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To determine the effect on aqueous flow of topical dorzolamide 2%, topical timolol 0.5%, or oral acetazolamide 250 mg when used alone or when dorzolamide is combined with either timolol or acetazolamide.In 30 patients with ocular hypertension, aqueous flow and intraocular pressure (IOP) were determined at baseline and on the following combinations of drugs in a crossover design: (1) vehicle alone, (2) dorzolamide alone, (3) acetazolamide alone, (4) timolol alone, (5) dorzolamide + acetazolamide, and (6) dorzolamide + timolol. Treated eyes were compared with control eyes and comparisons were made between treatments.Compared with baseline, significant (P0.04) IOP reductions in the order of efficacy were: dorzolamide + timololdorzolamide + acetazolamide = acetazolamide = timololdorzolamide. Aqueous flow was reduced more by dorzolamide + timolol than by each drug alone (P0.04) and more by dorzolamide + acetazolamide than by dorzolamide alone (P0.04).The combination of dorzolamide and timolol demonstrated significant aqueous flow additivity and had greater IOP efficacy than the combination of dorzolamide and acetazolamide.

Bimatoprost (Lumigan [Allergan, Inc, Irvine CA]) and travoprost (Travatan [Alcon, Ft Worth, TX]) are two new intraocular pressure (IOP)-lowering drugs for use in patients with glaucoma and ocular hypertension. This review evaluates recent studies comparing these new drugs with timolol and with latanoprost. In each study, the statistical analyses support the conclusion that these agents were more effective than timolol and as effective as latanoprost in terms of their ability to reduce IOP. The side effect profiles for bimatoprost, latanoprost, and travoprost were similar, but with statistically higher occurrences of hyperemia and eyelash growth for bimatoprost or travoprost versus latanoprost or timolol.

To evaluate the mechanism of the intraocular pressure (IOP) elevation in ocular hypertension (OHT), aqueous humor dynamics were compared in patients with OHT versus age-matched ocular normotensive (NT) volunteers.In this retrospective study, one group included patients diagnosed with OHT (IOPs21 mm Hg, n = 55) for at least six months. All eye medications were discontinued for at least three weeks before the study visit. A second group included age-matched NT subjects (n = 55) with no eye diseases. The study visit included measurements of IOP by pneumatonometry, aqueous flow and outflow facility by fluorophotometry, anterior chamber depth and corneal thickness by pachymetry and episcleral venous pressure by venomanometry. Uveoscleral outflow and anterior chamber volume were calculated mathematically.Significant differences in the OHT versus the NT groups were as follows: increased IOP (21.4 +/- 0.6 versus 14.9 +/- 0.3 mm Hg, respectively; P0.0001), reduced uveoscleral outflow (0.66 +/- 0.11 versus 1.09 +/- 0.11 microL/min; P = 0.005) and reduced fluorophotometric outflow facility (0.17 +/- 0.01 versus 0.27 +/- 0.02 microL/min/mm Hg; P0.0001). With respect to age, anterior chamber volume decreased in both groups at a rate of 2.4 +/- 0.3 microL/year (r(2) = 0.5, P.001) and aqueous flow decreased at a rate of 0.013 +/- 0.005 microL/min/year (r(2) = 0.07, P = 0.005).The increased IOP in ocular hypertensive patients is caused by a reduction in trabecular outflow facility and uveoscleral outflow. Aqueous flow remains normal. When both ocular normotensive and hypertensive groups are combined, aqueous flow and anterior chamber volume decrease slightly with age.

This article addresses the issue of using students' native language (L1) versus second language (L2) in testing instruments for reading comprehension in the L2 classroom. Four groups of students of third-semester, college-level Spanish were tested under four different conditions involving combinations of L1 and L2. The test consisted of a reading passage in L2 and seven open-ended questions. The results suggest that open-ended reading comprehension tests may be better assessment instruments if some of the questions are phrased in the L1 and test takers are given the opportunity to respond in the L1.

PURPOSE The effects of brimonidine on daytime and nighttime intraocular pressure (IOP) and aqueous humor dynamics were evaluated in volunteers with ocular hypertension (OHT). PATIENTS AND METHODS Thirty participants with OHT (58.6±1.7 years old, mean±SEM) were enrolled into this randomized, double-masked, cross-over study. For 6 weeks, participants self-administered 0.2% brimonidine or placebo 3 times daily. During daytime and nighttime visits, measurements included aqueous flow (Fa) by fluorophotometry, outflow facility (C) by tonography, episcleral venous pressure (Pev) by venomanometry, and seated and supine IOP by pneumatonometry. Uveoscleral outflow (U) was calculated mathematically. RESULTS When treated with placebo, nighttime supine Pev (11.2±0.25 mm Hg) was higher (P

Maestría en Historia Universidad Nacional Autónoma de México. Programa de Posgrado en Historia

Recent work in the robotics community has lead to the emergence of cloud-based solutions and remote clients. Such work allows robots to effectively distribute complex computations across multiple machines, and allows remote clients, both human and automata, to control robots across the globe. With the increasing use and importance of such ideas, it is crucial not to overlook the critical issue of security in these systems. In this work, we discuss the use of web tokens for achieving secure authentication for remote, non-native clients in the widely-used Robot Operating System (ROS) middleware. Written in a system-independent manner, we demonstrate its use with an application for securing clients within the popular rosbridge protocol.

Preclinical Research FR-190997 (8-[2,6-dichloro-3-[N-[(E)-4-(N-methylcarbamoyl) cinnaminoacetyl]-N-methylamino]benzyloxy]-2-methyl-4- (2-pyridylmethoxy) quinoline), a nonpeptide bradykinin (BK) B2-receptor-selective agonist, represents a novel class of ocular hypotensive agents. FR-190997 exhibited a high affinity for the human cloned B2-receptor (Ki = 9.8 nM) and a relatively high potency (EC50 = 155 nM) for mobilizing intracellular Ca(2+) ([Ca(2+)]i) in human ocular cells from nonpigmented ciliary epithelium; trabecular meshwork [h-TM]; ciliary muscle [h-CM] that are involved in regulating intraocular pressure (IOP). Unlike BK, FR-190997 behaved as a partial agonist (Emax = 38-80%) in these cells and its [Ca(2+)]i-mobilizing effects were blocked by the B2-receptor-selective antagonists (HOE-140, Ki = 0.8-7 nM; WIN-64338, Ki = 157-425 nM). FR-190997 stimulated the production of prostaglandins (PGs) in h-CM and h-TM cells (EC50 = 15-19 nM; Emax = 27-33%); an effect that was reduced by the cyclooxygenase-2 inhibitor bromfenac, and by HOE-140. FR-190997 also induced pro-matrix metalloproteinase (MMP)-1 and MMP-3 release from h-CM cells. FR-190997 significantly lowered IOP (37% [P 0.001] with 30 μg, 24 h post-topical ocular dosing) in ocular hypertensive eyes of conscious Cynomolgus monkeys. This effect was reduced by bromfenac and completely blocked by a B2-antagonist. FR-190997 primarily stimulated uveoslceral outflow (UVSO) of aqueous humor (2.6 to 3.9-fold above baseline). In conclusion, FR-190997 is a B2-receptor selective partial agonist that activates phospholipase C, mobilizes [Ca(2+)]; induces PG and pro-MMP production, and that profoundly lowers IOP by promoting UVSO in ocular hypertensive Cynomolgus monkey eyes.

PURPOSE To determine improvement in outflow facility (C) in human anterior segments implanted with a novel Schlemm's canal scaffold or two trabecular micro-bypasses. METHODS Human anterior segments were isolated from 12 pairs of eyes from donors with no history of ocular disease and then perfused at 50, 40, 30, 20, and 10 mm Hg pressures for 10 minutes each. Baseline C was calculated from perfusion pressures and flow rates. The scaffold was implanted into Schlemm's canal of one anterior segment, and two micro-bypasses were implanted three clock-hours apart in the contralateral anterior segment. Outflow facility and resistance were compared at various standardized perfusion pressures and between each device. RESULTS Compared to baseline, C increased by 0.16 ± 0.12 μL/min/mm Hg (74%) with the scaffold, and 0.08 ± 0.12 μL/min/mm Hg (34%) with two micro-bypasses. The scaffold increased C at perfusion pressures of 50, 40, 30, and 20 mm Hg (P < 0.005). Two micro-bypasses increased C at a perfusion pressure of 40 mm Hg (P < 0.05). CONCLUSIONS Both implants effectively increased C in human eyes ex vivo. The scaffold increased C by a greater percentage (73% vs. 34%) and at a greater range of perfusion pressures (20 to 50 mm Hg vs. 40 mm Hg) than the two micro-bypasses, suggesting that the 8-mm dilation of Schlemm's canal by the scaffold may have additional benefits in lowering the outflow resistance. The Hydrus Microstent scaffold may be an effective therapy for increasing outflow facility and thus reducing the IOP in patients with glaucoma.

Previous studies reported reduced aqueous humor flow through the anterior segment of the eye in patients with type 1 diabetes. This study investigates whether reduced flow is the result of the diabetic state or of alterations in glucose or insulin concentrations.A cross-sectional study, involving patients with type 1 diabetes and healthy controls, measured aqueous flow at different insulin concentrations. Eleven patients with type 1 diabetes (hemoglobin A1C = 7.0 +/- 0.3% [mean +/- SEM], normal6.5) with no microvascular complications and 17 controls were prospectively studied. Controls were studied fasting and during a hyperinsulinemic-euglycemic clamp (insulin 2 mU/kg per minute). Patients with type 1 diabetes were similarly studied during two euglycemic clamp procedures (insulin 0.5 and 2.0 mU/kg per minute). Aqueous flow was measured by fluorophotometry. Pulsatile ocular blood flow and intraocular pressure were measured with a Langham flow probe.Control subjects had no change in aqueous flow during fasting and hyperinsulinemic conditions (3.0 +/- 0.1 vs 2.8 +/- 0.1 microl per minute). In the patients with type 1 diabetes, aqueous flow was not decreased with hyperinsulinemia, compared with the low insulin state (P =.7). Compared with control subjects, patients with type 1 diabetes had lower aqueous flow during hyperinsulinemia (2.4 +/- 0.1 microl per minute, P =.03) and at lower insulin conditions (2.6 +/- 0.1 microl per minute, P.05). No differences in intraocular pressure or pulsatile ocular blood flow were noted between groups or between insulin states within groups.Aqueous flow is decreased in patients with type 1 diabetes under euglycemic conditions of high and relatively low insulin concentrations, despite the absence of microvascular complications.

To determine the ocular hypotensive mechanism underlying the additivity of latanoprost and pilocarpine.This randomized, double-masked study included 30 patients with ocular hypertension on no ocular medications for at least 3 weeks. On each of six visits to the clinic, measurements were taken of aqueous flow and outflow facility by fluorophotometry, intraocular pressure by tonometry, and episcleral venous pressure by venomanometry. Uveoscleral outflow was calculated. Clinic visits were scheduled on baseline day; on day 8 of four times daily pilocarpine (2%) to one eye and vehicle to the other; on day 8 of continued pilocarpine/vehicle treatment plus latanoprost (0.005%) once daily to both eyes; after a 3-week washout period; on day 8 of once-daily latanoprost to one eye and vehicle to the other; and on day 8 of continued latanoprost/vehicle treatment plus pilocarpine four times a day to both eyes. Drug-treated eyes were compared with contralateral vehicle-treated eyes and with baseline day by paired t tests. Combined pilocarpine and latanoprost-treated eyes were compared with individual drug-treated eyes and with baseline day using the Bonferroni test.Compared with baseline, pilocarpine reduced intraocular pressure from 18.9 to 16.2 mm Hg (P =.001) and increased outflow facility from 0.18 to 0.23 microl per minute per mm Hg (P =.03). No other parameters were affected. Adding latanoprost further reduced intraocular pressure to 13.7 mm Hg (P.001) and increased uveoscleral outflow from 0.82 to 1.36 microl per minute (P =.02). Latanoprost alone reduced intraocular pressure from 17.6 to 14.3 mm Hg (P.0001) and increased uveoscleral outflow from 0.89 to 1.25 microl per minute (P =.05). Adding pilocarpine to the latanoprost treatment further reduced intraocular pressure to 12.7 mm Hg (P.001) and increased outflow facility from 0.21 to 0.30 microl per minute per mm Hg (P =.03).Latanoprost and pilocarpine predominantly increase uveoscleral outflow and outflow facility, respectively, when given alone. These drugs are additive because pilocarpine does not inhibit the uveoscleral outflow increase induced by latanoprost.

This study determines the effects of laser-induced glaucoma on aqueous humor dynamics of 18 cynomolgus monkeys. Baseline measurements of 12 monkeys included intraocular pressure (IOP) by pneumatonometry, aqueous flow by fluorophotometry and outflow facility by tonography. Beginning 4 to 14 days later, the trabecular meshwork of one eye was treated repeatedly with laser photocoagulation until elevated IOP was induced. Thirty-six to 75 days after the last laser treatment, all measurements were repeated. Between 1.7 and 11.4 years after laser treatment, the same 12 monkeys plus 6 additional monkeys underwent IOP and aqueous flow measurements. In addition, outflow facility was determined with fluorophotometry, and uveoscleral outflow was both calculated (n=18) and measured with an intracameral tracer (n=7). In glaucoma eyes compared to control eyes (n=12), IOP was increased (p

Topical prostaglandins (PGs) are very effective at reducing intraocular pressure (IOP) in a variety of animals and in humans with relatively few side effects. The mechanisms of action of several PGs, their prodrugs and analogues have been studied in rabbits, cats, monkeys and humans. PGF2 alpha and its analogues evaluated in monkeys include PGF2 alpha-tromethamine salt, PGF2 alpha -isopropylester (-IE), S-1033, PhXA34, PhDH100A and latanoprost (PhXA41). Aqueous flow and outflow facility are either increased or remain unchanged by these agents. PGF2 alpha-IE, PHXA34, PhDH100A and latanoprost increase uveoscleral outflow, accounting for most of the IOP reduction. PGA2 in cats increases aqueous flow and outflow facility, but it reduces IOP primarily by stimulating uveoscleral outflow. The PGD2 analogue BW245C is unique in that it is the only PG that decreases aqueous flow. Mechanistic studies in humans have been performed with PGF2 alpha -IE, unoprostone, PhXA34 and latanoprost. In two clinical studies with latanoprost, a significant increase in uveoscleral outflow was found which, as in animals, accounts for most of the IOP reduction. A slight but inconsistent increase in outflow facility may also be involved. The doses tested had minimal effects on the permeability of the blood-aqueous barrier (BAB). In vitro studies of human tissue have been conducted to elucidate the PG effect on outflow facility and uveoscleral outflow. Studies of isolated human anterior segment preparations show that PGE2 increases outflow facility whereas PGF2 alpha has no measurable effect on this parameter. Studies of human ciliary muscle cells in tissue culture indicate that PGs may directly modulate extracellular matrix metabolism, which may be related to the increased uveoscleral drainage. This review summarizes in vitro and in vivo studies of the effects of PGs on aqueous humor dynamics and BAB integrity in humans, cats and monkeys.

Purpose To assess the biocompatibility of a novel implant made of Nitinol (nickel-titanium alloy), designed to improve aqueous humor outflow. Materials and methods In the first arm of biocompatibility testing, microstents were surgically inserted into Schlemm's canal (SC) of 2 non-human primates (NHPs), and a third NHP served as a surgical sham control. After 13 weeks the animals were killed, and the eyes were examined by light and scanning electron microscopy. Two masked investigators evaluated the histology sections. The second arm utilized 8 New Zealand white rabbits; each rabbit received a microstent inserted into the sclera and subconjunctival space by means of passage across the anterior chamber thus providing contact with several representative ocular tissues. The fellow eye of each rabbit underwent a sham procedure without microstent insertion. The rabbits were killed after 26 weeks, and a trained ocular pathologist examined the specimens using light microscopy. Results Histologic and scanning electron microscopy analysis of the NHPs demonstrated that the microstents were located in SC. There was no evidence of an acute or chronic inflammatory response, granulation response, or fibrosis in the outflow system or in adjacent tissues. Rabbit eyes showed minimal mononuclear cell infiltration and minimal fibrotic responses at the site of the implants when compared with sham-treated control eyes. Conclusions The Hydrus Microstent was associated with minimal inflammation in both NHP and rabbit eyes with extended follow-up. These preclinical studies demonstrate that the Hydrus Microstent appears to have excellent long-term biocompatibility.

To develop a minimally invasive rabbit model of postoperative anterior chamber (AC) inflammation using a commercially available frequency doubled Nd:YAG laser [intended for selective laser trabeculoplasty (SLT)].Escalating laser energy was applied to the iris of male Dutch-belted rabbits and the subsequent inflammatory response was observed to determine the laser dose required to generate self-limiting inflammation of at least 3 days' duration. In subsequent experiments, 10 eyes of 10 male Dutch-belted rabbits underwent baseline slit lamp examination, intraocular pressure (IOP), and AC flare meter readings. Starting 1 day before laser application, 5 animals received topical 20 μL dexamethasone 1% to 1 eye 4 times daily for 5 days. Five control animals were treated with saline. Masked assessments of flare, cells, and IOP were made daily for 7 days. Histopathologic changes were assessed in enucleated eyes.Compared to controls, dexamethasone-treated rabbits had less postlaser AC flare on postoperative day (POD)2 (19±5 vs. 44±21photons/ms, P=0.03) and POD3 (16±9 vs. 33±11 photons/ms, P=0.03). In dexamethasone-treated rabbits, clinically graded flare (on POD1) and cells (on POD1 and 2) were lower than controls, but did not reach statistical significance. In the control group, IOP was significantly lower than the dexamethasone-treated group on POD2 (14.1±3.4 vs. 19.8±1.1 mmHg, P=0.03) and POD3 (14.2±2.2 vs. 19.0±2.2 mmHg, P=0.01). Histopathology showed pigment clumping and changes limited to anterior layers of the iris.Commercially available SLT laser can be used to create a minimally invasive, steroid-responsive animal model of anterior uveitis with the potential for use in the evaluation and comparison of drugs intended to treat AC inflammation.

PURPOSE. To study the effect on outflow facility and outflow resistance of a nitinol microstent implanted into Schlemm’s canal. METHODS. Using a constant pressure perfusion method, outflow facility and outflow resistance were measured in 26 pairs of dissected anterior segments from donated human eyes. Measurements were made at perfusion pressures of 10, 20, 30 and 40 mm Hg. The Hydrus Microstent was placed in Schlemm’s canal of one eye and the contralateral eye underwent a sham procedure. Outflow facility and outflow resistance were measured again after the microstent implantation or sham procedure. RESULTS. The Hydrus Microstent significantly increased outflow facility from 0.33 6 0.17 lL/min/mm Hg to 0.52 6 0.19 lL/ min/mm Hg (P < 0.001). Outflow resistance was significantly reduced from 4.38 6 3.03 mm Hg/lL/min at baseline to 2.34 6 1.04 mm Hg/lL/min (P < 0.001) with the microstent. There was a linear correlation between outflow resistance at baseline and decrease in outflow resistance with the microstent (R 2 ¼ 0.89, P < 0.0001). CONCLUSIONS. The increase in outflow facility and decrease in resistance supports the potential use of the Hydrus Microstent as a surgical option to reduce intraocular pressure (IOP). The IOP-lowering effect may be higher in eyes with higher outflow resistance (and IOP) as compared with eyes with lower outflow resistance (and IOP). (Invest Ophthalmol Vis Sci. 2013;54:1698‐1704) DOI:10.1167/iovs.12-11373

The seventh annual ARVO/Pfizer Ophthalmic Research Institute conference was held Friday and Saturday, April 29 and 30, 2011, at the Fort Lauderdale Hyatt Regency Pier 66, Fort Lauderdale, Florida. The conference, funded by The ARVO Foundation for Eye Research through a grant from Pfizer Ophthalmics, provided an opportunity to gather experts from within and outside ophthalmology to determine the state of knowledge pertaining to molecular biomarkers associated with glaucoma, as well as the methods to identify and validate them to predict (a) those who would be susceptible to development of glaucoma; (b) markers that will enable prediction of glaucoma progression; and (c) markers that will predict efficacy of treatment of glaucoma. Identification of such biomarkers will aid in prevention of glaucoma-related vision loss and blindness. The conference focused on an evaluation of glaucoma molecular biomarkers and progress needed for future validation of glaucoma biomarkers. A working group of 21 glaucoma researchers, 7 scientists focused on diseases other than glaucoma and with expertise in areas such as proteomic biomarkers or molecular mechanisms for neurodegeneration, and 60 observers from ARVO, Pfizer, and clinical and basic ophthalmic research convened to evaluate current understanding of the molecular biomarkers of glaucoma. The meeting format emphasized discussion and concentrated on questions within areas of glaucoma molecular biomarker research: Session I: How to define a biomarker in medicine? Current knowledge about biomarkers in human health and in glaucoma Session II: Genetic biomarkers in glaucoma Session III: Proteomic biomarkers in glaucoma Session IV: Pre-immune and immune events: Immunoproteomics and its possible applications in glaucoma Session V: From bench to bedside: How can a translational approach be successful? Each session began with a 10-minute overview by a glaucoma researcher followed by a 30-minute presentation by an outside expert, with parallels between their fields of expertise and the eye included. Invited outside experts covered several areas of research, including proteomic biomarker discovery in cancer (Emanuel Petricoin, PhD, George Mason University, Maryland; and Akhilesh Pandey, MD, PhD, Johns Hopkins University, Maryland) and astroglial cells in neurodegeneration (Stephen D. Miller, PhD, Northwestern University, Illinois).

Purpose A fluorophotometer designed to measure aqueous flow in murine eyes was tested with artificial fluorescein chambers and in live mice with different anesthesia regimens, aqueous flow suppressants, and an anterior chamber cannulation method. Methods Two hours following topical fluorescein application, one group of CD-1 mice was anesthetized with ketamine/xylazine, 2,2,2-tribromoethanol, or ketamine alone. Cornea and anterior chamber fluorescein concentrations were measured periodically for 60 to 90 minutes by fluorophotometric scans to calculate aqueous flow. Later, a subgroup of mice underwent aqueous flow measurement by anterior chamber cannulation. A third group was treated with timolol, dorzolamide, and vehicle in a crossover manner 1 hour prior to fluorophotometric scans. Results Aqueous flow with ketamine/xylazine anesthesia (0.09 ± 0.05 μL/min, mean ± SD, n = 24) was slower than with tribromoethanol or ketamine alone (P < 0.001). Timolol reduced aqueous flow from 0.20 ± 0.07 μL/min to 0.07 ± 0.03 μL/min (P = 0.001) under tribromoethanol anesthesia and from 0.14 ± 0.03 μL/min to 0.10 ± 0.02 μL/min (P = 0.004) under ketamine anesthesia but not under ketamine/xylazine anesthesia. Dorzolamide reduced aqueous flow from 0.09 ± 0.03 to 0.06 ± 0.03 μL/min (P = 0.04) under ketamine/xylazine anesthesia. Aqueous flow by anterior chamber cannulation (0.20 ± 0.13 μL/min) was greater (P = 0.05) than by fluorophotometry (0.09 ± 0.07 μL/min). Conclusions A new noninvasive fluorophotometric method detected effects of general anesthesia and known aqueous suppressants on aqueous flow in mice. Aqueous flow measured by fluorophotometry was slower than by cannulation, and was technically easier with less variability. The mouse fluorophotometer is useful for repeated measurements of aqueous flow in the murine eye making crossover and longitudinal studies possible.

PURPOSE. An intracanalicular scaffold (Hydrus microstent) designed to reduce intraocular pressure as a glaucoma treatment was tested in human anterior segments to determine changes in outflow facility (C). METHODS. Human eyes with no history of ocular disease or surgeries were perfused within 49 hours of death. The anterior segments were isolated and connected to a perfusion system. Flow rates were measured at pressures of 10, 20, 30, and 40 mm Hg. The scaffold was inserted into Schlemm’s canal of the experimental eye, while a control eye underwent a sham procedure. Flow rate measurements were repeated at the four pressure levels. Individual C values were computed by dividing the flow rate by its corresponding pressure, and by averaging the four individual C measurements. The change in C between control and experimental eyes was assessed by the ratio of the baseline and second C measurement. In two eyes, the placement of the scaffold was evaluated histologically. RESULTS. After scaffold implantation in the experimental eyes, the average C increased significantly from baseline (n ¼ 9, P < 0.05). Ratios of C at all pressure levels, except for 10 mm Hg, were significantly higher in experimental eyes (n ¼ 9) than control eyes (P < 0.05, n ¼ 7). Histologically, the scaffold dilated Schlemm’s canal with no visible damage to the trabecular meshwork. CONCLUSIONS. The Hydrus Microstent provided an effective way to increase outflow facility in human eyes ex vivo. (Invest Ophthalmol Vis Sci. 2012;53:6115‐6121) DOI:10.1167/ iovs.12-9570

Objective To evaluate the interaction of intraocular pressure (IOP)–lowering medications with physiologic day and night changes in aqueous humor dynamics in participants with ocular hypertension. Methods Thirty participants were enrolled in this double-masked, randomized, crossover study. Each participant underwent aqueous humor dynamics measurements at baseline and at 2 weeks of dosing in random order with latanoprost in the evening and placebo in the morning, timolol maleate twice daily, and dorzolamide hydrochloride twice daily. Measurements included central corneal thickness by ultrasound pachymetry, anterior chamber depth by A-scan, seated and habitual IOP by pneumatonometry, blood pressure by sphygmomanometry, episcleral venous pressure by venomanometry, and aqueous flow by fluorophotometry. Outflow facility was assessed by fluorophotometry and by tonography. Uveoscleral outflow was mathematically calculated using the Goldmann equation. Results Latanoprost use significantly decreased IOP during the day and night. It increased daytime uveoscleral outflow by a mean (SD) of 0.90 (1.46) μL/min (P = .048), but a nighttime increase of 0.26 (1.10) μL/min (P = .47) did not reach statistical significance. Timolol use decreased IOP during the day by reducing aqueous flow by 25%. Dorzolamide use lowered IOP only at the noon measurement and reduced daytime aqueous flow by 16%. Neither dorzolamide nor timolol use added to the physiologic 47% reduction in nighttime aqueous flow. Conclusions The daytime IOP-lowering effects of latanoprost are mediated by an increase in uveoscleral outflow, and those of timolol and dorzolamide are mediated by aqueous flow suppression. Nighttime physiologic changes in uveoscleral outflow limit the nighttime pharmacodynamic efficacy of latanoprost. Aqueous flow suppression with timolol and dorzolamide was ineffective in obtaining IOP lowering at night. Trial Registration clinicaltrials.gov Identifier: NCT00572936

Research on robot learning from demonstration has seen significant growth in recent years, but existing evaluations have focused exclusively on algorithmic performance and not on usability factors, especially with respect to naive users. Here we present findings from a comparative user study in which we asked non-experts to evaluate three distinctively different robot learning from demonstration algorithms - Behavior Networks, Interactive Reinforcement Learning, and Confidence Based Autonomy. Participants in the study showed a preference for interfaces where they controlled the robot directly (teleoperation and guidance) instead of providing retroactive feedback for past actions (reward and correction). Our results show that the best policy performance in most metrics was achieved using the Confidence Based Autonomy algorithm.

To evaluate the differences in aqueous humor dynamics between nighttime and daytime in participants with ocular hypertension.Thirty participants (mean [SD] age, 59.2 [11.1] years) with ocular hypertension were enrolled in the study, which included 1 daytime and 1 nighttime visit. During each visit, measurements included central cornea thickness by ultrasound pachymetry, intraocular pressure (IOP) by pneumatonometry, aqueous flow by fluorophotometry, outflow facility by tonography, and blood pressure by sphygmomanometry. Uveoscleral outflow was calculated using the Goldmann equation. Daytime measurements were made only of episcleral venous pressure by venomanometry, anterior chamber depth by A-scan, and outflow facility by fluorophotometry. Repeated-measures analysis of variance and 2-tailed t tests were used for statistical comparisons.Compared with daytime seated IOP (21.3 [3.5] mm Hg), nighttime seated IOP (17.2 [3.7] mm Hg) was reduced (P.001) and nighttime supine IOP (22.7 [4.6] mm Hg) was increased (P = .03). Central cornea thickness was increased at night from 570 (39) μm to 585 (46) μm (P.001). There was a 48% nocturnal reduction in aqueous flow from 2.13 (0.71) μL/min during the day to 1.11 (0.38) μL/min at night (P.001). Uveoscleral outflow was significantly reduced (P = .03) by 0.61 μL/min at night when using supine IOP, tonographic outflow facility, and episcleral venous pressure adjusted for postural changes in the Goldmann equation. All other measurements had no significant changes.Significant ocular changes occur at night in individuals with ocular hypertension, including a reduction in seated IOP but an increase in habitual IOP, thickening of the cornea, and decreases in aqueous flow and uveoscleral outflow. Outflow facility does not change significantly at nighttime.

Wet age-related macular degeneration (AMD), which accounts for most AMD-related vision loss, is characterized by choroidal neovascularization (CNV). The underlying mechanism of CNV is poorly understood, but evidence indicates pathologic recruitment of normal angiogenic signaling pathways such as the VEGF pathway. Recent evidence suggests that the VEGF pathway regulates angiogenesis in concert with Notch signaling. Here, the authors examined the role of Notch signaling in CNV in the backdrop of Notch signaling-mediated regulation of retinal angiogenesis.Choroid sclera complexes, after laser-induced CNV, were examined for changes in CNV lesion volume and in proangiogenic and antiangiogenic gene expression after perturbation in Notch signaling. Retinal vessels and angiogenic gene expression in retinal endothelial cells were analyzed in postnatal rats after perturbations in Notch signaling. Notch signaling was activated and inhibited by intravitreal or systemic injection of Jagged1 peptide and gamma secretase inhibitor DAPT, respectively.The authors demonstrated that activation of the canonical Notch pathway reduced the volume of CNV lesions as it attenuated the development of postnatal retinal vasculature. In contrast, inhibition of the Notch pathway exacerbated CNV lesions as it led to the development of hyperdense retinal vasculature. The authors also identified genes associated with proangiogenesis (Vegfr2, Ccr3, and Pdgfb) and antiangiogenesis (Vegfr1 and Unc5b) as targets of Notch signaling-mediated vascular homeostasis, the disruption of which might underlie CNV.This study suggests that Notch signaling is a key regulator of CNV and thus a molecular target for therapeutic intervention in wet AMD.

One of the most serious complications of chronic or fulminant liver failure is hepatic encephalopathy (HE), associated most commonly with cirrhosis. In the presence of chronic liver disease, HE is a sign of decompensation, while in fulminant liver failure its development represents a worrying sign and usually indicates that transplantation will be required. Despite the significance of HE in the course of liver disease, the progress in development of new therapeutic options has been unremarkable over the last 20 years. An up-to-date review regarding HE, including both research and review articles. HE is a serious and progressive, but potentially reversible, disorder with a wide spectrum of neuropsychiatric abnormalities and motor disturbances that ranges from mild alteration of cognitive and motor function to coma and death. Although a clear pathogenesis is yet to be determined, elevated ammonia in serum and the central nervous system is the mainstay for pathogenesis and treatment of HE. Management includes early diagnosis and prompt treatment of precipitating factors. Clinical trials and extensive clinical experience have established the efficacy of diverse substances in HE treatment. Novel therapies with clinical promise include: L-ornithine L-aspartate, sodium benzoate, phenylacetate, AST-120, and the molecular adsorbent recirculating system. Eventually, liver transplantation is often the most successful long-term therapy for HE. © Med Sci Monit.

PhXA41, a new phenyl-substituted analog of a prostaglandin F2 alpha (PGF2 alpha) prodrug (13,14-dihydro-17-phenyl-18,19,20-trinor-prostaglandin F2 alpha-1-isopropyl ester), is an effective ocular hypotensive agent in patients with glaucoma. To understand its mechanism of action, various components of aqueous humor dynamics were examined after topical application to human eyes.In a randomized, double-masked, placebo-controlled study, PhXA41 (0.006%) was given topically twice daily for 1 week to one eye each of 22 volunteers with normotension or ocular hypertension. The other eye was similarly treated with vehicle. Intraocular pressure (IOP) was measured by pneumatonometry and tonographic outflow facility by pneumatonography. Aqueous flow and outflow facility were determined either directly or indirectly by a fluorophotometric technique, and uveoscleral outflow was calculated secondarily. Comparison of values obtained in treated versus contralateral control eyes and on baseline versus day 8 of treatment were made.Compared with baseline measurements, PhXA41 significantly (P0.001) reduced IOP by 5.5 +/- 0.6 mmHg (mean +/- standard error of the mean) as measured 3 hours after the last dose on the eighth day of treatment. Aqueous flow, tonographic outflow facility, and fluorophotometric outflow facility were not changed by PhXA41. However, uveoscleral outflow was significantly greater in the PhXA41-treated eyes (0.87 +/- 0.22 microliter/minute) compared with either the contralateral vehicle-treated eyes (0.14 +/- 0.30; P0.02) or baseline measurements (0.39 +/- 0.20 microliter/minute; P0.05).PhXA41 decreases IOP in humans by increasing uveoscleral outflow without significantly affecting other parameters of aqueous humor dynamics.

The aim of the study was to investigate the ocular hypotensive activity of a nitric oxide (NO)-donating latanoprost, BOL-303259-X, following topical administration. The effect of BOL-303259-X (also known as NCX 116 and PF-3187207) on intraocular pressure (IOP) was investigated in monkeys with laser-induced ocular hypertension, dogs with naturally-occurring glaucoma and rabbits with saline-induced ocular hypertension. Latanoprost was used as reference drug. NO, downstream effector cGMP, and latanoprost acid were determined in ocular tissues following BOL-303259-X administration as an index of prostaglandin and NO-mediated activities. In primates, a maximum decrease in IOP of 31% and 35% relative to baseline was achieved with BOL-303259-X at doses of 0.036% (9 μg) and 0.12% (36 μg), respectively. In comparison, latanoprost elicited a greater response than vehicle only at 0.1% (30 μg) with a peak effect of 26%. In glaucomatous dogs, IOP decreased from baseline by 44% and 10% following BOL-303259-X (0.036%) and vehicle, respectively. Latanoprost (0.030%) lowered IOP by 27% and vehicle by 9%. Intravitreal injection of hypertonic saline in rabbits increased IOP transiently. Latanoprost did not modulate this response, whereas BOL-303259-X (0.036%) significantly blunted the hypertensive phase. Following BOL-303259-X treatment, latanoprost acid was significantly elevated in rabbit and primate cornea, iris/ciliary body and aqueous humor as was cGMP in aqueous humor. BOL-303259-X lowered IOP more effectively than latanoprost presumably as a consequence of a contribution by NO in addition to its prostaglandin activity. The compound is now in clinical development for the treatment of glaucoma and ocular hypertension.

Better control of intraocular pressure (IOP) is the most effective way to preserve visual field function in glaucomatous patients. While prostaglandin FP analogs are leading the therapeutic intervention for glaucoma, new target classes also are being identified with new lead compounds being developed for IOP reduction. One target class currently being investigated includes the prostaglandin EP receptor agonists. Recently PF-04217329 (Taprenepag isopropyl), a prodrug of CP-544326 (active acid metabolite), a potent and selective EP(2) receptor agonist, was successfully evaluated for its ocular hypotensive activity in a clinical study involving patients with primary open angle glaucoma. In the current manuscript, the preclinical attributes of CP-544326 and PF-0421329 have been described. CP-544326 was found to be a potent and selective EP(2) agonist (IC(50) = 10 nM; EC(50) = 2.8 nM) whose corneal permeability and ocular bioavailability were significantly increased when the compound was dosed as the isopropyl ester prodrug, PF-04217329. Topical ocular dosing of PF-04217329 was well tolerated in preclinical species and caused an elevation of cAMP in aqueous humor/iris-ciliary body indicative of in vivo EP(2) target receptor activation. Topical ocular dosing of PF-04217329 resulted in ocular exposure of CP-544326 at levels greater than the EC(50) for the EP(2) receptor. PF-04217329 when dosed once daily caused between 30 and 50% IOP reduction in single day studies in normotensive Dutch-belted rabbits, normotensive dogs, and laser-induced ocular hypertensive cynomolgus monkeys and 20-40% IOP reduction in multiple day studies compared to vehicle-dosed eyes. IOP reduction was sustained from 6 h through 24 h following a single topical dose. In conclusion, preclinical data generated thus far appear to support the clinical development of PF-04217329 as a novel compound for the treatment of glaucoma.

To assess aqueous humor dynamics in pigment dispersion syndrome (PDS).Four groups of age-matched participants included 2 experimental groups with PDS (PDS with ocular hypertension [PDS-OHT], 17 eyes; PDS without ocular hypertension [PDS-ONT], 18 eyes) and 2 control groups without PDS (OHT, 18 eyes; ONT, 18 eyes). Assessments included intraocular pressure measured by pneumatonometry, episcleral venous pressure by venomanometry, aqueous flow and outflow facility by fluorophotometry, corneal thickness and anterior chamber depth by pachymetry, and uveoscleral outflow by mathematical calculation. Comparisons were made by analysis of variance and 2-tailed unpaired t tests.The PDS-OHT group had higher intraocular pressures than the ONT and PDS-ONT groups (P.001) and higher episcleral venous pressure (P = .04) and lower outflow facility (P = .01) than the ONT group. Anterior chamber volume was larger in the PDS-OHT group than in the other groups (P.05 for all). No other comparisons between the PDS-OHT group and the other groups yielded statistically significant differences at a significance level of less than .05.The elevated intraocular pressure in PDS is caused by reduced outflow facility. This differs from OHT without PDS, in which reductions in uveoscleral outflow and outflow facility have been reported.

Ocular aqueous humor circulation and drainage are essential in maintaining intraocular pressure and keeping avascular tissues of the anterior segment healthy. Slowing aqueous flow decreases intraocular pressure and provides a means of treating glaucoma. The classes of drugs that reduce aqueous flow are beta (β) blockers, carbonic anhydrase inhibitors, alpha-2 (α2) adrenergic agonists, and other sympathomimetics. These drugs work by different mechanisms to achieve the same effect. Stimulating aqueous flow increases intraocular pressure and may provide a means of treating hypotony. Effective aqueous flow stimulants remain elusive. Aqueous humor production and the pharmacological ways to alter it are the topics of this article.

Except for the Romanesque choir, built in the second half of the XIIth century, Saint-Nicolas's in Avesnes-le-Comte dates back to the flamboyant period. Heir to the forms derived of the Carolingian churches, through its porch- steeple, this church bears a strong testimony to the religious architectural forms of XVth and XVIth century Artois through its plan, its stone vaults and its elevation. Thus classified in the extensive family of the hall-churches of northern France in its French version, it offers a large and beautiful nave which juxtaposes itself gently along the choir, this precious witness of the introduction of the ogival arch in our regions in the XIIth century. A monument exemplary of Artois religious architecture, Saint-Nicolas's in Avesnes-le-Comte combines tradition and evolution of forms. It translates with simplicity, picturesqueness and freedom, the religious impetus it was built to serve., Op het romaanse koor uit de tweede helft van de xne eeuw na dateert de Sint-Niklaaskerk te Avesnes-le-Comte uit de tijd van de vlammende gotiek. Naast zijn portaaltoren afgeleid van de Karolingische kerken vertoont de kerk vooral de invloed van de in Artezië gebruikelijke vormen in de XVe en xvie eeuw, in het plan, de stenen overwelving en de opstand. Zij maakt deel uit van de grote reeks Noordfranse hallekerken en toont een mooi en brood schip dat harmonisch aansluit bij het koor, een kostbaar reliot uit de tijd van de invoering van de kruisboog in onze gewesten in de XIIe eeuw. De Sint-Niklaaskerk is een voorbeeld van de Artezische kerkelijke architec- tuur waarin de traditie samengaat met een nieuwe vormentaal. De religieuze bezieling die tot de bouw geleid heeft word hier op een eenvoudige, schilde- rachtige en vrije manier vertaald., Toris Cauwel Isabelle. L'église Saint-Nicolas d'Avesnes-le-Comte, de l'art roman au gothique flamboyant. In: Revue du Nord, tome 74, n°297-298, Juillet-décembre 1992. pp. 523-539.