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PURPOSE: To report on the treatment of exudative age-related macular degeneration by intravitreal bevacizumab (Avastin). METHODS: A 78-year-old patient experienced a progressive loss of visual acuity in her right eye due to an occult subfoveal neovascular membrane in age-related macular degeneration. She received an intravitreal injection of 1.5 mg bevacizumab. RESULTS: Within 4 weeks after the injection, visual acuity improved from 0.40 to 0.60 with complete resolution of subretinal and intraretinal leakage and edema as shown on optical coherence tomography. Pre-existing metamorphopsias disappeared. Intraocular pressure remained in the normal range. During the follow-up, there were no sings of intraocular inflammation or any other intraocular pathology induced by the intravitreal injection. CONCLUSIONS: Intravitreal bevacizumab may potentially be helpful in the treatment of exudative age-related macular degeneration and may deserve further evaluation.

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High-performance liquid chromatography purification followed by mass spectrometry analyses highlighted that human senile cataractous lens includes a 8182 Da species which is absent in the normal lens, whereas a 8566/8583 Da species is present in both lenses. Western blot analysis identified both species as ubiquitin. The species at lower molecular weight is a shorter form due to the cleavage of the C-terminal residues 73-76. As it is the last amino acid of ubiquitin which is involved in the protein degradation mechanism, we suggest that this structure modification compromises the function of ubiquitin and consequently the physiologically occurring degradation of the lens proteins.

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Chromatographic separation of alpha-crystallin incubated with [3H]-labelled galactose showed the radioactivity to be concentrated in the low molecular mass subunits (20 and 40 kDa). The effect of glycation on the structural organization of alpha-crystallin was evaluated by FPLC analysis of native (pH 6.8 and 8.2) and glycated protein in dissociating conditions. Results suggest that the glycation acts on the protein surface by altering its charge distribution.

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The effect of lipid peroxidation on fatty acid composition in membrane phospholipids of transparent and cataractous lens nuclei was investigated. The preliminary results demonstrate a trend toward an increase in the content of palmitic acid with a decrease in the content of oleic acid, linolenic acid and docosahexaenoic acid in the opaque nuclei as compared to the transparent ones of senile cataractous lenses.

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The effect of malondialdehyde on structural features of bovine alpha-crystallin has been investigated by absorption and fluorescence spectroscopy as well as by far-UV circular dichroism. Experimental evidence suggests the occurrence of intermolecular cross-linking induced by malondialdehyde. This cross-linking does not seem to affect the tryptophan environment, as suggested by intrinsic protein fluorescence. On the contrary, the time dependence of far-UV dichroic activity indicates that the cross-linking is accompanied by a secondary structure change. The formation of high molecular mass aggregates, evidence by electrophoresis in denaturing conditions, leads to irreversible alpha-crystallin aggregation due to extensive intermolecular cross-linking. Since malondialdehyde is produced in vivo as a breakdown product of lipid peroxidation the possible involvement of this molecule in the pathological mechanism of cataract formation has been briefly discussed.

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Since many years experimental evidences have suggested an association between nutrition and lens opacities. A dietary deficiency of antioxidants and reactive oxygen scavengers may be involved in the pathogenesis of the "idiopathic" human senile cataract, as it has been demonstrated in some experimental cataracts. We tested the levels of ascorbic acid (vit. C), alpha-tocopherol (vit. E), reduced glutathione (GSH) and malondialdehyde (MDA) in the plasma or in the red blood cells (RBC) of 42 patients who were affected by surgically significant cataract and of 40 age-matched controls. Plasma vit. C mean level was 4.46 gamma/ml in cataracts and 4.62 gamma/ml in controls, while vit. E level was 7.70 and 7.09 gamma/ml respectively. RBC GSH was found to be 342 gamma/ml in cataracts and 346 in controls, while the MDA content was 4.06 picoMol/ml and 4.08 picoMol/ml respectively. The level of each tested nutrient or metabolite was not found to be statistically different between cataractous patients and controls, nor any significant trend was found to be present when the nutrients and metabolites were correlated to each other. Our results do not support the hypothesis of a nutritional deficiency in human senile cataracts. However, a defect in the antioxidative metabolism pathways could be present either systemically or at lens level.

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In the present paper a study on the enzymatic methyl esterification of proteins in the bovine lens has been presented. The data obtained show that the synthesis of the methyl donor (AdoMet) as well as the methyl esterification of proteins are operative in the lens incubated in the presence of L-(methyl-14C) methionine and the amount of labelled methyl esters decreases during cell ageing. Furthermore, the Authors suggest the usefulness of this model system in the evaluation of the overall AdoMet metabolism in aging.

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We have used quasielastic light scattering to detect and quantitatively characterize the molecular changes associated with the early stages of cataractogenesis in the living human lens. The autocorrelation function of the fluctuations in the light scattered by the lens shows the presence of two major species responsible for the scattering. The first, fast diffusing species (f), has a diffusivity of approximately 3 x 10(-7) cm2/sec and corresponds to the alpha crystallin proteins. The second, slow diffusing species (s), has a diffusivity of approximately 10(-9) cm2/sec and corresponds to the diffusivity of a large aggregate. The intensity of light If and Is scattered into the collection optics by each of these species was also measured. We studied a group of 49 individuals ranging in age from 21 years to 82 years. In this group 40 presented with preoperative cataract development. In this patient population we found that regardless of age, or position in the lens that a plot of Itot = If+Is versus Is could be well fitted by a straight line with a slope less than unity and a positive intercept Ifo. It has been possible to explain this finding using a two state model for the molecular changes associated with early cataractogenesis. In this model the proteins in the slow diffusing species are aggregates each containing a definite number of rapidly diffusing proteins. The early development of cataract is represented by the redistribution of protein between the unaggregated form (f) and the aggregated form (s). The prediction for the relationship between Itot and Is based on this two state model is in very good agreement with our experimental data. Indeed the measured position of the point (Itot, Is) along this line provides a sensitive, and quantitative measure of the degree of cataract development at any selected location in the lens.

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Proton magnetic resonance imaging (MRI) was employed to obtain information on early vitreal changes preceding ophthalmoscopically visible proliferative vitreoretinopathy. Rabbits were injected close to the posterior pole with a suspension of 250 000 cultured homologous fibroblasts. The MRI was carried out using a 1.4-tesla (T) superconducting imager (at a proton frequency of 61.4 MHz). The images were obtained over a span of six days, prior to any detection of proliferative vitreoretinopathy with ophthalmoscopy. As early as two days after injection, an area of increased spin-spin relaxation time (T2) corresponding to the vitreal injection site became visible. The MRI observations paralleled in vitro changes in proton relaxation times (T1 [spin-lattice relaxation time] and T2) after addition of beta-N-acetylglucosaminidase to the vitreous. Our data suggest that hyaluronate disruption due to the activity of fibroblastic enzymes may result in fibroblast dispersion and movement in the vitreous and that MRI can provide early signs of vitreal changes that lead to retinal detachment.

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We have been able to analyze the autocorrelation function of the light scattered from the rabbit lens in vivo in terms of a two component, exponential fit. We have measured the intensity and the decay rate associated with each of these two components as a function of age and position in the lens. As far as is possible we have interpreted these results in terms of molecular changes in the state of association of the protein constituents in the aging rabbit lens. These studies suggest that the method of quasielastic light scattering spectroscopy can provide a useful probe of the protein modifications that occur in both normal and cataractous human lenses.

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High doses of orally administered vitamin E (1000 IU/day) have been given to ten normal volunteers. Ten control subjects received placebo. Red blood cell glutathione was significantly higher in treated subjects than in the controls (controls: 267.5 +/- 15.7 micrograms/mL; treated: 374.8 +/- 17.3 micrograms/mL). These findings could be explained by an increase of glutathione synthesis brought about by the stimulation of glutathione synthetase activity. An alternative possibility is a reduced utilization of glutathione for the detoxification of free radicals. These two mechanisms could be effective in counteracting the glutathione content feedback of the synthetizing enzymes.

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Lysophosphatidylcholine (LPC) has been shown to be toxic to the lens in organ culture. An investigation into whether vitamin E counteracts the in vitro damaging effect of LPC on rat lenses was undertaken. A concentration higher than 10 micrograms ml-1 LPC in the culture medium is necessary to damage rat lenses, as assessed by protein content of the medium and Na+ and K+ content of the lens. Vitamin E affords its protection when present at a concentration of 10(-3) M: both the protein efflux from the lens and the lenticular cation imbalance are prevented, also if LPC concentration is 100 micrograms ml-1. This effect may be due more to the physicochemical properties of vitamin E in the stabilization of biological membranes, than to its chemical behaviour as an antioxidant.

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High doses of parenterally administered vitamin E (30 mg/kg/die) have been given to albino rabbits. We have found a significant elevation of red blood cells reduced glutathione, while the percent level of oxidized versus the reduced form falls from 2% to 1.3%. This finding could be explained with an elevation of the synthesis of this tripeptide, depending on the stimulation of glutathione-synthetase activity. On the other hand, a reduced utilization of this tripeptide for the free radicals detoxifying activity could be claimed for.

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We tried to counteract the appearance of galactosemic cataracts in weaned rats by high doses of vitamin E. Rats were fed a diet containing 33% galactose. Cataract development was monitored by biomicroscopy and by several biochemical parameters: K+/Na+ ratio, aldose reductase activity, level of protein and non-protein sulfhydryl (SH) groups. Vitamin E was given parenterally at a dose of 100 mg/kg/day. The K+/Na+ ratio drops after 15 days of galactosemia, while the level of the aldose reductase rises after only 5 days of treatment. The non-protein SH groups lens contents fall from the 5th day of treatment onwards, while protein SH groups are not affected. In short-term experiments vitamin E does not prevent biochemical changes caused by galactosemia. The oxidative insult does not seem to be primarily involved in galactose cataract.

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In vitro experimental evidence suggests tryptophan (TRP) is involved in protein modifications which could cause cataract formation in vivo. Previous studies of tryptophan plasma and serum metabolism are conflicting. In this study free and bound TRP plasma levels were measured in patients with senile cataract and in controls after an oral load of L-TRP (20 mg/kg b.w.). Free TRP levels were higher in patients than in controls one hour after L-TRP administration.

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Red cell glutathione has been assayed in a family affected by Leber's optic atrophy. The results are in agreement with a defective cyanide metabolism. The transmission mechanism of the disease is discussed. Lastly, a preventive and therapeutic approach is proposed.

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Serum free and total tryptophan levels have been measured in patients with cataracts and compared with the same levels in controls with clear lenses. No statistically significant differences have been demonstrated between the two groups of examined fasting subjects. Preliminary results seem to indicate that differences could be evident after L-tryptophan oral load.

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In this review some of the so far identified mechanisms implicated in experimental and human cataractogenesis are reviewed. The oxidative insult, the osmotic insult (sugar cataracts and ionic imbalance cataracts), the role of tryptophan, of lysophosphatidylcholine and docohexanoic acid in primary and secondary cataracts are summarized. It is not always possible to identify the primary effect of cataractogenic mechanisms: the human "idiopathic" cataract is probably a multifactorial disease. In the aging lens and under stress conditions (osmotic and oxidative) the physiologic defense systems of the lens appear to be inadequate. Even if conditions of avitaminosis aren't the cause of deterioration of the adult human lens, it has been demonstrated that the supplementation or the deficiency of some nutritional factors may influence the course of cataract.

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