Controlled Elevation of Intraocular Pressure (CEI) Glaucoma Model in Rats.

Experimental elevation of intraocular pressure (IOP), a major glaucoma risk factor, has been a mainstay of research into mechanisms of glaucomatous optic nerve damage for decades. Methods that produce sustained IOP elevation can mimic the chronic nature of glaucoma and produce optic nerve damage. However, the pressure course for individual animals can be variable, unpredictably high at times, and difficult to monitor with current tonometry methods.

Controlled elevation of intraocular pressure in anesthetized mice.

Our purpose was to develop a protocol for prolonged anesthesia in mice and evaluate optic nerve axon injury in response to 4 h of controlled elevation of intraocular pressure (CEI). During CEI, C57BL/6 male mice (3-5 months old) were anesthetized with 1.5% isoflurane with 100% oxygen for 4 h and placed on a warm platform, with expired gas and anesthetic actively evacuated.

Optic Nerve Head Gene Transcription Sequelae to a Single Elevated IOP Exposure Provides Insights Into Known Responses to Chronically Elevated IOP.

Purpose: To clarify the optic nerve head (ONH) gene expression responses associated with a single, axon-damaging exposure to elevated IOP in relation to the composite cellular events previously identified in models of chronically elevated IOP.

Methods: Anesthetized rats were exposed unilaterally to an 8-hour pulse-train controlled elevation of IOP (PT-CEI) at 60 mm Hg, while others received normotensive CEI at 20 mm Hg. ONH RNA was harvested at 0 hours and 1, 2, 3, 7, and 10 days after either CEI and from naïve animals.

Paternal Borderline Symptoms and Offspring Outcomes in Young Adulthood.

Borderline personality disorder symptoms (BPDsx) in mothers have been linked to psychopathology in their offspring. However, it is still unclear whether BPDsx in fathers influences offspring psychopathology and, if so, how this risk transmission may occur. A total of 448 father-mother-offspring triads completed a longitudinal study following children from birth until age 20 and included self-report questionnaires and clinical interviews when children were 15 and 20 years old.

Early Optic Nerve Head Glial Proliferation and Jak-Stat Pathway Activation in Chronic Experimental Glaucoma.

Purpose: We previously reported increased expression of cell proliferation and Jak-Stat pathway-related genes in chronic experimental glaucoma model optic nerve heads (ONH) with early, mild injury. Here, we confirm these observations by localizing, identifying, and quantifying ONH cellular proliferation and Jak-Stat pathway activation in this model.

Methods: Chronic intraocular pressure (IOP) elevation was achieved via outflow pathway sclerosis.

Optic Nerve Head Astrocytes Display Axon-Dependent and -Independent Reactivity in Response to Acutely Elevated Intraocular Pressure.

Purpose: Optic nerve head (ONH) astrocytes provide support for axons, but exhibit structural and functional changes (termed reactivity) in a number of glaucoma models. The purpose of this study was to determine if ONH astrocyte structural reactivity is axon-dependent.

Methods: Using rats, we combine retrobulbar optic nerve transection (ONT) with acute controlled elevation of intraocular pressure (CEI), to induce total optic nerve axon loss and ONH astrocyte reactivity, respectively.

A Methodology for Individual-Specific Modeling of Rat Optic Nerve Head Biomechanics in Glaucoma.

Glaucoma is the leading cause of irreversible blindness and involves the death of retinal ganglion cells (RGCs). Although biomechanics likely contributes to axonal injury within the optic nerve head (ONH), leading to RGC death, the pathways by which this occurs are not well understood. While rat models of glaucoma are well-suited for mechanistic studies, the anatomy of the rat ONH is different from the human, and the resulting differences in biomechanics have not been characterized.

In Vivo Small Molecule Delivery to the Optic Nerve in a Rodent Model.

Small molecule delivery to the optic nerve would allow for exploration of molecular and cellular pathways involved in normal physiology and optic neuropathies such as glaucoma, and provide a tool for screening therapeutics in animal models. We report a novel surgical method for small molecule drug delivery to the optic nerve head (ONH) in a rodent model. In proof-of-principle experiments, we delivered cytochalasin D (Cyt D; a filamentous actin inhibitor) to the junction of the superior optic nerve and globe in rats to target the actin-rich astrocytic cytoskeleton of the ONH.

Utilizing RNA-Seq to Identify Differentially Expressed Genes in Glaucoma Model Tissues, Such as the Rodent Optic Nerve Head.

Understanding the cellular pathways activated by elevated intraocular pressure (IOP) is crucial for the development of more effective glaucoma treatments. Microarray studies have previously been used to identify several key gene expression changes in early and extensively injured ONH, as well as in the retina. Limitations of microarrays include that they can only be used to detect transcripts that correspond to existing genomic sequencing information and their narrower dynamic range.

Investigation of MicroRNA Expression in Experimental Glaucoma.

MicroRNAs are small, endogenous noncoding RNAs that modulate post-transcriptional gene expression. Recent evidence suggests that they may have a potential role in the regulation of the complex biological responses that develop in response to elevated intraocular pressure. However, contemporary microRNA assay techniques (e.

Hypertonic Saline Injection Model of Experimental Glaucoma in Rats.

A reliable method of creating chronic elevation of intraocular pressure (IOP) in rodents is an important tool in reproducing and studying the mechanisms of optic nerve injury that occur in glaucoma. In addition, such a model could provide a valuable method for testing potential neuroprotective treatments. This paper outlines the basic methods for producing obstruction of aqueous humor outflow and IOP elevation by injecting hypertonic saline (a sclerosant) into the aqueous outflow pathway.

The effect of age on the response of retinal capillary filling to changes in intraocular pressure measured by optical coherence tomography angiography.

Purpose: To compare the effect of elevated intraocular pressure (IOP) on retinal capillary filling in elderly vs adult rats using optical coherence tomography angiography (OCTA).

Methods: The IOP of elderly (24-month-old, N=12) and adult (6-8month-old, N=10) Brown Norway rats was elevated in 10mmHg increments from 10 to 100mmHg. At each IOP level, 3D OCT data were captured using an optical microangiography (OMAG) scanning protocol and then post-processed to obtain both structural and vascular images.

Comparison of MicroRNA Expression in Aqueous Humor of Normal and Primary Open-Angle Glaucoma Patients Using PCR Arrays: A Pilot Study.

Purpose: MicroRNAs (miRNAs) are small, endogenous noncoding RNAs that have been detected in human aqueous humor (AH). Prior studies have pooled samples to obtain sufficient quantities for analysis or used next-generation sequencing. Here, we used PCR arrays with preamplification to identify and compare miRNAs from individual AH samples between patients with primary open-angle glaucoma (POAG) and normal controls.

A Period of Controlled Elevation of IOP (CEI) Produces the Specific Gene Expression Responses and Focal Injury Pattern of Experimental Rat Glaucoma.

Purpose: We determine if several hours of controlled elevation of IOP (CEI) will produce the optic nerve head (ONH) gene expression changes and optic nerve (ON) damage pattern associated with early experimental glaucoma in rats.

Methods: The anterior chambers of anesthetized rats were cannulated and connected to a reservoir to elevate IOP. Physiologic parameters were monitored.

Astrocyte Structural and Molecular Response to Elevated Intraocular Pressure Occurs Rapidly and Precedes Axonal Tubulin Rearrangement within the Optic Nerve Head in a Rat Model.

Glaucomatous axon injury occurs at the level of the optic nerve head (ONH) in response to uncontrolled intraocular pressure (IOP). The temporal response of ONH astrocytes (glial cells responsible for axonal support) to elevated IOP remains unknown. Here, we evaluate the response of actin-based astrocyte extensions and integrin-based signaling within the ONH to 8 hours of IOP elevation in a rat model.

A Case Review: In-Flight Births Over a 4-Year Period in the Northern Territory, Australia.

Objective: There has been much newspaper and online news coverage of in-flight obstetric births on commercial aircraft over several decades. This case series reviews several cases of in-flight birth and immediate maternal and neonatal outcomes from air medical retrievals in the Northern Territory of Australia over a 4-year [corrected] period.

Methods: This is a retrospective written case note and electronic medical retrieval record analysis of 4 patients undergoing in-flight, at altitude, obstetric birth.

MicroRNA Expression in the Glaucomatous Retina.

Purpose: MicroRNAs are small, endogenous noncoding RNAs that modulate posttranscriptional gene expression. Although the contribution of microRNAs to the pathogenesis of glaucomatous damage is unknown, supporting evidence from central nervous system (CNS) research suggests they may play a role. It was therefore hypothesized that microRNAs known to be altered in CNS injury are also altered in experimental glaucoma.

Expansions of the neurovascular scleral canal and contained optic nerve occur early in the hypertonic saline rat experimental glaucoma model.

Purpose: To characterize early optic nerve head (ONH) structural change in rat experimental glaucoma (EG).

Methods: Unilateral intraocular pressure (IOP) elevation was induced in Brown Norway rats by hypertonic saline injection into the episcleral veins and animals were sacrificed 4 weeks later by perfusion fixation. Optic nerve cross-sections were graded from 1 (normal) to 5 (extensive injury) by 5 masked observers.

Evaluation of the effect of elevated intraocular pressure and reduced ocular perfusion pressure on retinal capillary bed filling and total retinal blood flow in rats by OMAG/OCT.

Purpose: To determine if retinal capillary filling is preserved in the face of acutely elevated intraocular pressure (IOP) in anesthetized rats, despite a reduction in total retinal blood flow (RBF), using optical microangiography/optical coherence tomography (OMAG/OCT).

Methods: OMAG provided the capability of depth-resolved imaging of the retinal microvasculature down to the capillary level. Doppler OCT was applied to measure the total RBF using an enface integration approach.

Rat, mouse, and primate models of chronic glaucoma show sustained elevation of extracellular ATP and altered purinergic signaling in the posterior eye.

Purpose: The cellular mechanisms linking elevated IOP with glaucomatous damage remain unresolved. Mechanical strains and short-term increases in IOP can trigger ATP release from retinal neurons and astrocytes, but the response to chronic IOP elevation is unknown. As excess extracellular ATP can increase inflammation and damage neurons, we asked if sustained IOP elevation was associated with a sustained increase in extracellular ATP in the posterior eye.

Rat optic nerve head anatomy within 3D histomorphometric reconstructions of normal control eyes.

The purpose of this study is to three-dimensionally (3D) characterize the principal macroscopic and microscopic relationships within the rat optic nerve head (ONH) and quantify them in normal control eyes. Perfusion-fixed, trephinated ONH from 8 normal control eyes of 8 Brown Norway Rats were 3D histomorphometrically reconstructed, visualized, delineated and parameterized. The rat ONH consists of 2 scleral openings, (a superior neurovascular and inferior arterial) separated by a thin connective tissue strip we have termed the "scleral sling".

Modeling glaucoma in rats by sclerosing aqueous outflow pathways to elevate intraocular pressure.

Injection of hypertonic saline via episcleral veins toward the limbus in laboratory rats can produce elevated intraocular pressure (IOP) by sclerosis of aqueous humor outflow pathways. This article describes important anatomic characteristics of the rat optic nerve head (ONH) that make it an attractive animal model for human glaucoma, along with the anatomy of rat aqueous humor outflow on which this technique is based. The injection technique itself is also described, with the aid of a supplemental movie, including necessary equipment and specific tips to acquire this skill.

Induction of autophagy in rats upon overexpression of wild-type and mutant optineurin gene.

Background: Optineurin is a gene associated with normal tension glaucoma and amyotrophic lateral sclerosis. It has been reported previously that in cultured RGC5 cells, the turnover of endogenous optineurin involves mainly the ubiquitin-proteasome pathway (UPP). When optineurin is upregulated or mutated, the UPP function is compromised as evidenced by a decreased proteasome β5 subunit (PSMB5) level and autophagy is induced for clearance of the optineurin protein.

Radiation pretreatment does not protect the rat optic nerve from elevated intraocular pressure-induced injury.

Purpose: Optic nerve injury has been found to be dramatically reduced in a genetic mouse glaucoma model following exposure to sublethal, head-only irradiation. In this study, the same radiation treatment was used prior to experimental induction of elevated intraocular pressure (IOP) to determine if radiation is neuroprotective in another glaucoma model.

Methods: Episcleral vein injection of hypertonic saline was used to elevate IOP unilaterally in two groups of rats: (1) otherwise untreated and (2) radiation pretreated, n > 25/group.