Defining the role of ab externo Xen gel stent in glaucomatous eyes with prior failed surgical intervention.

PURPOSE: To evaluate the safety and efficacy of Xen45 Gel stent (Xen; Allergan) in eyes that have failed prior surgical intervention, compared to traditional glaucoma drainage device (GDD) or continuous-wave cyclophotocoagulation (CPC). Since this population has low expected success rates with additional surgery, it is vital to compare to standard-of-care surgical options. METHODS: Retrospective, single-center, case-control study of ab externo transconjunctival Xen shunt in eyes that have previously undergone trabeculectomy and/or GDD surgery. Postoperative data were collected for 18 months. Failure was defined as no light perception, additional glaucoma surgery required, or intraocular pressure (IOP) of < 6 mmHg after 6 weeks postoperatively. RESULTS: Eighteen Xen eyes and 36 control eyes matched on both glaucoma type and previous glaucoma surgeries were included. Seventy-two percent had primary open angle glaucoma, 11% uveitic, 6% primary angle closure, 6% pseudoexfoliation, and 6% pigmentary glaucoma. Fifty-six percent of eyes in each group had prior trabeculectomy, 28% of Xen and 31% of control eyes had prior GDD, and 17% of Xen and 14% of control eyes had both. Baseline medicated IOP was lower in the Xen group (21.8 ± 7.2) compared to controls (27.5 ± 9.4, P = 0.043). The cumulative failure rate at year 1 was 17% for Xen and 20% for controls (P = 0.57). Mean survival time was 14.1 (± 1.5) months and 11.4 (± 0.6) months for controls. There was no difference in minor complication rates between groups (P = 0.65), but the Xen group had a significantly lower rate of serious complications (P = 0.043) defined as vision threatening or requiring surgical intervention in the operating room. When censored for additional glaucoma procedures, there were no differences at year 1 in IOP, change in IOP, number of IOP-lowering medications, or number of medications reduced from baseline. CONCLUSIONS: The Xen shunt provides a reasonable alternative to current standard of care, with a similar failure rate at year 1, with a noninferior IOP reduction compared to GDD and CPC, and a preferred safety profile.

Personalized pediatric ophthalmology: a case report.

The availability of genetic sequencing has given physicians a new tool for diagnosis and treatment of disease, and "personalized medicine" has become an increasingly common term in general but not in pediatric ophthalmology. We present a case of a toddler who developed ataxia, opsoclonus, myoclonus, and developmental regression following anesthesia for a common otolaryngology procedure. The child was found to have a variant in the MT-ND6 gene (m.14484T>C), most commonly associated with Leber hereditary optic neuropathy, despite a phenotype more closely resembling Leigh syndrome. The incongruence of phenotype and genotype prompted whole exome sequencing, which identified an unexpected intronic missense mutation in RB1 (1960+5G>A), with a 90% penetrance for retinoblastoma. Limited evaluation of the posterior pole in clinic did not identify any lesions, and the risks and benefits of examination under anesthesia were discussed among neurology, ophthalmology, and anesthesiology. We report the outcome of these discussions. The value and risks of personalized medicine are discussed.

Intraoperative Optical Coherence Tomography-Assisted Descemet Stripping Automated Endothelial Keratoplasty for Anterior Chamber Fibrous Ingrowth.

PURPOSE: Here, we present the first reported case of intraoperative optical coherence tomography (OCT)-assisted Descemet membrane stripping automated endothelial keratoplasty (DSAEK) in a patient with anterior segment fibrous ingrowth. METHODS: A 61-year-old woman with corneal edema and chronic angle-closure glaucoma secondary to fibrous ingrowth after 2 glaucoma shunt device implantations underwent dissection and removal of anterior chamber fibrous ingrowth and DSAEK. The surgical techniques using intraoperative OCT and outcome are described. RESULTS: Intraoperative OCT provided a clear dissection plane of the fibrous membranes in the anterior chamber and view of their relation to the iris and corneal endothelium, despite an opacified cornea. The placement of the donor lenticule and absence of interface fluid were also verified intraoperatively. The postoperative course was uncomplicated with satisfactory outcome. CONCLUSIONS: We conclude that intraoperative OCT is a useful tool during DSAEK surgery, particularly in complicated cases such as anterior segment fibrous ingrowth and significant corneal edema.

Alzheimer's therapeutics targeting amyloid beta 1-42 oligomers I: Abeta 42 oligomer binding to specific neuronal receptors is displaced by drug candidates that improve cognitive deficits.

Synaptic dysfunction and loss caused by age-dependent accumulation of synaptotoxic beta amyloid (Abeta) 1-42 oligomers is proposed to underlie cognitive decline in Alzheimer's disease (AD). Alterations in membrane trafficking induced by Abeta oligomers mediates reduction in neuronal surface receptor expression that is the basis for inhibition of electrophysiological measures of synaptic plasticity and thus learning and memory. We have utilized phenotypic screens in mature, in vitro cultures of rat brain cells to identify small molecules which block or prevent the binding and effects of Abeta oligomers. Synthetic Abeta oligomers bind saturably to a single site on neuronal synapses and induce deficits in membrane trafficking in neuronal cultures with an EC50 that corresponds to its binding affinity. The therapeutic lead compounds we have found are pharmacological antagonists of Abeta oligomers, reducing the binding of Abeta oligomers to neurons in vitro, preventing spine loss in neurons and preventing and treating oligomer-induced deficits in membrane trafficking. These molecules are highly brain penetrant and prevent and restore cognitive deficits in mouse models of Alzheimer's disease. Counter-screening these compounds against a broad panel of potential CNS targets revealed they are highly potent and specific ligands of the sigma-2/PGRMC1 receptor. Brain concentrations of the compounds corresponding to greater than 80% receptor occupancy at the sigma-2/PGRMC1 receptor restore cognitive function in transgenic hAPP Swe/Ldn mice. These studies demonstrate that synthetic and human-derived Abeta oligomers act as pharmacologically-behaved ligands at neuronal receptors--i.e. they exhibit saturable binding to a target, they exert a functional effect related to their binding and their displacement by small molecule antagonists blocks their functional effect. The first-in-class small molecule receptor antagonists described here restore memory to normal in multiple AD models and sustain improvement long-term, representing a novel mechanism of action for disease-modifying Alzheimer's therapeutics.

A pharmacological screening approach for discovery of neuroprotective compounds in ischemic stroke.

With the availability and ease of small molecule production and design continuing to improve, robust, high-throughput methods for screening are increasingly necessary to find pharmacologically relevant compounds amongst the masses of potential candidates. Here, we demonstrate that a primary oxygen glucose deprivation assay in primary cortical neurons followed by secondary assays (i.e. post-treatment protocol in organotypic hippocampal slice cultures and cortical neurons) can be used as a robust screen to identify neuroprotective compounds with potential therapeutic efficacy. In our screen about 50% of the compounds in a library of pharmacologically active compounds displayed some degree of neuroprotective activity if tested in a pre-treatment toxicity assay but just a few of these compounds, including Carbenoxolone, remained active when tested in a post-treatment protocol. When further examined, Carbenoxolone also led to a significant reduction in infarction size and neuronal damage in the ischemic penumbra when administered six hours post middle cerebral artery occlusion in rats. Pharmacological testing of Carbenoxolone-related compounds, acting by inhibition of 11-ß-hydroxysteroid dehydrogenase-1 (11ß-HSD1), gave rise to similarly potent in vivo neuroprotection. This indicates that the increase of intracellular glucocorticoid levels mediated by 11ß-HSD1 may be involved in the mechanism that exacerbates ischemic neuronal cell death, and inhibiting this enzyme could have potential therapeutic value for neuroprotective therapies in ischemic stroke and other neurodegenerative disorders associated with neuronal injury.

Computational analysis of stresses acting on intermodular junctions in thoracic aortic endografts.

PURPOSE: To evaluate the biomechanical and hemodynamic forces acting on the intermodular junctions of a multi-component thoracic endograft and elucidate their influence on the development of type III endoleak due to disconnection of stent-graft segments. METHODS: Three-dimensional computer models of the thoracic aorta and a 4-component thoracic endograft were constructed using postoperative (baseline) and follow-up computed tomography (CT) data from a 69-year-old patient who developed type III endoleak 4 years after stent-graft placement. Computational fluid dynamics (CFD) techniques were used to quantitate the displacement forces acting on the device. The contact stresses between the different modules of the graft were then quantified using computational solid mechanics (CSM) techniques. Lastly, the intermodular junction frictional stability was evaluated using a Coulomb model. RESULTS: The CFD analysis revealed that curvature and length are key determinants of the displacement forces experienced by each endograft and that the first 2 modules were exposed to displacement forces acting in opposite directions in both the lateral and longitudinal axes. The CSM analysis revealed that the highest concentration of stresses occurred at the junction between the first and second modules of the device. Furthermore, the frictional analysis demonstrated that most of the surface area (53%) of this junction had unstable contact. The predicted critical zone of intermodular stress concentration and frictional instability matched the location of the type III endoleak observed in the 4-year follow-up CT image. CONCLUSION: The region of larger intermodular stresses and highest frictional instability correlated with the zone where a type III endoleak developed 4 years after thoracic stent-graft placement. Computational techniques can be helpful in evaluating the risk of endograft migration and potential for modular disconnection and may be useful in improving device placement strategies and endograft design.