The inherited form of primary open angle glaucoma, a disorder characterized by increased intraocular pressure and retina degeneration, is linked to mutations in the olfactomedin (OLF) domain of the myocilin gene. Disease-causing myocilin variants accumulate within trabecular meshwork cells instead of being secreted to the trabecular extracellular matrix thought to regulate aqueous humor flow and control intraocular pressure. Like other diseases of protein misfolding, we hypothesize myocilin toxicity originates from defects in protein biophysical properties. In this thesis, the first preparative recombinant high-yield expression and purification system for the C-terminal OLF domain of myocilin (myoc-OLF) is described. To determine the relative stability of wild-type (WT) and mutant OLF domains, a fluorescence thermal stability assay was adapted to provide the first direct evidence that mutated OLF is folded but less thermally stable than WT. In addition, mutant myocilin can be stabilized by chemical chaperones. Together, this work provides the first quantitative demonstration of compromised stability among identified OLF variants and placing myocilin glaucoma in the context of other complex diseases of protein misfolding. Subsequent investigations into the biophysical properties of WT myoc-OLF provide insight into its structure and function. In particular, myoc-OLF is stable in the presence of glycosaminoglycans (GAGs), as well as over a wide pH range in buffers with functional groups reminiscent of such GAGs. Myoc-OLF contains significant â-sheet and â-turn secondary structure as revealed by circular dichroism analysis. At neutral pH, thermal melts indicate a highly cooperative transition with a melting temperature of ~55°C. A compact core structural domain of OLF was identified by limited proteolysis and consists of approximately residues 238-461, which retains the single disulfide bond and is as stable as the full myoc-OLF construct. This construct also is capable of generating 3D crystals for structure determination. This data, presented in Chapter 3, inform new testable hypotheses for interactions with specific trabecular extracellular matrix components. To gain further insight into the biological function of myoc-OLF, a facile fluorescence chemical stability assay was designed to identify possible ligands and drug candidates. In the assay described in Chapter 4, the target protein is initially destabilized with a chemical denaturant and is tested for re-stabilization upon the addition of small molecules. The assay requires no prior knowledge of the structure and/or function of the target protein, and it is amendable to high-throughput screening. Application of the assay using a library of 1,280 compounds revealed 14 possible ligands and drug candidates for myoc-OLF that may also generate insights into myoc-OLF function. Due to the high â-sheet content of monomeric myoc-OLF and presence of an aggregated species upon myoc-OLF purification, the ability of myoc-OLF to form amyloid fibrils was suspected and verified. The fibril forming region was confirmed to reside in the OLF domain of myocilin. Kinetic analyses of fibril formation reveal a self-propagating process common to amyloid. The presence of an aggregated species was confirmed in cells transfected with WT myocilin, but to a greater extent in cells transfected with P370L mutant myocilin. Both cell lines stained positive for amyloid. Taken together, these results provide further insights into the structure of myocilin and suggest a new hypothesis for glaucoma pathogenesis. Finally, in a related study, small molecule drug candidates were investigated to treat acid â-glucosidase (GCase), the deficient lysosomal enzyme in Gaucher disease, another protein conformational disorder. Three new GCase active-site directed 3,4,5,6-tetrahydroxylazepane inhibitors were synthesized that exhibit half inhibitory concentrations (IC50) in the low millimolar to low micromolar range. Although the compounds thermally stabilize GCase at pH 7.4, only one of the synthesized analogs exhibits chaperoning activity under typical assay conditions. This successful pharmacological chaperone is also one in which GCase is in its proposed active conformation as revealed by X-ray crystallography. Probing the plasticity of the active-site of GCase offers additional insight into possible molecular determinants for an effective small molecule therapy for GD.

It is well known that ultraviolet (UV) B (280-315 nm) and blue light (400-500 nm) radiation can produce phototoxic lesions in the neural retina and the retinal pigment epithelium (RPE). In the first section of this thesis, bovine lens cells (epithelium and superficial cortical fibre cell) and human retinal pigment epithelial (ARPE-19) cells were used to characterize in vitro changes following oxidative stress with UVB radiation in ocular lens optics and cellular function in terms of mitochondrial dynamics. In the second part, human retinal pigment epithelial (ARPE-19) cells and in vitro bioassays were used together to develop an in vitro approach for UV radiation-induced retinal toxicology research. In the third chapter, the in vitro approach developed above was used with intraocular lens (IOL) materials to evaluate the UV radiation blocking efficiency of commercially available IOL’s. Lastly, narrowband blue light irradiation and in vitro assays were used to determine more precisely the wavelengths of blue light responsible for photochemical lesions of the retina as an effort to contribute to future IOL designs. The results from mitochondrial dynamics of lens cells and RPE cells show significant decreases in mitochondrial movement after UVB irradiation in a dose dependent manner. Results obtained from four in vitro assays (Alamar blue assay, confocal microscopy for mitochondrial distribution and nucleic acids damage, phagocytotic activity assay) for evaluating the UVB-induced damage in ARPE-19 show significant decreases in cell viability as well as phagocytotic activity of RPE cells after UVB radiation. In addition, the results show that UV radiation can also induce the degradation of DNA/RNA and mitochondria of RPE cells in a dose dependent manner. The results of the UV blocking efficiency test of commercially available IOL materials show very effective UV blocking ability, allowing no cellular damage at all, in comparison to an IOL uncovered control cell. The results of three different wavelengths of blue light exposure show that only 400 nm blue light radiation can cause significant damage to RPE cells, while 420 and 435.8 nm blue light radiation cause no cellular damage at all. In conclusion, UVB and blue light radiation can cause phototoxic damage to the retinal pigment epithelium as a result of oxidative stress, and in vitro bioassays used for this research may offer a sensitive, and meaningful biomarker approach, not only for evaluating RPE function after oxidative and chemical stress, but also for evaluating IOL effectiveness.

It is well known that ultraviolet (UV) B (280-315 nm) and blue light (400-500 nm) radiation can produce phototoxic lesions in the neural retina and the retinal pigment epithelium (RPE). In the first section of this thesis, bovine lens cells (epithelium and superficial cortical fibre cell) and human retinal pigment epithelial (ARPE-19) cells were used to characterize in vitro changes following oxidative stress with UVB radiation in ocular lens optics and cellular function in terms of mitochondrial dynamics. In the second part, human retinal pigment epithelial (ARPE-19) cells and in vitro bioassays were used together to develop an in vitro approach for UV radiation-induced retinal toxicology research. In the third chapter, the in vitro approach developed above was used with intraocular lens (IOL) materials to evaluate the UV radiation blocking efficiency of commercially available IOL’s. Lastly, narrowband blue light irradiation and in vitro assays were used to determine more precisely the wavelengths of blue light responsible for photochemical lesions of the retina as an effort to contribute to future IOL designs. The results from mitochondrial dynamics of lens cells and RPE cells show significant decreases in mitochondrial movement after UVB irradiation in a dose dependent manner. Results obtained from four in vitro assays (Alamar blue assay, confocal microscopy for mitochondrial distribution and nucleic acids damage, phagocytotic activity assay) for evaluating the UVB-induced damage in ARPE-19 show significant decreases in cell viability as well as phagocytotic activity of RPE cells after UVB radiation. In addition, the results show that UV radiation can also induce the degradation of DNA/RNA and mitochondria of RPE cells in a dose dependent manner. The results of the UV blocking efficiency test of commercially available IOL materials show very effective UV blocking ability, allowing no cellular damage at all, in comparison to an IOL uncovered control cell. The results of three different wavelengths of blue light exposure show that only 400 nm blue light radiation can cause significant damage to RPE cells, while 420 and 435.8 nm blue light radiation cause no cellular damage at all. In conclusion, UVB and blue light radiation can cause phototoxic damage to the retinal pigment epithelium as a result of oxidative stress, and in vitro bioassays used for this research may offer a sensitive, and meaningful biomarker approach, not only for evaluating RPE function after oxidative and chemical stress, but also for evaluating IOL effectiveness.

Made available in DSpace on 2015-07-22T20:49:36Z (GMT). No. of bitstreams: 0 Previous issue date: 2010-01-27 / Objetivo: Avaliar os métodos biométricos do olho humano em pacientes portadores de catarata e com indicação de implante de lente intra-ocular. Métodos: Oitenta e quatro pacientes com média de idade de 58,82 ± 10,03 anos foram submetidos às biometrias óptica e ultra-sônica (imersão e contato) em ambos os olhos (n = 168). Os dados do comprimento axial, profundidade da câmara anterior, espessura do cristalino, profundidade da câmara vítrea e curvatura da córnea foram analisados. Foi avaliada a diferença das médias de cada método biométrico usado e a concordância foi investigada pela análise gráfica intra-individual de Bland-Altman de um método em relação ao outro. Resultados: Não houve diferença estatisticamente significante para as médias do comprimento axial (P=0,245), profundidade da câmara anterior (P=0,073), espessura do cristalino (P=0,8794) e profundidade da câmara vítrea (P=0,7640) entre os métodos usados. A diferença das médias da curvatura da córnea entre o IOLMaster® e o ceratômetro manual OM-4® foi estatisticamente significante (P<0,0001). Apesar da boa reprodutibilidade dos resultados, os gráficos de Bland- Altman mostraram algumas medidas fora dos limites de concordância estabelecidos em todas as variáveis analisadas. Houve menor concordância das medidas ceratométricas na comparação entre o IOLMaster® e o ceratômetro OM- 4®. Conclusões: Não houve diferença das médias dos métodos biométricos usados nesse estudo, exceto a curvatura da córnea que apresentou uma diferença estatisticamente significante entre as médias apresentadas. Os métodos demonstraram boa concordância, entretanto algumas medidas se apresentaram discordantes e podem ocasionar erros no cálculo do poder dióptrico da lente intraocular. / TEDE / BV UNIFESP: Teses e dissertações

Orientador: Cláudia Valéria Seullner Brandão / Resumo: O estudo objetivou descrever valores de referência para importantes testes diagnósticos oftalmológicos, como sensibilidade corneal, produção lacrimal, pressão intraocular, espessura corneal e microbiota conjuntival em saguis de tufo preto (Callithrix penicillata) saudáveis e sem alterações oculares. Foram utilizados 13 saguis de tufo preto, totalizando 26 olhos, provenientes do CEMPAS da Faculdade de Medicina Veterinária e Zootecnia - UNESP, Botucatu, São Paulo, Brasil. Os saguis foram submetidos a contenção química com anestesia dissociativa à base de cetamina e midazolam, para realização dos exames. Os resultados obtidos para sensibilidade corneal com estesiômetro Cochet-Bonnet foi de 5,8 ± 0,6cm; produção lacrimal com ponta de papel absorvente endodôntica estéril de 13 ± 3mm/min; pressão intraocular com tonômetro de rebote Tonovet Plus Icare® de 22,2 ± 2,9mmHg; espessura corneal 340,7 ± 25,5µm; e predomínio de bactérias Gram-positivas nas amostras de microbiota conjuntival. Não houve diferença significativa considerando lateralidade e sexo dos animais (P>0,05). Os resultados obtidos nos testes diagnósticos oftalmológicos poderão auxiliar médicos veterinários oftalmologistas a diagnosticar e tratar doenças oculares em saguis de tufo preto, além de contribuir para pesquisas na área de visão. / Abstract: The study aimed to describe reference values for important ophthalmic diagnostic tests, such as corneal sensitivity, tear production, intraocular pressure, corneal thickness and conjunctival microbiota in black tufted marmosets (Callithrix penicillata). Thirteen black tuft marmosets were used, totaling 26 eyes, followed by CEMPAS by the Faculty of Veterinary Medicine and Zootechnics - UNESP, Botucatu, São Paulo, Brazil. The procedures were used for chemical containment with dissociative anesthesia based on ketamine and midazolam, to perform the exams. The results obtained for corneal sensitivity with a Cochet-Bonnet esthesiometer were 5.8 ± 0.6 cm; tear production with sterile endodontic absorbent paper tip of 13 ± 3mm / min; intraocular pressure with Tonovet Plus Icare® rebound tonometer of 22.2 ± 2.9mmHg; corneal thickness 340.7 ± 25.5 µm; and predominance of Gram-positive bacteria in conjunctival microbiota. There was no significant difference considering the laterality and sex of the animals (P> 0.05). The results obtained in ophthalmological diagnostic tests can help veterinary ophthalmologists to diagnose and treat eye diseases in the black tufted marmosets, in addition to contributing to research in the field of vision. / Mestre

Der Einsatz von Ketamin erfolgt in der Humananästhesie, vor allem aufgrund seiner vielfältigen Nebenwirkungen, nur noch nach strenger Indikation. In der Veterinärmedizin ist Ketamin tierartenübergreifend für die Injektionsnarkose weit verbreitet. Um den bekannten Nebenwirkungen vorzubeugen, wird Ketamin mit verschiedenen anderen Anästhetika kombiniert und stellt so ein sicheres Narkoseverfahren bei Tieren dar. Eine besondere Herausforderung ist die Anästhesie bei ophthalmologischen Patienten unter Berücksich-tigung der Kontrolle des Intraokularen Drucks (IOP). In diesem Zusammenhang gibt es in der Literatur widersprüchliche Angaben zur Auswirkung von Ketamin auf den IOP beim Menschen und verschiedenen Tierarten. Auch für die Auswirkungen von Propofol und der endotrachealen Intubation auf den IOP existieren widersprüchliche Aussagen. In der vorliegenden Arbeit wurde untersucht, ob gängige Ketamin-Kombinationsnarkosen bei der augengesunden Katze einen Einfluss auf den IOP haben. Angeregt durch Berichte in der Literatur wurde zudem untersucht, ob die Applikation von Propofol sowie die endotracheale Intubation den IOP bei der Katze beeinflussen. Methodik: Untersucht wurden 48 adulte, augengesunde Katzen, die dem chirurgischen Patientengut der Klinik für Kleintiere der Universität Leipzig entstammten. Es handelt sich um eine prospektive, randomisierte Blindstudie. Die Patienten wurden vier Untersuchungsgruppen zugeordnet. Zur intramuskulären Narkoseeinleitung erhielten Tiere der KX-Gruppe Ketamin (10 mg/kg) und Xylazin (1 mg/kg), der KXAtr-Gruppe Ketamin (10 mg/kg), Xylazin (1 mg/kg) und Atropin (0,025 mg/kg), der KA-Gruppe Ketamin (20 mg/kg) und Acepromazin (0,5 mg/kg) und der KM-Gruppe Ketamin (10 mg/kg) und Medetomidin (50 g/kg). Bei allen Patienten wurde mittels Tono-Pen® XL zu verschiedenen Zeitpunkten der IOP bestimmt: vor Narkoseeinleitung (Ausgangswert), nach Narkoseeinleitung nach 5, Zusammenfassung 86 10, 15 und 20 Minuten und direkt nach der Intubation sowie final nach Beendigung der Narkose während der Aufwachphase. Einige Tiere erhielten zur Vertiefung der Narkose vor der Intubation Propofol. Im Anschluss erfolgte eine ophthalmologische Untersuchung der Patienten, um eine Augenerkrankung auszuschließen. Ergebnisse: Der mittlere Ausgangs-IOP aller Tiere beträgt 15,8 mmHg. Mit p = 0,756 besteht kein signifikanter Unterschied zwischen den Gruppen. Getrennt nach linken (OS) und rechten (OD) Augen ist der mittlere IOP 15,7 und 15,8 mmHg. Dieser Unterschied ist nicht signifikant (p = 0,442). Daher wird für die Auswertung der Mittelwert aller 6 Datenpunkte pro Tier und Messzeitpunkt zugrunde gelegt. Im Vergleich zum Ausgangswert zeigt die KX-Gruppe keine signifikanten IOP-Änderungen. Die KXAtr-Gruppe und die KM-Gruppe weisen zur Final-Messung einen signifikanten IOP-Abfall um 16 % (p = 0,012) bzw. 17 % (p = 0,021) im Vergleich zum Ausgangswert auf. Die KA-Gruppe zeigt zur 15-Minuten-Messung den stärksten IOP-Abfall mit 21 % Prozent (p = 0,001) gegenüber dem Ausgangswert. Ab der 10-Minuten-Messung bis zur post-Intubations-Messung ist der IOP-Abfall der KA-Gruppe signifikant. Für die Gesamtstichprobe hat die Intubation keinen signifikanten Einfluss auf den IOP (p = 0,063). Die Gabe von Propofol zur Vertiefung der Narkose bei einzelnen Tieren hat ebenfalls keinen signifikanten Einfluss auf den IOP (p = 0,42). Schlussfolgerung: Die verwendeten Ketamin-basierten Narkoseprotokolle bewirken bei der augengesunden Katze keinen signifikanten IOP-Anstieg. Die Gruppen KX, KXAtr und KM gewährleisten für den Zeitraum von 20 Minuten nach Narkoseeinleitung einen relativ stabilen IOP. Trotz des signifikanten IOP-Abfalls in der KA-Gruppe sind sämtliche IOP-Schwankungen aller Gruppen klinisch nicht relevant. Die gemessenen IOP-Werte bewegen sich alle im physiologischen Bereich. Zudem geben die Ergebnisse keinen Hinweis auf eine IOP-Steigerung infolge Propofolgabe und Intubation bei der Katze. / Ketamine is used in human medicine based on strict indications, mainly due to its numerous side effects. In veterinary medicine however Ketamine is commonly used to induce anesthesia intramuscularly throughout all species. To minimize the well known side effects Ketamine is used in combination with several other anesthetics and thus represents a safe anesthetic procedure in animals. Ophthalmological patients are a particular challenge for anesthetists with regard to maintaining the intraocular pressure (IOP). Conflicting data can be found in the literature about the effects of Ketamine on IOP in humans and various animal species. The literature also contains various statements about the effects of Propofol and endotracheal intubation on IOP. In this clinical trial we investigated the effects of commonly used Ketamine-based anesthetic protocols on IOP in cats. Motivated by conflicting statements in the literature the analysis of the effects of Propofol and endotracheal intubation on IOP was included in the study. Methods: This is a prospective, randomized, blinded study. 48 adult cats without ophthalmological abnormalities, recruited from the pool of admitted surgical patients of the Department of Small Animal Medicine of the University of Leipzig were included in the study. The patients were assigned to one of the following four groups and anesthesia was induced intramuscularly. Cats in the KX-group were induced with Ketamine (10 mg/kg) and Xylazine (1 mg/kg). Cats in the KXAtr-group were induced with Ketamine (10 mg/kg), Xylazine (1 mg/kg) and Atropine (0,025 mg/kg). Cats in the KA-group were induced with Ketamine (20 mg/kg) and Acepromazine (0,5 mg/kg). Cats in the KM-group were induced with Ketamine (10 mg/kg) and Medetomidine (50 g/kg). In all patients the IOP was measured three times per eye using the Tono-Pen® XL at particular times: baseline IOP before induction of anesthesia, at 5, 10, 15 and 20 minutes after induction of anesthesia, after intubation and final IOP after completion of surgery. Some cats received a single bolus of Propofol to be able to tolerate endotracheal intubation. After the final IOP-measurement all Zusammenfassung 88 cats were subjected to an ophthalmological examination, including slitlamp biomicroscopy and gonioscopy, in order to exclude patients with ophthalmological pathologies. Results: The mean baseline IOP for all animals is 15,8 mmHg (SD 4,0). There is no significant difference between the four groups (p = 0,756). The mean IOP for the right (OD) and left eyes (OS) of all patients was 15,8 mmHg and 15,7 mmHg, respectively. There is no significant difference between right (OD) and left eyes (OS) (p = 0,442). Therefore all further analyses are based on the mean of all six data points per animal and measuring time. The KX-group shows no significant IOP-change relative to baseline-IOP. The KXAtr and KM-group show a significant decrease in IOP of 16 % and 17 %, respectively, at the final measurement compared with baseline-IOP. The KA-group shows a significant decrease in IOP starting at 10 minutes after induction of anesthesia until the post-intubation measurement. The maximum decrease in IOP in this group is 21 % relative to baseline-IOP 15 minutes after induction of anesthesia. For the total data no significant influence of endotracheal intubation on IOP could be detected (p = 0,063). The application of Propofol in a total of 14 cats has no significant effect on IOP (p = 0,42). Conclusion: The Ketamine-based anesthetic protocols used in this study do not cause a significant increase in IOP in cats without ophthalmological abnormalities. The KX, KXAtr and KM-group ensure a relatively stable IOP for the time period of 20 minutes after induction of anesthesia. Despite the significant IOP-decrease in the KA-group none of the IOP-changes in all groups examined are of clinical relevance. All of the collected IOP-values are within the physiological range for cats. There is no evidence for an increase in IOP caused by endotracheal intubation or the application of Propofol.

Univerzita Karlova 1. lékařská fakulta Studijní program: Zobrazovací metody v lékařství (P5150) Studijní obor: Zobrazovací metody v lékařství (5103V000) MUDr. Adam Kopecký Změny na předním segmentu po 25G+ PPV Changes in the Anterior Segment after 25G+ PPV Abstract Vedoucí závěrečné práce/Školitel: doc. MUDr. Jiří Pašta, CSc., FEBO Praha, 2019 Abstract: Pars plana vitrectomy is a dominant surgical method in posterior segment surgery of the eye. The principle of this method is the surgical approach via the pars plana anatomical region. With this approach, surgeon performs the posterior segment surgery without directly affecting the anterior segment of the eye. Short-term effect of pars plana vitrectomy on the anterior segment of the eye has been repeatedly proven. That might be an important factor both in assessing the complications of this method and planning the surgery in complicated patients. Generally, it is presumed that we do not observe long-term effects on anterior segment after pars plana vitrectomy. The aim of our work is to evaluate the long-term changes in the anterior segment after the uncomplicated 25G + PPV with gas tamponde. The group of 20 patients was selected according to strict indication criteria. Using a series of examinations, we examined specific parameters such as: intraocular...

Ralph Schönfelder Untersuchungen zum Einfluss verschiedener Dosierungsintervalle von Dorzolamid, Dorzolamid-Timolol und Latanoprost auf den Intraokulardruck normotensiver Hunde Klinik für Kleintiere, Veterinärmedizinische Fakultät der Universität Leipzig Eingereicht im März 2010 Bibliografische Angaben: 93 S., 27 Abb., 14 Tab., 224 Lit., Anhang mit 2 Abb., 4 Tab. Schlüsselwörter: Glaukom, Intraokulardruck, Prostaglandine, Karboanhydrasehemmer, Timolol, Hund Das Glaukom beim Hund ist ein Notfall, der eine rasche Senkung des erhöhten Intraokulardruckes verlangt, um dem Verlust der Sehfähigkeit und den auftretenden Schmerzen entgegen zu wirken. Die medikamentöse Behandlung ist dabei ein wichtiger Bestandteil. Das Ziel der vorliegenden Arbeit war es, den Effekt der lokal applizierten Wirkstoffe Dorzolamid, Dorzolamid-Timolol und Latanoprost zur Senkung des Intraokulardruckes bei verschiedenen Dosierungsintervallen zu untersuchen. Für jeden Wirkstoff wurden an vier aufeinander folgenden Tagen tonometrische Messungen des Intraokulardruckes mit dem Tonopen-XL als Kontrolle durchgeführt. Anschließend erfolgte eine Verlaufsuntersuchung, in welcher der Einfluss jedes der drei Wirkstoffe auf den Intraokulardruck bei ein- und zweimal täglicher Applikation jeweils vier Tage lang untersucht wurde. Dabei erfolgten Messungen von Intraokularduck, Pupillendurchmesser und konjunktivaler Irritation beider Augen von zehn Hunden (Beagle) jeweils 8.00; 10.00; 12.00; 16.00; 20.00; 22.00; 24.00; 4.00 Uhr. Bei dreimal täglicher Applikation von Dorzolamid und Dorzolamid-Timolol erfolgten zusätzlich 7.00, 15.00 und 23.00 Uhr Tonometrien. Die einmalige Applikation des Wirkstoffes erfolgte 8.00, die zweimalige Applikation 8.00 und 20.00 Uhr sowie 7.00, 15.00 und 23.00 Uhr die dreimalige Applikation. Für jeden Wirkstoff wurde an Tag fünf, nach Beendigung der Applikationen, die Normalisierung des Intraokulardruckes überprüft. Die Ergebnisse wurden nach Applikationshäufigkeit sowie vergleichend analysiert. Dies erfolgte mittels Friedman-Test für drei und mehr k-verbundene Stichproben als Zwei-Weg Varianzanalyse. Ohne Dorzolamidapplikation betrug der Mittelwert des Intraokulardruckes ± SEM am 91 ersten Tag 12,3 ± 0,5 sowie am zweiten, dritten und vierten Tag 12,5 ± 0,4 mmHg, 11,2 ± 0,4 mmHg und 11,0 ± 0,4 mm Hg. Die einmal tägliche Applikation von Dorzolamid führte mit 7,6 ± 0,4 mm Hg am ersten Tag sowie nachfolgend 8,7 ± 0,3 mmHg, 8,6 ± 0,2 sowie 8,3 ± 0,2 mm Hg zu einer signifikanten Drucksenkung. Die zweimalige Applikation von Dorzolamid wies mit 9,6 ± 0,4 mmHg am ersten Tag sowie 7,4 ± 0,4 mmHg, 6,7 ± 0,3 mmHg und 6,6 ± 0,3 mmHg am zweiten, dritten und vierten Tag, das größte Potential zu einer signifikant stärkeren Absenkung des Intraokulardruckes im Vergleich zu Dorzolamid-Timolol und Latanoprost auf. Nach dreimal täglicher Applikation von Dorzolamid trat mit 8,0 ± 0,2 mmHg am ersten Tag und 7,0 ± 0,3 am zweiten sowie 7,6 ± 0,3 mm Hg am dritten und vierten Tag, eine signifikant stärkere, den Intraokulardruck senkende Wirkung im Vergleich zu Dorzolamid-Timolol ein. Ohne Applikation von Dorzolamid-Timolol lag der Mittelwert des IOD ± SEM vom ersten bis vierten Tag bei 10,6 ± 0,4 mmHg, 11,6 ± 0,5 mm Hg, 11,6 ± 0,6 mmHg und 11,2 ± 0,4 mmHg. Bei einmal täglicher Applikation wurden vom ersten bis vierten Tag folgende Werte mit signifikanter Senkung des IOD bestimmt: 7,6 ± 0,4 mmHg, 7,1 ± 0,3 mmHg, 8,6 ± 0,3 mmHg und 9,6 ± 0,3 mmHg. Bei zweimal täglicher Applikation lag der Mittelwert des IOD bei 9,8 ± 0,5 mmHg, am zweiten bis vierten Tag 8,2 ± 0,4 mmHg, 8,6 ± 0,4 mmHg und 7,3 ± 0,2 mmHg. Die dreimalige Applikation führte zu einem Mittelwert des IOD von 8,1 ± 0,3 mmHg am ersten Tag sowie 8,7 ± 0,3 mmHg, 7,8 ± 0,3 mmHg und 7,3 ± 0,3 mmHg am zweiten bis vierten Tag der Studie. Bei der Untersuchung von Latanoprost lag der Mittelwert des IOD ± SEM ohne Applikation bei 9,9 ± 0,3 mmHg am ersten sowie 10,0 ± 0,3 mmHg, 10,0 ± 0,3 mmHg und 9,8 ± 0,2 mmHg am zweiten bis vierten Tag. Bei einmaliger Applikation lag dieser entsprechend bei 9,8 ± 0,3 mmHg, 8,7 ± 0,2 mmHg, 9,0 ± 0,3 und 10,1 ± 0,4 mmHg Nach zweimaliger Applikation betrug er am ersten Tag 9,9 ± 0,3 mmHg, am zweiten bis vierten Tag 9,3 ± 0,4 mmHg, 8,9 ± 0,4 mmHg sowie 8,9 ± 0,3 mmHg. Der Einfluss alller drei Wirkstoffe auf den mittleren Pupillendurchmesser wurde untersucht. Bei einmal- und zweimal-täglicher Applikation von Latanoprost trat mit einer Differenz im Median von 2,5 bzw. 4,7 im Vergleich ohne Applikation eine ausgeprägte Miosis auf. Schließlich wurde die Wirkung auf die Bindehaut durch Ermittlung des Grades der konjunktivalen Irritation bestimmt. Die Applikation von Latanoprost führte dabei zu deutlichen Reizungen der Konjunktiva bis hin zu verstärkter Hyperämie, in einigen Fällen zu konjunktivalem Ödem sowie vereinzelt zu Juckreiz.

OBJECTIVE: Ocular function is fundamental for environmental adaptation and survival capacity. Growth factors are necessary for a mature eyeball, needed for adequate vision. However, the consequences of the deficiency of circulating growth hormone (GH) and its effector insulin-like growth factor I (IGF-I) on the physical aspects of the human eye are still debated. A model of untreated isolated GH deficiency (IGHD), with low but measurable serum GH, may clarify this issue. The aim of this study was to assess the ocular aspects of adult IGHD individuals who have never received GH therapy. DESIGN: Cross sectional study. METHODS: Setting University Hospital, Federal University of Sergipe, Brazil. Patients: Twenty-five adult (13 males, mean age 50.1 years, range 26 to 70 years old) IGHD subjects homozygous for a null mutation (c.57+1G>A) in the GHRH receptor gene, and 28 (15 males, mean age 51.1 years, range 26 to 67 years old) controls were submitted to an endocrine and ophthalmological assessment. Forty-six IGHD and 50 control eyes were studied. Main outcome measures: Visual acuity, intraocular pressure (IOP), refraction (spherical equivalent), ocular axial length (AL), anterior chamber depth (ACD),lens thickness (LT), vitreous depth (VD), mean corneal curvature (CC) and central corneal thickness (CCT). RESULTS: IGHD subjects exhibited unmeasurable serum IGF-I levels, similar visual acuity, intraocular pressure and LT, higher values of spherical equivalent and CC, and lower measures of AL, ACD, VD and CCT in comparison to controls, but within their respective normal ranges. While mean stature in IGHD group was 78 % of the control group, mean head circumference was 92 % and axial AL was 96 %. CONCLUSIONS: These observations suggest mild ocular effects in adult subjects with severe IGF-I deficiency due to non-treated IGHD. / OBJETIVO: A função ocular é fundamental para a adaptação ambiental e a capacidade de sobrevivência. Fatores de crescimento são julgados necessáriospara alcançar um globo ocular maduro, e conseqüente visão adequada. No entanto, as consequências da deficiência isoladadohormônio de crescimento circulante (GH) edo seu efetor, o fator de crescimento semelhante à insulina I (IGF-I) nos aspectos físicos do olho humano ainda são debatidas. Um modelo de deficiência isolada de GH não tratada (DIGH) pode esclarecer esta questão. O objetivo deste estudo foi avaliar os aspectos físicos do globo ocular de indivíduos adultos com DIGH que nunca receberam terapia com GH. DESENHO: Estudo transversal. MÉTODOS: Ambiente: Hospital Universitário, Universidade Federal de Sergipe, Brasil. Pacientes: 25 indivíduosadultos (13 homens,com média de idade de 50,1 anos, entre 26 e 70 anos), com DIGH homozigotos para uma mutação nula (c.57 + 1G> A) no gene do receptorGHRH do grupo DIGH e 28 controles (15 homens, com média de idade de 51,1 anos, entre 26 e 67 anos), pareados, foram submetidos à avaliação endócrina e oftalmológica. Principais medidas: acuidade visual(AV), pressão intraocular(PIO),refração (equivalente esférico, EE), comprimento axial ocular (CA), profundidade da câmara anterior(PCA), medida da espessura do cristalino(EC), profundidade do vítreo(PV), curvatura corneana média(CCM) e espessura central corneana(ECC). RESULTADOS:Indivíduos com DIGH apresentaram IGF-I sérico não mensurável, similarAV, PIO e EC, valores mais altos doEEe CCM, e menores valores do CA, PCA, PV e ECC em comparação com os controles, mas dentro das respectivas faixas normais. Enquanto a estaturamédia no grupo DIGH foi de 78% do grupo de controle, a média da circunferência da cabeça foi de 92% e a média docomprimento axial foi de 96%. CONCLUSÃO: Essas observações sugerem efeitos oculares discretosem indivíduos adultos com grave deficiência de IGF-I devido à DIGH não tratada.

OBJECTIVE: Ocular function is fundamental for environmental adaptation and survival capacity. Growth factors are necessary for a mature eyeball, needed for adequate vision. However, the consequences of the deficiency of circulating growth hormone (GH) and its effector insulin-like growth factor I (IGF-I) on the physical aspects of the human eye are still debated. A model of untreated isolated GH deficiency (IGHD), with low but measurable serum GH, may clarify this issue. The aim of this study was to assess the ocular aspects of adult IGHD individuals who have never received GH therapy. DESIGN: Cross sectional study. METHODS: Setting University Hospital, Federal University of Sergipe, Brazil. Patients: Twenty-five adult (13 males, mean age 50.1 years, range 26 to 70 years old) IGHD subjects homozygous for a null mutation (c.57+1G>A) in the GHRH receptor gene, and 28 (15 males, mean age 51.1 years, range 26 to 67 years old) controls were submitted to an endocrine and ophthalmological assessment. Forty-six IGHD and 50 control eyes were studied. Main outcome measures: Visual acuity, intraocular pressure (IOP), refraction (spherical equivalent), ocular axial length (AL), anterior chamber depth (ACD),lens thickness (LT), vitreous depth (VD), mean corneal curvature (CC) and central corneal thickness (CCT). RESULTS: IGHD subjects exhibited unmeasurable serum IGF-I levels, similar visual acuity, intraocular pressure and LT, higher values of spherical equivalent and CC, and lower measures of AL, ACD, VD and CCT in comparison to controls, but within their respective normal ranges. While mean stature in IGHD group was 78 % of the control group, mean head circumference was 92 % and axial AL was 96 %. CONCLUSIONS: These observations suggest mild ocular effects in adult subjects with severe IGF-I deficiency due to non-treated IGHD. / OBJETIVO: A função ocular é fundamental para a adaptação ambiental e a capacidade de sobrevivência. Fatores de crescimento são julgados necessáriospara alcançar um globo ocular maduro, e conseqüente visão adequada. No entanto, as consequências da deficiência isoladadohormônio de crescimento circulante (GH) edo seu efetor, o fator de crescimento semelhante à insulina I (IGF-I) nos aspectos físicos do olho humano ainda são debatidas. Um modelo de deficiência isolada de GH não tratada (DIGH) pode esclarecer esta questão. O objetivo deste estudo foi avaliar os aspectos físicos do globo ocular de indivíduos adultos com DIGH que nunca receberam terapia com GH. DESENHO: Estudo transversal. MÉTODOS: Ambiente: Hospital Universitário, Universidade Federal de Sergipe, Brasil. Pacientes: 25 indivíduosadultos (13 homens,com média de idade de 50,1 anos, entre 26 e 70 anos), com DIGH homozigotos para uma mutação nula (c.57 + 1G> A) no gene do receptorGHRH do grupo DIGH e 28 controles (15 homens, com média de idade de 51,1 anos, entre 26 e 67 anos), pareados, foram submetidos à avaliação endócrina e oftalmológica. Principais medidas: acuidade visual(AV), pressão intraocular(PIO),refração (equivalente esférico, EE), comprimento axial ocular (CA), profundidade da câmara anterior(PCA), medida da espessura do cristalino(EC), profundidade do vítreo(PV), curvatura corneana média(CCM) e espessura central corneana(ECC). RESULTADOS:Indivíduos com DIGH apresentaram IGF-I sérico não mensurável, similarAV, PIO e EC, valores mais altos doEEe CCM, e menores valores do CA, PCA, PV e ECC em comparação com os controles, mas dentro das respectivas faixas normais. Enquanto a estaturamédia no grupo DIGH foi de 78% do grupo de controle, a média da circunferência da cabeça foi de 92% e a média docomprimento axial foi de 96%. CONCLUSÃO: Essas observações sugerem efeitos oculares discretosem indivíduos adultos com grave deficiência de IGF-I devido à DIGH não tratada.