Biomarkers for primary open-angle glaucoma progression.

Glaucoma is a heterogeneous group of progressive optic neurodegenerative. Although most patients with primary open angle glaucoma (POAG) are stable for many years, certain subgroups of POAG patients could progress over time even with treatment. This study is to identify aqueous humor (AH) biomarkers that may be associated with disease progression in POAG patients. Gene differential expression study of prospectively collected AH from patients with stable or progressive POAG. Metagenomic deep sequencing (MDS) was performed on the aqueous fluid of 20 patients with stable POAG and 20 patients with progressive POAG. Differential gene expression analysis was performed to identify host transcriptome signatures. A total of 21 transcripts were differentially expressed between groups. Differential transcripts identified by MDS. Twenty transcripts were up-regulated and 1 transcript was down-regulated in progressive POAG patients compared to stable patients. Of those, 11 transcripts were eye-related, and 5 transcripts were related to glaucomatous phenotypes (Fibronectin type III domain containing 3B (FNDC3B), Clusterin (CLU), Proprotein convertase subtilisin/kexin type 6 (PCSK6), Cadherin EGF LAG seven-pass G-type receptor 1 (Celsr1), and Rho guanine nucleotide exchange factor 4 (ARHGEF4)). Biomarkers associated with POAG progression can be identified from aqueous fluid. Identification of the biomarkers may improve glaucoma surveillance for progressive POAG.

Factors impacting cumulative dissipated energy levels and postoperative visual acuity outcome in cataract surgery.

PURPOSE: To determine factors impacting cumulative dissipated energy (CDE) and postoperative best-corrected visual acuity (BCVA) in phacoemulsification. DESIGN: Review of 1102 cases at University of California, San Francisco (UCSF) and at Zhongshan Ophthalmic Center (ZOC), China. SUBJECTS: Patients who underwent cataract surgery at UCSF 03/2014-03/2019 and at ZOC 10/2018-05/2019. METHODS: Patient demographics, medical history, routine ocular examination, and surgical information, including disassembly method, complications, and surgeon training level were recorded. Univariable and multivariable regression models were used to determine factors associated with CDE and good postoperative BCVA (20/40 or better) at 1 month. OUTCOME MEASURES: CDE, postoperative BCVA. RESULTS: In multivariable analysis, patient age at time of surgery, diabetes, degree of nuclear sclerosis (NS), white-to-white corneal diameter, disassembly method, preoperative BCVA, surgeon training level, and surgical center were significantly associated with CDE. Log10CDE increased by 0.20-0.31 for patient age ≥ 70 years, by 0.07 if the patient had diabetes, by 0.12-0.41 for NS grade ≥ 2, by 0.48 per 10 mm increase in white-to-white corneal diameter, by 0.34-0.47 for disassembly method other than non-stop chop, by 0.16 per unit increase in preoperative logMAR BCVA, and by > 0.09 when phacoemulsification was performed by residents early in their training. Log10CDE was 0.33 higher at UCSF than ZOC. In multivariable analysis, worse baseline visual acuity and age above 90 years at time of surgery decreased the odds of good BCVA (OR = 0.26 per unit increase in preoperative logMAR BCVA; OR = 0.12 for age > 90); comorbid retinal issues decreased the odds of good postoperative BCVA (OR = 0.13-0.39); greater anterior chamber depth (ACD) or shorter axial length (AL), increased the odds of good postoperative outcome (OR = 2.64 per 1 mm increase ACD, OR = 0.84 per 1 mm increase AL). CONCLUSIONS: Cataract grade determined by slit lamp exam and, for the first time, older patient age, were noted to be important predictors of high CDE. CDE was not a risk factor for postoperative BCVA measured at postoperative 1 month. When surgery was performed by trainees under supervision, lower training level was associated with higher CDE, but not with worse postoperative BCVA.

Optogenetic intervention of seizures improves spatial memory in a mouse model of chronic temporal lobe epilepsy.

OBJECTIVE: To determine if closed-loop optogenetic seizure intervention, previously shown to reduce seizure duration in a well-established mouse model chronic temporal lobe epilepsy (TLE), also improves the associated comorbidity of impaired spatial memory. METHODS: Mice with chronic, spontaneous seizures in the unilateral intrahippocampal kainic acid model of TLE, expressing channelrhodopsin in parvalbumin-expressing interneurons, were implanted with optical fibers and electrodes, and tested for response to closed-loop light intervention of seizures. Animals that responded to closed-loop optogenetic curtailment of seizures were tested in the object location memory test and then given closed-loop optogenetic intervention on all detected seizures for 2 weeks. Following this, they were tested with a second object location memory test, with different objects and contexts than used previously, to assess if seizure suppression can improve deficits in spatial memory. RESULTS: Animals that received closed-loop optogenetic intervention performed significantly better in the second object location memory test compared to the first test. Epileptic controls with no intervention showed stable frequency and duration of seizures, as well as stable spatial memory deficits, for several months after the precipitating insult. SIGNIFICANCE: Many currently available treatments for epilepsy target seizures but not the associated comorbidities, therefore there is a need to investigate new potential therapies that may be able to improve both seizure burden and associated comorbidities of epilepsy. In this study, we showed that optogenetic intervention may be able to both shorten seizure duration and improve cognitive outcomes of spatial memory.

5-Fluorouracil Management of Oculofacial Scars: A Systematic Literature Review.

PURPOSE: To review the literature for the safety and efficacy of intralesional 5-fluorouracil (5-FU) in the management of oculofacial scars. METHODS: A literature search was performed in July 2019 in the PubMed database to identify reports of the use of 5-FU injections for modulating oculofacial cutaneous scars. The search yielded 152 articles, of which 15 met criteria outlined for assessment. Data were abstracted from these 15 relevant articles. RESULTS: While there were no high-level prospective randomized controlled trials, 8 were lower-quality randomized controlled trial, 3 were retrospective cohort studies, and 4 were case series. Most studies pooled results of facial and nonfacial cutaneous applications. Three studies focused solely on oculofacial applications, and these were all lower-level evidence studies. The study outcomes included scar dimension reduction, erythema, patient satisfaction score, observer assessment of scar improvement, and recurrence rates. 5-Fluorouracil was administered as monotherapy or as part of multimodality treatment with other agents (usually corticosteroids) or with CO2 laser, radiotherapy, or pulsed dye laser. 5-Fluorouracil was usually given as an intralesional injection, but in some studies, it was applied topically after micropuncture of the skin. The number and timing of treatments varied between studies. Overall, the level of safety of 5-FU was high. Pain with injection was the most common reported side effect. Other common adverse side effects included pruritus, telangiectasias, changes in pigmentation, and purpura, and 2 studies noted more serious events, such as ulceration, superficial necrosis, and local infection. There were no severe side effects such as anaphylaxis, immune suppression, secondary malignancy, systemic infection, blindness, or death. In all studies, 5-FU was associated with prophylaxis of oculofacial scars or improvement of keloids or hypertrophic scars in terms of reducing size, erythema, and pruritus. 5-Fluorouracil application was associated with favorable patient satisfaction and observer assessment scores especially compared with corticosteroid injections alone. CONCLUSIONS: High-quality randomized controlled trials are currently lacking, and the existing literature is predominately not specific to use of 5-FU on the face. These studies, however, suggest that intralesional 5-FU is safe and probably more effective than other options in the management of cutaneous scars in the oculofacial region. The delivery methods, timing, dosing, and concomitant therapies were highly variable. Further high-quality controlled studies specific to oculofacial scars may be indicated to assess the efficacy of 5-FU and to establish the best protocols for administering this medication.

Keratoconus Diagnosis and Treatment: Recent Advances and Future Directions.

Keratoconus is a disorder characterized by progressive corneal thinning and steepening that may result in significant visual impairment secondary to high astigmatism, corneal scarring, or even corneal perforation. Early detection and screening of keratoconus are essential for effective management and treatment. Several screening methods, such as corneal topography and tomography, corneal biomechanics, and genetic testing, are being developed to detect keratoconus at an early stage. Once detected, prevention of progression is the mainstay of keratoconus management. Corneal collagen cross-linking is a minimally invasive treatment option that can slow or halt the progression of keratoconus. Additionally, recent studies have investigated the potential use of copper sulfate eye drops (IVMED-80) and extracellular vesicles to prevent the progression of keratoconus as non-invasive treatment options. For visual rehabilitation, currently available treatments include scleral lenses, intracorneal ring segments, corneal allogenic intrastromal ring segments, and deep anterior lamellar keratoplasty. The safety and efficacy of these emerging treatment options for keratoconus are currently being investigated.

Multimodal Imaging in Ocular Siderosis.

Purpose: This report aims to characterize ocular changes in a case of ocular siderosis with iron toxicity using multimodal imaging and electroretinography. Methods: A 34-year-old woman presented with ocular siderosis of the left eye following penetrating injury with an iron-containing foreign body. The patient's uncorrected visual acuities were 20/60 and 20/150 in the right and left eye, respectively, with abnormal pupillary function and presence of a cataract in the left eye. She underwent successful intraocular foreign body removal and cataract surgery with no postoperative complications. Cone contrast threshold (CCT), full-field electroretinogram, spectral-domain optical coherence tomography (OCT), and OCT angiography (OCTA) were used to characterize ocular alterations preoperatively and postoperatively. Results: CCT color vision testing showed abnormal color vision, and OCTA revealed increased vascular flow density associated with the foreign body. Conclusions: CCT color vision testing, OCTA, OCT, and full-field electroretinogram can characterize retinal changes in cases of ocular siderosis.

Dentate gyrus mossy cells control spontaneous convulsive seizures and spatial memory.

Temporal lobe epilepsy (TLE) is characterized by debilitating, recurring seizures and an increased risk for cognitive deficits. Mossy cells (MCs) are key neurons in the hippocampal excitatory circuit, and the partial loss of MCs is a major hallmark of TLE. We investigated how MCs contribute to spontaneous ictal activity and to spatial contextual memory in a mouse model of TLE with hippocampal sclerosis, using a combination of optogenetic, electrophysiological, and behavioral approaches. In chronically epileptic mice, real-time optogenetic modulation of MCs during spontaneous hippocampal seizures controlled the progression of activity from an electrographic to convulsive seizure. Decreased MC activity is sufficient to impede encoding of spatial context, recapitulating observed cognitive deficits in chronically epileptic mice.

Seizing Control: From Current Treatments to Optogenetic Interventions in Epilepsy.

The unpredictability and severity of seizures contribute to the debilitating nature of epilepsy. These factors also render the condition particularly challenging to treat, as an ideal treatment would need to detect and halt the pathological bursts of hyperactivity without disrupting normal brain activity. Optogenetic techniques offer promising tools to study and perhaps eventually treat this episodic disorder by controlling specific brain circuits in epileptic animals with great temporal precision. Here, we briefly review the current treatment options for patients with epilepsy. We then describe the many ways optogenetics has allowed us to untangle the microcircuits involved in seizure activity, and how it has, in some cases, changed our perception of previous theories of seizure generation. Control of seizures with light is no longer a dream, and has been achieved in numerous different animal models of epilepsy. Beyond its application as a seizure suppressor, we highlight another facet of optogenetics in epilepsy, namely the ability to create "on-demand" seizures, as a tool to systematically probe the dynamics of networks during seizure initiation and propagation. Finally, we look into the future to discuss the possibilities and challenges of translating optogenetic techniques to clinical use.

Cannabinoid Control of Learning and Memory through HCN Channels.

The mechanisms underlying the effects of cannabinoids on cognitive processes are not understood. Here we show that cannabinoid type-1 receptors (CB1Rs) control hippocampal synaptic plasticity and spatial memory through the hyperpolarization-activated cyclic nucleotide-gated (HCN) channels that underlie the h-current (Ih), a key regulator of dendritic excitability. The CB1R-HCN pathway, involving c-Jun-N-terminal kinases (JNKs), nitric oxide synthase, and intracellular cGMP, exerts a tonic enhancement of Ih selectively in pyramidal cells located in the superficial portion of the CA1 pyramidal cell layer, whereas it is absent from deep-layer cells. Activation of the CB1R-HCN pathway impairs dendritic integration of excitatory inputs, long-term potentiation (LTP), and spatial memory formation. Strikingly, pharmacological inhibition of Ih or genetic deletion of HCN1 abolishes CB1R-induced deficits in LTP and memory. These results demonstrate that the CB1R-Ih pathway in the hippocampus is obligatory for the action of cannabinoids on LTP and spatial memory formation.