Unexpected vision performance with photochromic contact lenses in normal and low light conditions: An analysis of two randomized trials / Rendimiento visual inesperado con lentes de contacto fotocromáticos en condiciones normales y de poca luz: un análisis de dos ensayos aleatorios

Purpose: Evaluate the performance of a photochromic contact lens in various lighting conditions throughout the day, including those indoor and outdoor environments where the photochromic contact lens is in a less active or inactive state. Methods: Data from two clinical trials of a photochromic contact lens were analyzed to evaluate its performance in various light environments. Both studies involved a photochromic test lens (ACUVUE® OASYS with Transitions™ Light Intelligent Technology™) and a similar non-photochromic control lens (ACUVUE® OASYS 2-week with HYDRACLEAR® PLUS). The studies were both multi-visit, multi-site, 2-treatment by 3-period randomized crossover (i.e., Test/Control/Control or Control/Test/Test) dispensing studies, with follow-up visits after each 2-week dispensing period. Results: A total of 250 subjects were dispensed lenses across both studies, of which 237 total subjects completed. In situations where exposure to an activating light source is common (e.g., outdoors), the Test lens was preferred nearly 6:1 over the control lens. In situations where exposure to an activating light source is less common – indoors, driving at night, using digital devices –, the Test lens was still preferred over the control lens by margins of 4:1, nearly 4:1, and over 3:1 respectively. The Test lens was superior with respect to quality of vision, ability to see comfortably, clarity of vision, reduction of squinting while using computers and reduction of bright light while driving at night. Conclusion: The photochromic test contact lens was rated superior to a non-photochromic control lens in environmental situations where the lens is in a less active or inactive state.(AU)

Unexpected vision performance with photochromic contact lenses in normal and low light conditions: An analysis of two randomized trials.

PURPOSE: Evaluate the performance of a photochromic contact lens in various lighting conditions throughout the day, including those indoor and outdoor environments where the photochromic contact lens is in a less active or inactive state. METHODS: Data from two clinical trials of a photochromic contact lens were analyzed to evaluate its performance in various light environments. Both studies involved a photochromic test lens (ACUVUE® OASYS with Transitions™ Light Intelligent Technology™) and a similar non-photochromic control lens (ACUVUE® OASYS 2-week with HYDRACLEAR® PLUS). The studies were both multi-visit, multi-site, 2-treatment by 3-period randomized crossover (i.e., Test/Control/Control or Control/Test/Test) dispensing studies, with follow-up visits after each 2-week dispensing period. RESULTS: A total of 250 subjects were dispensed lenses across both studies, of which 237 total subjects completed. In situations where exposure to an activating light source is common (e.g., outdoors), the Test lens was preferred nearly 6:1 over the control lens. In situations where exposure to an activating light source is less common - indoors, driving at night, using digital devices -, the Test lens was still preferred over the control lens by margins of 4:1, nearly 4:1, and over 3:1 respectively. The Test lens was superior with respect to quality of vision, ability to see comfortably, clarity of vision, reduction of squinting while using computers and reduction of bright light while driving at night. CONCLUSION: The photochromic test contact lens was rated superior to a non-photochromic control lens in environmental situations where the lens is in a less active or inactive state.

Silicone hydrogel contact lenses retain and document ocular surface lipid mediator profiles.

CLINICAL RELEVANCE: A leading reason for patients to abandon their contact lenses is discomfort. Mechanisms and biomarkers for lens discomfort remain to be elucidated. BACKGROUND: Physical stress and tear film interaction are likely factors for lens discomfort. Lipid mediators are generated from polyunsaturated fatty acids. They regulate ocular surface physiology and pathophysiology, are constituents of human tears and may interact with contact lenses. This study set out to determine if hydrogel lenses and silicone hydrogel lenses interact with tear film polyunsaturated fatty acids and polyunsaturated fatty acids-derived mediators. METHODS: In vitro incubations, rat experiments and analysis of worn human lenses assessed polyunsaturated fatty acids and lipid mediator interactions with lenses. Silicone hydrogel and hydrogel lenses were incubated with lipid mediators and polyunsaturated fatty acids up to 24 hours. Rats were fitted with custom silicone hydrogel lenses and basal tears collected. Silicone hydrogel lenses worn for 2 weeks were obtained from 57 human subjects. Tear and lens lipidomes were quantified by mass spectrometry. RESULTS: Silicone hydrogel lenses retained polyunsaturated fatty acids and lipid mediators within 15 minutes in vitro. Lenses contained 90% of total polyunsaturated fatty acids and 83-89% of total monohydroxy fatty acids by 12 hours. Retention correlated with polarity of lipid mediators and lipophilic properties of silicone hydrogel lenses. Polyunsaturated fatty acids and lipid mediators such as lipoxygenase- and cyclooxygenase-derived eicosanoids were present in tears and worn lenses from rats. Worn silicone hydrogel lenses from human subjects established robust and lens-type specific lipidomes with high levels of polyunsaturated fatty acids, lipoxygenase-pathway markers and subject-specific differences in lipoxin A4 and leukotriene B4. CONCLUSION: Worn silicone hydrogel lenses rapidly retain and accumulate tear polyunsaturated fatty acids and lipid mediators. Marked subject and lens type differences in the lipidome may document changes in ocular surface physiology, cell activation or infection that are associated with lens wear. If contact lens discomfort and adverse events induce specific tear and lens fatty acid and lipid mediator profiles warrants further studies.

The Effects of a Senofilcon A Contact Lens With and Without a Photochromic Additive on Positive Dysphotopsia Across Age.

OBJECTIVE: The visual effects of wearing a photochromic contact lens (test) were directly compared with a nonphotochromic contact lens (control). Positive dysphotopsia (halos, starbursts) and intraocular scatter (behaviorally determined) were assessed. Both younger and middle-aged subjects were evaluated to examine the influence of age. METHODS: Fifty-four subjects (18-62 years) were tested using a contralateral design. Subjects were fit with a photochromic contact lens on one eye and a nonphotochromic contact lens on the other eye, randomly assigned. Testing occurred with and without photochromic activation (darkened) by use of a violet activator (365 nm, half-bandwidth 20 nm). The extent of dysphotopsia (halos and spokes) was measured using an aperture (∼4 mm) that created a bright point source of light 45 inches from the plane of the eye. Between the point source and subject, a centering precision caliper was used to measure lateral spread. Two-point thresholds were determined by measuring the minimum distance between two points of broadband xenon light. RESULTS: The photochromic contact lens produced smaller halo diameters than the control contact lens, both activated (41% on average) and inactivated (21% on average), and age strata was a significant factor (P<0.001) with the older group showing a greater reduction. The photochromic contact lens produced smaller starburst diameters than the control contact lens, both activated (37% on average) and inactivated (23% on average), and age strata was a significant factor (P=0.001) with the older group showing a greater reduction. The two-point thresholds were reduced (25% activated, 9% inactivated) on average but the age effect was not significant (P<0.10). CONCLUSIONS: The senofilcon A lens with photochromic additive reduced the extent of positive dysphotopsia compared with the same lens without the additive, regardless whether the lens was activated or not. The visual benefit was greatest with the older subjects.

Lens fitting and subjective acceptance of senofilcon A with photochromic additive on a neophyte population.

PURPOSE: To determine the proportion of contact lens neophytes that can be successfully fitted with a photochromic contact lens, and to survey subjective performance outcomes compared to habitual spectacles. It was hypothesized that at least 50 % of lens fits would be successful. METHODS: Eleven sites enrolled contact lens neophytes with up-to-date spectacles. Subjects were fitted bilaterally with a photochromic Test contact lens (ACUVUE® OASYS with Transitions™) for one month of daily, reusable wear. Follow-up visits occurred at 1 week, 2 weeks (lenses replaced), and at 4 weeks after initial dispensing. The investigator judged lens fitting success based on overall assessment of physiology, mechanical fitting, comfort, vision, and handling at the 4-week visit. Following this visit, subjects returned to wearing habitual spectacles for one week and evaluated the performance of the study lens compared to their spectacles. RESULTS: From a total of 127 subjects who were dispensed contact lenses, 105 completed the study per protocol (mean age: 25.5 ± 5.9 years; 57 % female; 80.0 % Caucasian; 71 % with dark iris color). Investigators judged that 97 % of the contact lenses were fitted successfully after 4 weeks of wear; thus, the primary hypothesis was met. Among per-protocol subjects, 60 % reported better vision outdoors, 53 % better vision in changing lighting conditions, 62 % less squinting, and 66 % being less often bothered by bright light. Additionally, 95 % would recommend the lens to others, and 71 % would recommend their eye care practitioner if offered the lens. CONCLUSION: Greater than 95 % of subjects were successfully fitted with the photochromic contact lens based on professional judgement of physiology, mechanical fitting, comfort, vision, and handling. Subjects new to contact lens wear expressed positive opinions for the study contact lenses compared to their up-to-date spectacles.

Rationally designed dehydroalanine (DeltaAla)-containing peptides inhibit amyloid-beta (Abeta) peptide aggregation.

Among the pathological hallmarks of Alzheimer's disease (AD) is the deposition of amyloid-beta (Abeta) peptides, primarily Abeta (1-40) and Abeta (1-42), in the brain as senile plaques. A large body of evidence suggests that cognitive decline and dementia in AD patients arise from the formation of various aggregated forms of Abeta, including oligomers, protofibrils and fibrils. Hence, there is increasing interest in designing molecular agents that can impede the aggregation process and that can lead to the development of therapeutically viable compounds. Here, we demonstrate the ability of the specifically designed alpha,beta-dehydroalanine (DeltaAla)-containing peptides P1 (K-L-V-F-DeltaA-I-DeltaA) and P2 (K-F-DeltaA-DeltaA-DeltaA-F) to inhibit Abeta (1-42) aggregation. The mechanism of interaction of the two peptides with Abeta (1-42) seemed to be different and distinct. Overall, the data reveal a novel application of DeltaAla-containing peptides as tools to disrupt Abeta aggregation that may lead to the development of anti-amyloid therapies not only for AD but also for many other protein misfolding diseases. (c) 2009 Wiley Periodicals, Inc. Biopolymers 91: 456-465, 2009.

Analysis of the reaction of carbachol with acetylcholinesterase using thioflavin T as a coupled fluorescence reporter.

Acetylcholinesterase (AChE) contains a narrow and deep active site gorge with two sites of ligand binding, an acylation site (or A-site) at the base of the gorge and a peripheral site (or P-site) near the gorge entrance. The P-site contributes to catalytic efficiency by transiently binding substrates on their way to the acylation site, where a short-lived acylated enzyme intermediate is produced. Carbamates are very poor substrates that, like other AChE substrates, form an initial enzyme-substrate complex with free AChE (E) and proceed to an acylated enzyme intermediate (EC), which is then hydrolyzed. However, the hydrolysis of EC is slow enough to resolve the acylation and deacylation steps on the catalytic pathway. Here, we focus on the reaction of carbachol (carbamoylcholine) with AChE. The kinetics and thermodynamics of this reaction are of special interest because carbachol is an isosteric analogue of the physiological substrate acetylcholine. We show that the reaction can be monitored with thioflavin T as a fluorescent reporter group. The fluorescence of thioflavin T is strongly enhanced when it binds to the P-site of AChE, and this fluorescence is partially quenched when a second ligand binds to the A-site to form a ternary complex. Analysis of the fluorescence reaction profiles was challenging because four thermodynamic parameters and two fluorescence coefficients were fitted from the combined data both for E and for EC. Respective equilibrium dissociation constants of 6 and 26 mM were obtained for carbachol binding to the A- and P-sites in E and of 2 and 32 mM for carbachol binding to the A- and P-sites in EC. These constants for the binding of carbachol to the P-site are about an order of magnitude larger (i.e., indicating lower affinity) than previous estimates for the binding of acetylthiocholine to the P-site.

Monitoring the reaction of carbachol with acetylcholinesterase by thioflavin T fluorescence and acetylthiocholine hydrolysis.

Acetylcholinesterase (AChE) contains a narrow and deep active site gorge with two sites of ligand binding, an acylation site (or A-site) at the base of the gorge and a peripheral site (or P-site) near the gorge entrance. The P-site contributes to catalytic efficiency by transiently binding substrates on their way to the acylation site, where a short-lived acyl enzyme intermediate is produced. Carbamates are very poor substrates that, like other AChE substrates, form an initial enzyme-substrate complex and proceed to an acylated enzyme intermediate which is then hydrolyzed. However, the hydrolysis of the carbamoylated enzyme is slow enough to resolve the acylation and deacylation steps on the catalytic pathway. Here we show that the reaction of carbachol (carbamoylcholine) with AChE can be monitored both with acetylthiocholine as a reporter substrate and with thioflavin T as a fluorescent reporter group. The fluorescence of thioflavin T is strongly enhanced when it binds to the P-site of AChE, and this fluorescence is partially quenched when a second ligand binds to the A-site to form a ternary complex. These fluorescence changes allow not only the monitoring of the course of the carbamoylation reaction but also the determination of carbachol affinities for the A- and P-sites.

Crystal structure of thioflavin T bound to the peripheral site of Torpedo californica acetylcholinesterase reveals how thioflavin T acts as a sensitive fluorescent reporter of ligand binding to the acylation site.

Acetylcholinesterase plays a key role in cholinergic synaptic transmission by hydrolyzing the neurotransmitter acetylcholine with one of the highest known catalytic rate constants. Hydrolysis occurs in a narrow and deep gorge that contains two sites of ligand binding: A peripheral site, or P-site, near the gorge entrance that contributes to catalytic efficiency both by transiently trapping substrate molecules as they enter the gorge and by allosterically accelerating the transfer of the substrate acyl group to a serine hydroxyl in an acylation site or A-site at the base of the gorge. Thioflavin T is a useful reporter of ligand interactions with the A-site. It binds specifically to the P-site with fluorescence that is enhanced approximately 1000-fold over that of unbound thioflavin T, and the enhanced fluorescence is quenched 1.5- to 4-fold when another ligand binds to the A-site in a ternary complex. To clarify the structural basis of this advantageous signal change, we here report the X-ray structure of the complex of thioflavin T with Torpedo californica acetylcholinesterase. The two aromatic rings in thioflavin T are coplanar and are packed snugly parallel to the aromatic side chains of Trp279, Tyr334, and Phe330. Overlays of this structure with the crystal structures of Torpedo californica acetylcholinesterase complexes with either edrophonium or m-( N, N, N-trimethylammonio)-2,2,2-trifluoroacetophenone, two small aromatic ligands that bind specifically to the A-site, indicate that the phenyl side chain of Phe330 must rotate to sterically accommodate both thioflavin T and the A-site ligand in the ternary complex. This rotation may allow some relaxation of the strict coplanarity of the aromatic rings in the bound thioflavin T and result in partial quenching of its fluorescence.

BRI2 (ITM2b) inhibits Abeta deposition in vivo.

Analyses of the biologic effects of mutations in the BRI2 (ITM2b) and the amyloid beta precursor protein (APP) genes support the hypothesis that cerebral accumulation of amyloidogenic peptides in familial British and familial Danish dementias and Alzheimer's disease (AD) is associated with neurodegeneration. We have used somatic brain transgenic technology to express the BRI2 and BRI2-Abeta1-40 transgenes in APP mouse models. Expression of BRI2-Abeta1-40 mimics the suppressive effect previously observed using conventional transgenic methods, further validating the somatic brain transgenic methodology. Unexpectedly, we also find that expression of wild-type human BRI2 reduces cerebral Abeta deposition in an AD mouse model. Additional data indicate that the 23 aa peptide, Bri23, released from BRI2 by normal processing, is present in human CSF, inhibits Abeta aggregation in vitro and mediates its anti-amyloidogenic effect in vivo. These studies demonstrate that BRI2 is a novel mediator of Abeta deposition in vivo.

Amyloid-beta(1-42) rapidly forms protofibrils and oligomers by distinct pathways in low concentrations of sodium dodecylsulfate.

Alzheimer's disease (AD) is characterized by large numbers of senile plaques in the brain that consist of fibrillar aggregates of 40- and 42-residue amyloid-beta (Abeta) peptides. However, the degree of dementia in AD correlates better with the concentration of soluble Abeta species assayed biochemically than with histologically determined plaque counts, and several investigators now propose that soluble aggregates of Abeta are the neurotoxic agents that cause memory deficits and neuronal loss. These endogenous aggregates are minor components in brain extracts from AD patients and transgenic mice that express human Abeta, but several species have been detected by gel electrophoresis in sodium dodecylsulfate (SDS) and isolated by size exclusion chromatography (SEC). Endogenous Abeta aggregation is stimulated at cellular interfaces rich in lipid rafts, and anionic micelles that promote Abeta aggregation in vitro may be good models of these interfaces. We previously found that micelles formed in dilute SDS (2 mM) promote Abeta(1-40) fiber formation by supporting peptide interaction on the surface of a single micelle complex. In contrast, here we report that monomeric Abeta(1-42) undergoes an immediate conversion to a predominant beta-structured conformation in 2 mM SDS which does not proceed to amyloid fibrils. The conformational change is instead rapidly followed by the near quantitative conversion of the 4 kDa monomer SDS gel band to 8-14 kDa bands consistent with dimers through tetramers. Removal of SDS by dialysis gave a shift in the predominant SDS gel bands to 30-60 kDa. While these oligomers resemble the endogenous aggregates, they are less stable. In particular, they do not elute as discrete species on SEC, and they are completed disaggregated by boiling in 1% SDS. It appears that endogenous oligomeric Abeta aggregates are stabilized by undefined processes that have not yet been incorporated into in vitro Abeta aggregation procedures.