Interpretation of uniocular and binocular trials of glaucoma medications: an observational case series

<p>Abstract</p> <p>Background</p> <p>To predict the effectiveness of topical glaucoma medications based on initial uniocular and binocular treatment. To test a traditional hypothesis that effectiveness following a uniocular trial is associated with the change in IOP in the initially treated eye minus the change in the initially untreated eye. To determine whether uniocular or binocular treatment trials are superior.</p> <p>Methods</p> <p>Based on a review of medical records, we identified 168 instances in 154 patients with bilateral primary open angle glaucoma of initial uniocular use of a topical glaucoma medication with well-documented intraocular pressure (IOP) readings at baseline (IOP_A), during the trial (IOP_B), and at follow-up (IOP_C). Abstracted data included demographic data, IOP, and medication use. Predictors of the IOP following the trial (IOP_C) in each eye were identified by multivariable linear regression. In 70 cases, the predictive ability of initial uniocular and binocular treatment could be directly compared.</p> <p>Results</p> <p>In a multivariable analysis, the follow-up pressure in the initially treated eye (IOP_1C) was directly correlated with treated eye IOP during initial uniocular use (IOP_1B, p < 0.001). In a multivariable analysis, the follow-up pressure in the initially untreated eye (IOP_2C) was directly correlated with its baseline IOP_2A(p < 0.001), and also tended to be associated with treated IOP_1B(p = 0.07). The multivariable regression coefficient (b) for the IOP change in the initially untreated eye was generally not close to the value of -1 expected by the classic teaching (for eye 1, b = 0.04, p = 0.35; for eye 2, b = 0.07, p = 0.50). In 70 cases, the uniocular and binocular trials predicted a similar fraction of the variance in follow-up IOP_1C(r²= 0.56 and 0.57, respectively) and IOP_2C(r²= 0.39 and 0.38, respectively).</p> <p>Conclusion</p> <p>1) For uniocular trials, the IOP change in the untreated eye should not be subtracted from that in the treated eye. 2) Uniocular and binocular trials have similar predictive value when interpreted correctly. Either may be selected based on clinical circumstances.</p

Preventive Effects of Omega-3 and Omega-6 Fatty Acids on Peroxide Mediated Oxidative Stress Responses in Primary Human Trabecular Meshwork Cells

Pathologic processes in glaucoma include increased apoptosis, accumulation of extracellular material in the trabecular meshwork and optic nerve, condensations of the cytoskeleton and precocious cellular senescence. Oxidative stress was shown to generate these alterations in primary ocular cells. Fatty acids omega-3 and -6 are alleged to constitute a prophylaxis against these deleterious effects. Here, we tested actual preventive effects omega-3 and -6 against peroxide induced stress responses in primary human trabecular meshwork cells. Changes of mitochondrial activity, proliferation, heat shock proteins, extracellular matrix components, and inflammatory markers were evaluated. Alterations of the cytoskeleton were evaluated by phalloidin labeling. Here we report a repressive effect of omega-6 on metabolic activity and proliferation, which was not detected for omega-3. Both agents were able to prevent the anti-proliferative effect of H2O2, but only omega-3 prevented metabolic repression. Expression of heat shock protein 27 was unaltered by both fatty acids, whereas heat shock protein 90 was significantly induced by both. Omega-6 increased fibronectin and connective tissue growth factor synthesis, as well as the amount of secreted fibronectin. Omega-3, instead, induced plasminogen activator inhibitor 1 synthesis. H2O2 further increased fibronectin production in omega-6 supplemented cells, which was not the case in omega-3 treated cells. H2O2 stimulation of plasminogen activator inhibitor 1 and connective tissue growth factor was repressed by both fatty acids. Both fatty acids appeared to abolish H2O2 mediated stimulation of nuclear factor κB and IL-6, but not IL-1α and IL-8. H2O2 induced formation of cross-linked actin networks and stress fibers, which was reduced by preemptive application of omega-3. Omega-6, in contrast, had no protective effect on that, and even seemed to promote condensation. Based on the observed side effects of omega-6, omega-3 appears to be the more beneficial fatty acid in respect of prophylactic intake for prevention of a glaucomatous disease

Trabecular Meshwork Gene Expression after Selective Laser Trabeculoplasty

BACKGROUND: Trabecular meshwork and Schlemm's canal are the tissues appointed to modulate the aqueous humour outflow from the anterior chamber. The impairment of their functions drives to an intraocular pressure increase. The selective laser trabeculoplasty is a laser therapy of the trabecular meshwork able to decrease intraocular pressure. The exact response mechanism to this treatment has not been clearly delineated yet. The herein presented study is aimed at studying the gene expression changes induced in trabecular meshwork cells by selective laser trabeculoplasty (SLT) in order to better understand the mechanisms subtending its efficacy. METHODOLOGY/PRINCIPAL FINDINGS: Primary human trabecular meshwork cells cultured in fibroblast medium underwent selective laser trabeculoplasty treatment. RNA was extracted from a pool of cells 30 minutes after treatment while the remaining cells were further cultured and RNA was extracted respectively 2 and 6 hours after treatment. Control cells stored in incubator in absence of SLT treatment were used as reference samples. Gene expression was evaluated by hybridization on miRNA-microarray and laser scanner analysis. Scanning electron microscopic examination was performed on 2 Trabecular meshwork samples after SLT at 4(th) and 6(th) hour from treatment. On the whole, selective laser trabeculoplasty modulates in trabecular meshwork the expression of genes involved in cell motility, intercellular connections, extracellular matrix production, protein repair, DNA repair, membrane repair, reactive oxygen species production, glutamate toxicity, antioxidant activities, and inflammation. CONCLUSIONS/SIGNIFICANCE: SLT did not induce any phenotypic alteration in TM samples. TM is a complex tissue possessing a great variety of function pivotal for the active regulation of aqueous humour outflow from the anterior chamber. SLT is able to modulate these functions at the postgenomic molecular level without inducing damage either at molecular or phenotypic levels

Nanoceria Inhibit the Development and Promote the Regression of Pathologic Retinal Neovascularization in the Vldlr Knockout Mouse

Many neurodegenerative diseases are known to occur and progress because of oxidative stress, the presence of reactive oxygen species (ROS) in excess of the cellular defensive capabilities. Age related macular degeneration (AMD), diabetic retinopathy (DR) and inherited retinal degeneration share oxidative stress as a common node upstream of the blinding effects of these diseases. Knockout of the Vldlr gene results in a mouse that develops intraretinal and subretinal neovascular lesions within the first month of age and is an excellent model for a form of AMD called retinal angiomatous proliferation (RAP). Cerium oxide nanoparticles (nanoceria) catalytically scavenge ROS by mimicking the activities of superoxide dismutase and catalase. A single intravitreal injection of nanoceria into the Vldlr-/- eye was shown to inhibit: the rise in ROS in the Vldlr-/- retina, increases in vascular endothelial growth factor (VEGF) in the photoreceptor layer, and the formation of intraretinal and subretinal neovascular lesions. Of more therapeutic interest, injection of nanoceria into older mice (postnatal day 28) resulted in the regression of existing vascular lesions indicating that the pathologic neovessels require the continual production of excessive ROS. Our data demonstrate the unique ability of nanoceria to prevent downstream effects of oxidative stress in vivo and support their therapeutic potential for treatment of neurodegenerative diseases such as AMD and DR

The Yeast Pif1 Helicase Prevents Genomic Instability Caused by G-Quadruplex-Forming CEB1 Sequences In Vivo

In budding yeast, the Pif1 DNA helicase is involved in the maintenance of both nuclear and mitochondrial genomes, but its role in these processes is still poorly understood. Here, we provide evidence for a new Pif1 function by demonstrating that its absence promotes genetic instability of alleles of the G-rich human minisatellite CEB1 inserted in the Saccharomyces cerevisiae genome, but not of other tandem repeats. Inactivation of other DNA helicases, including Sgs1, had no effect on CEB1 stability. In vitro, we show that CEB1 repeats formed stable G-quadruplex (G4) secondary structures and the Pif1 protein unwinds these structures more efficiently than regular B-DNA. Finally, synthetic CEB1 arrays in which we mutated the potential G4-forming sequences were no longer destabilized in pif1Δ cells. Hence, we conclude that CEB1 instability in pif1Δ cells depends on the potential to form G-quadruplex structures, suggesting that Pif1 could play a role in the metabolism of G4-forming sequences

Twenty-four-hour intraocular pressure and ocular perfusion pressure characteristics in newly diagnosed patients with normal tension glaucoma

PurposeTo determine the mean 24-h intraocular pressure (IOP) and mean ocular perfusion pressure (MOPP) characteristics of newly diagnosed, previously untreated, Caucasian, normal tension glaucoma (NTG) patients and to identify relationships between these features and visual field (VF) loss at diagnosis.MethodsConsecutive newly diagnosed NTG patients underwent 24-h habitual IOP and blood pressure (BP) monitoring. Parameters from pooled measurements obtained in the sitting (0800-2200 hours) and supine (1200-0600 hours) positions were compared and associations were sought with VF mean deviation (MD) and pattern standard deviation (PSD).ResultsSixty-two Caucasian NTG patients (24 men and 38 women) successfully completed circadian IOP and BP monitoring. In habitual position, 8 subjects (12.9%) exhibited a diurnal acrophase, 42 subjects (67.7%) demonstrated a nocturnal acrophase, one subject (1.6%) showed a flat rhythm and 11 patients (17.7%) revealed a biphasic/polyphasic rhythm. Nighttime MOPP values (supine position) were significantly greater than diurnal values (sitting position); (P<0.001). No association could be demonstrated between glaucomatous damage, as indicated by VF parameters, and either mean habitual 24-h IOP (P=0.20 and P=0.12 for MD and PSD, respectively), or habitual 24-h MOPP (P=0.96 and 0.29, for MD and PSD, respectively).ConclusionsIn this cohort of Caucasian NTG patients, most patients exhibited a nocturnal IOP acrophase when evaluated in a habitual position. No association was found between 24-h IOP or MOPP and VF damage.Eye advance online publication, 29 July 2016; doi:10.1038/eye.2016.168

Common aspects between glaucoma and brain neurodegeneration

Neurodegeneration can be defined as progressive cell damage to nervous system cells, and more specifically to neurons, which involves morphologic alterations and progressive loss of function until cell death. Glaucoma exhibits many aspects of neurodegenerative disease. This review examines the pathogenesis of glaucoma, comparing it with that of Alzheimer's disease (AD) and Parkinson's disease (PD), highlighting their common features. Indeed, in all three diseases there are not only the same types of pathogenic events, but also similarities of temporal cadences that determine neuronal damage. All three age-related illnesses have oxidative damage and mitochondrial dysfunction as the first pathogenic steps. The consequence of these alterations is the death of visual neurons in glaucoma, cognitive neurons in AD and regulatory motor neurons (substantia nigra) in PD. The study of these common pathogenic events (oxidative stress, mitochondrial dysfunction, protein degradation, apoptosis and autophagy) leads us to consider common therapeutic strategies for the treatment and prevention of these diseases. Also, examination of the genetic aspects of the pathways involved in neurodegenerative processes plays a key role in shedding light on the details of pathogenesis and can suggest new treatments. This review discusses the common molecular aspects involved in these three oxidative-stress and age-related diseases