny case fixing. It can be conjectured that such characteristics are associate with greater resistance to foot diseases of this animals, although additional studies are needed. Analysis of microtomography and nanohardness test showed increased medial digit of forelimbs and side-digit of hindlimbs exhibit increased horn tubules with larger diameters. But the abaxial wall of forelimbs digit showed higher values than hindlimbs digit. Even there was not significant difference between the digits analyzed, this study could clarify important aspects of the nanohardness of different regions of the corneal case of buffalo’s digits. 3D microtomography analysis revealed that the dorsal wall presents a greater hardness compared to the abaxial wall of intermediate hardness, and with the sole of the hoof, that showed the lowest hardness among the evaluated areas. It was inferred that tridimensional microtomography testing is more specific than Vickers nanohardness test for this structure. However, further research are required. Biochemical tests generated parameters about structural elements of the corneal case, which showed different concentrations in relation to the region and anatomical position of the hull. These differences are related to the digits wich recive higher load of body weight and impact. This study generated knowledge and parameters to be used in further researches on different bovine species and breeds.
As enfermidades de cascos, apesar de ser alvo de poucos estudos na espécie bubalina, apresentam aspectos científicos importantes uma vez que estes animais, mesmo criados em condições adversas, apresentam resistência diferenciada quanto à ocorrência de doenças podais, quando comparados aos bovinos, com destaque para os de aptidão leiteira. Acredita-se que o conhecimento microestrutural do casco de bubalinos gerou informações importantes para melhor entendimento da resistência podal intrínseca dos bubalinos às enfermidades podais. O presente estudo teve por finalidade pesquisar a microestrutura do estojo córneo de búfalas adultas, raça Jafarabadi, por meio de avaliações histomorfométricas, microtomografia bidimensional, tridimensional, teste de nanodureza e composição bioquímica. As avaliações histomorfométricas em bubalinos revelaram características importantes ainda não investigadas por outros pesquisadores, destacando o comportamento estrutural das papilas epidérmicas nas diferentes regiões do estojo córneo, a morfologia e disposição dos túbulos córneos, a arquitetura da queratina extratubular e intratubular e ainda organização dos melanossomas. Pode-se observar nessas avaliações que as médias de comprimento das papilas, espessura e espaçamento nos dígitos dos membros pélvicos e torácicos não apresentaram diferenças estatísticas significativas entre si. Todavia, ao comparar as médias do córion coronário, córion laminar da muralha e sola, observou-se entre as regiões do estojo córneo, um aumento da espessura das papilas do córion laminar da muralha e do espaçamento comparando-se as demais regiões. Os achados dessa pesquisa quando comparados aos achados de outros pesquisadores, demonstraram que as papilas epidérmicas nos cascos desses animais, apresentam-se maiores que as papilas epidérmicas de bovinos das raças, Holandesa e Gir, sugerindo que possuem maior capacidade de produção de queratina e melhor fixação da epiderme ao estojo córneo. Contudo, pôde-se conjecturar tais características com a maior resistência desses animais as enfermidades podais, embora haja a necessidade de estudos adicionais. Por meio das análises de microtomografia e teste de nanodureza, pode-se verificar que os dígitos mediais dos membros torácicos e os dígitos laterais dos membros pélvicos apresentaram maior quantidade de túbulos córneos com diâmetros maiores. Porém, a muralha abaxial dos dígitos dos membros torácicos apresentaram valores superiores aos dígitos dos membros pélvicos. Apesar de não ter sido observada diferença significativa entre os dígitos estudados, o presente estudo pôde esclarecer, ainda, aspectos importantes sobre a nanodureza das diferentes regiões do estojo córneo dos dígitos de bubalinos. A análise de microtomografia 3D revelou que a muralha dorsal apresenta maior dureza quando comparada com a muralha abaxial, de dureza intermediária, bem como, com a sola do casco, que apresentou menor dureza entre as regiões avaliadas. Inferiu-se assim que o teste de microtomografia tridimensional seja mais específico que o teste de nanodureza de Vickers para a estrutura considerada. No entanto, tal afirmação requer pesquisas adicionais. Os testes bioquímicos geraram parâmetros quanto aos elementos estruturais do estojo córneo, que demonstraram diferentes concentrações em relação à região e posição anatômica do casco, sendo essas diferenças associadas aos dígitos que recebem maior sobrecarga de massa corporal e impacto. O presente estudo gerou conhecimento e parâmetros a serem utilizados em outras investigações científicas, em outras espécies e raças de bovídeos.
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Villar, Menéndez Izaskun. "Regulación epigenética de la expresión estriatal del receptor de adenosina A(2A) en enfermedades neurológicas con trastorno motor asociado." Doctoral thesis, Universitat de Barcelona, 2014. http://hdl.handle.net/10803/145900.
Full textAbstract:
La adenosina es un metabolito presente en todo el organismo con distintas funciones fisiológicas. En el sistema nervioso central, desempeña un importante papel como neuromodulador a través de la interacción con sus receptores de membrana: los receptores de adenosina A(1), A(2A), A(2B) y A(3), siendo los más abundantes en el cerebro el A(1 )y el A(2A).
El receptor de adenosina A(2A) (A(2A)R) presenta una elevada expresión en el estriado, especialmente en las neuronas GABAérgicas medianas espinosas que conforman la vía indirecta de los ganglios basales. La actividad de esta vía está relacionada con la inhibición motora. La actividad del A(2A)R puede modular de hecho la actividad motora. Es bien conocido cómo, tanto en modelos animales como en humanos, los antagonistas del receptor, como la cafeína, estimulan el movimiento, mientras que sus agonistas tienen actividad sedante.
Las tres enfermedades abordadas en este trabajo han sido previamente relacionadas con alteraciones del sistema adenosinérgico. En la enfermedad de Parkinson, coincidiendo con una sintomatología hipocinética, se ha descrito una sobreexpresión patológica del A(2A)R en el estriado. La reducción de los niveles del receptor ha sido descrita en la misma región cerebral en el contexto de la enfermedad de Huntington, en la que se da una sintomatología hipercinética. La esquizofrenia, a su vez, ha sido relacionada con una disfunción de los ganglios basales y un déficit en la señalización adenosinérgica.
La línea de investigación en la que se enmarca este trabajo había determinado previamente cómo la expresión tejido específica del A(2A)R en el cerebro está controlada por la metilación de la región 5'UTR de su gen, ADORA2A. A lo largo de la presente tesis se ha investigado si éste u otros mecanismos epigenéticos están implicados en la aparición de niveles anómalos del receptor en las enfermedades de Parkinson y Huntington. Además, se han explorado los niveles de expresión del receptor en el estriado en personas con esquizofrenia. Para todo ello se ha trabajado fundamentalmente con muestras de putamen postmortem, una de las regiones del estriado que ha sido vinculada más estrechamente con el control motor.
Este trabajo ha permitido confirmar que la sobreexpresión patológica del A2A en el estriado en la enfermedad de Parkinson se produce ya en los primeros estadios de la enfermedad (estadios de Braak 1 a 3), coincidiendo con una bajada de los niveles del microARN hsa-miR-34b. El descenso en los niveles de este microARN había sido previamente descrito en cerebros postmortem de personas con Parkinson pero en otras regiones cerebrales, relacionándolo con estrés mitocondrial. En este trabajo se ha validado el A(2A)R como diana para este microARN mediante ensayos funcionales in vitro, por lo que se propone que el descenso del hsa-miR-34b promueve un aumento de los niveles del A(2A)R en el putamen desde las primeras etapas de la progresión patológica.
En cuanto a los resultados en la enfermedad de Huntington, se ha mostrado cómo la reducción de la expresión del A(2A)R en el estriado humano coincide con un incremento en los niveles de metilación y una reducción en los niveles de hidroximetilación de la región 5'UTR del ADORA2A.
El estudio llevado a cabo en la esquizofrenia ha revelado un importante descenso de la expresión del A(2A)R en la mitad de los casos patológicos analizados, coincidiendo con hipermetilación de la región 5'UTR del ADORA2A. Estos casos presentan además una sintomatología motora particular, lo que ha permitido proponer la existencia de un subgrupo de pacientes en esta enfermedad.
Esto resultados ofrecen soporte a ciertas estrategias terapéuticas propuestas para estas enfermedades y basadas en la modulación de la actividad o de la expresión del A(2A)R. Indican además un uso potencial para la medida de los niveles del A(2A)R en los pacientes con trastorno motor. Esta información permitiría una mayor personalización de los tratamientos y una mejora en la interpretación de las respuestas individuales a los fármacos.Adenosine is a metabolite distributed throughout the entire organism with multiple physiological functions. In the central nervous system it plays a main role as neuromodulator, interacting with specific membrane receptors: A(1), A(2A), A(2B) and A(3). The most brain-enriched are A1 and A2A. Adenosine receptor A(2A) (A(2A)R) is highly expressed in the striatum, specially in the GABAergic medium-sized spiny neurons that form the indirect pathway of the basal ganglia, whose activity has been related with motor inhibition. There is evidence for A(2A)R activity involvement in motor behavior: A(2A)R antagonists, as caffeine, stimulate locomotion, while A(2A)R agonists are sedative. The three diseases studied in this work have previously been related to adenosinergic system dysfunction. In Parkinson's disease, characterized by hypokinesia, a pathological overexpression of striatal A(2A)R has been described. In Huntington's disease, characterized by hyperkinesia, striatal A(2A)R expression is reduced. Schizophrenia has been related to basal ganglia dysfunction and reduced adenosinergic signaling. In previous studies, the group described how DNA methylation regulates ADORA2A (A(2A)R gen) basal expression in different cell lines as well as its tissue-specific expression in brain. In the present thesis, it was studied whether this or other epigenetic mechanisms were involved in A(2A)R pathological expression levels detected in Parkinson or Huntington diseases. Besides, A(2A)R levels were analyzed in striatum of schizophrenia patients. The work has been performed mainly using human postmortem putamen samples, a striatal region strongly related to motor control. Overall, the obtained results (i) reinforce the relation between A(2A)R striatal expression and motor control, (ii) demonstrate involvement of epigenetic mechanisms in pathological A(2A)R expression in different neuropathological contexts and (iii) support therapeutic strategies previously proposed based on the modulation of A(2A)R expression, and indicate potential usefulness of A(2A)R levels measure in patients with motor alterations, considering that this information would allow a better personalization of treatments and a better understanding of individual reactions to drugs.
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Mattson, Matthew Sanford. "Understanding and Treating Eye Diseases: Mechanical Characterization and Photochemical Modification of the Cornea and Sclera." Thesis, 2008. https://thesis.library.caltech.edu/5210/1/MSM_Thesis_7May2008.pdf.
Full textAbstract:
Proper vision depends on the physical properties of the eye tissues. Diseases that alter the chemical and mechanical states of the tissue can result in a loss of functionality. Degenerative myopia and keratoconus are diseases that exhibit such changes in the sclera and cornea, respectively. These diseases may be treatable by engineering the mechanical properties of the sclera and cornea.
We have developed an intact globe expansion method for mechanical characterization of eyes in vitro, which provides reliable measurements, with relatively few samples, and mimics the type and distribution of stresses inherent in the natural boundary conditions of the eye. Furthermore, application of high intraocular pressures provides a way to study shape changes of the sclera and cornea which are similar to those exhibited in myopia and keratoconus. Potential treatments that show an ability to prevent ocular distension in this method have a chance of preventing the deformations that occur in vivo in the diseases.
Our studies in vitro indicate that crosslinking can improve tissue mechanical stability and resistance to deformation. Light activated crosslinking provides spatial and temporal control of treatments, and photoinitiator systems such as Eosin Y (EY) and triethanolamine (TEOA) allow this control with safe doses of visible light.
For myopia treatment, we demonstrate in vitro stabilization of eyes using the intact globe method after drug is delivered to the sclera in vitro or in vivo on 2–3 week old rabbits. Biocompatibility studies of the scleral treatments indicate excellent tolerance to the light and drug in both rabbits and guinea pigs. Further, we have developed treatment protocols for use in a guinea pig form-deprivation model of myopia. In normally growing guinea pig eyes, treatments can create substantial changes to eye shape. These changes are manifested in shifts in the refractive error and ocular length that persist for the duration over which the animals are monitored.
For keratoconus, treatment in vitro on rabbit eyes using EY/TEOA demonstrates similar capabilities of corneal stabilization as a treatment currently in clinical trials. The EY/TEOA treatment shows advantages of reduced treatment time and the possibility of treatment without removal of the epithelium.
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Qahwaji, Rami S. R., Stanley S. Ipson, S. Hayajneh, R. Alzubaidi, A. Brahma, and Mhd Saeed Sharif. "An Efficient System For Preprocessing Confocal Corneal Images For Subsequent Analysis." 2014. http://hdl.handle.net/10454/7675.
Full textAbstract:
YesA confocal microscope provides a sequence of images of the various corneal layers and structures at different depths from which medical clinicians can extract clinical information on the state of health of the patient’s cornea. Preprocessing the confocal corneal images to make them suitable for analysis is very challenging due the nature of these images and the amount of the noise present in them. This paper presents an efficient preprocessing approach for confocal corneal images consisting of three main steps including enhancement, binarisation and refinement. Improved visualisation, cell counts and measurements of cell properties have been achieved through this system and an interactive graphical user interface has been developed.
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Alzubaidi, R., Mhd Saeed Sharif, Rami S. R. Qahwaji, Stanley S. Ipson, and A. Brahma. "In vivo confocal microscopic corneal images in health and disease with an emphasis on extracting features and visual signatures for corneal diseases: a review study." 2015. http://hdl.handle.net/10454/11646.
Full textAbstract:
YesThere is an evolution in the demands of modern ophthalmology from descriptive findings to assessment of cellular level changes by using in vivo confocal microscopy. Confocal microscopy, by producing grey-scale images, enables a microstructural insight into the in vivo cornea in both health and disease, including epithelial changes, stromal degenerative or dystrophic diseases, endothelial pathologies, and corneal deposits and infections. Ophthalmologists use acquired confocal corneal images to identify health and disease states and then to diagnose which type of disease is affecting the cornea. This paper presents the main features of the healthy confocal corneal layers, and reviews the most common corneal diseases. It identifies the visual signature of each disease in the affected layer and extracts the main features of this disease in terms of intensity, certain regular shapes with both their size and diffusion, and some specific region of interest. These features will lead towards the development of a complete automatic corneal diagnostic system which predicts abnormalities in the confocal corneal data sets.
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Cockinos, Chrissanthie. "Bacterial keratitis at St. John Eye Hospital with emphasis on causation and management." Thesis, 1998. http://hdl.handle.net/10539/22832.
Full textAbstract:
A dissertation submitted to the Faculty of Health Sciences,
University of the Witwatersrand, Johannesburg
in partial fuifillment of the requirements for the degree
of Master of Medicine in Ophthalmology,This dissertation describes the causation and management of bacterial keratitis at St John Eye Hospital. [Abbreviated Abstract. Open document to view full version]
AC2017