Physiology and Pharmacology Episcleral Venous Pressure and IOP Responses to Central Electrical Stimulation in the Rat

PURPOSE. Histological evidence suggests a role for the central nervous system in controlling episcleral venous pressure (EVP). Based on prior studies that identified candidate regions in the brain stem, the present study assessed the effect of electrical stimulation at the location of the superior salivatory nucleus (SSN) on EVP in rats. METHODS. Male Sprague-Dawley rats (n ¼ 11) were anesthetized using pentobarbital sodium (50 mg/kg intraperitoneally initially, supplemented intravenously [IV] as needed) and paralyzed with gallamine triethiodide (1 mg/kg, IV). The animals were artificially ventilated and the femoral artery and vein were cannulated for blood pressure measurement and drug administration. Carotid blood flow was measured with an ultrasound flow probe and heart rate with a cardiotachometer. IOP was measured through a cannula in the vitreous compartment and EVP was measured through a micropipette in episcleral veins using the servonull technique. After a craniotomy was performed, a unipolar stainless steel electrode was inserted into the brainstem at the coordinates of the SSN using a stereotactic instrument. Stimulations were performed at 20Hz, 9 lA, 1 ms pulse duration, and 200 pulses. RESULTS. Stimulation at the SSN coordinates increased IOP from 10.6 6 0.4 to 11.8 6 0.6 mm Hg (P < 0.01) and EVP from 7.8 6 1.3 to 10.7 6 1.1 mm Hg (P < 0.01). Mean arterial pressure, carotid blood flow, and heart rate remained unaltered. CONCLUSIONS. The present study indicates that the SSN may participate in regulating EVP. Keywords: episcleral venous pressure, superior salivatory nucleus, stimulation, IOP S teady-state IOP can be described by the Goldmann equation as the relationship between aqueous flow, uveoscleral outflow, outflow facility, and episcleral venous pressure (EVP). 1,2 EVP is the pressure that has to be overcome for fluid to leave the eye via the trabecular outflow pathway and, in humans under normal conditions, EVP accounts for roughly 60% of IOP. Despite its importance for IOP homeostasis, the physiology of the episcleral venous pressure is poorly understood. The current de facto standard for measuring EVP is the venomanometer described by Zeimer et al. 12 Recently, a study by Samuels et al. The brainstem, however, appears to be the first relay station for nerves supplying the eye, and, thus, the nuclei there are likely to be more specialized than higher-order centers in the diencephalon. METHODS The study was approved by the institutional animal care and use committee of the University of Texas Health Science Center at San Antonio and conducted in accordance with the ARVO guidelines for animal use in vision research. All animals were euthanized with an anesthetic overdose at the end of the experiment without regaining consciousness. Animal Preparation Male Sprague Dawley rats (n ¼ 11, 305.4 6 8.6 g) were anesthetized using pentobarbital sodium (Sigma-Aldrich, 50 mg/kg intraperitoneally, supplemented intravenously as needed). A tracheotomy was performed and the animal was respire

The HYLAN M Study: Efficacy of 0.15% High Molecular Weight Hyaluronan Fluid in the Treatment of Severe Dry Eye Disease in a Multicenter Randomized Trial

The aim of the HYLAN M study was to investigate if symptoms and/or signs of patients suffering from severe dry eye disease (DED) can be improved by substituting individually optimized artificial tear therapy by high molecular weight hyaluronan (HMWHA) eye drops. In this international, multicenter study, patients with symptoms of at least ocular surface disease index (OSDI) 33 and corneal fluorescein staining (CFS) of at least Oxford grade 3 were included. A total of 84 per-protocol patients were randomized in two study arms. The control group continued to use their individual optimum artificial tears over the study period of eight weeks; in the verum group, the artificial tears were substituted by eye drops containing 0.15% HMWHA. At the week 8 visit, the average OSDI of the verum group had improved by 13.5 as compared to the control group (p = 0.001). The best corrected visual acuity (BCVA) had improved by 0.04 logMAR (p = 0.033). CFS, tear film break-up time (TBUT), Schirmer I, lid wiper epitheliopathy (LWE), mucocutaneous junction (Yamaguchi score), and tear osmolarity were not significantly different between the verum and control groups (p > 0.050). We conclude that for most patients with severe DED, 0.15% HMWHA eye drops provide excellent improvement of symptoms without impairment of dry eye signs

Mitochondrial Haplogroups and Control Region Polymorphisms in Age-Related Macular Degeneration: A Case-Control Study

Background: Onset and development of the multifactorial disease age-related macular degeneration (AMD) are highly interrelated with mitochondrial functions such as energy production and free radical turnover. Mitochondrial dysfunction and overproduction of reactive oxygen species may contribute to destruction of the retinal pigment epithelium, retinal atrophy and choroidal neovascularization, leading to AMD. Consequently, polymorphisms of the mitochondrial genome (mtDNA) are postulated to be susceptibility factors for this disease. Previous studies from Australia and the United States detected associations of mitochondrial haplogroups with AMD. The aim of the present study was to test these associations in Middle European Caucasians. Methodology/Principal Findings: Mitochondrial haplogroups (combinations of mtDNA polymorphisms) and mitochondrial CR polymorphisms were analyzed in 200 patients with wet AMD (choroidal neovascularization, CNV), in 66 patients with dry AMD, and in 385 controls from Austria by means of multiplex primer extension analysis and sequencing, respectively. In patients with CNV, haplogroup H was found to be significantly less frequent compared to controls, and haplogroup J showed a trend toward a higher frequency compared to controls. Five CR polymorphisms were found to differ significantly in the two study populations compared to controls, and all, except one (T152C), are linked to those haplogroups. Conclusions/Significance: It can be concluded that haplogroup J is a risk factor for AMD, whereas haplogroup H seems t

A rabbit model to study orbital venous pressure, intraocular pressure, and ocular hemodynamics simultaneously

PURPOSE. To measure orbital venous pressure (OVP) and determine the effects of changes in mean arterial pressure (MAP) on OVP, intraocular pressure (IOP), episcleral venous pressure (EVP), and ciliary and choroidal blood flows. METHODS. The experiments were performed in anesthetized rabbits. In all animals, MAP, IOP, and OVP were measured by direct cannulation of the central ear artery, the vitreous, and the orbital venous sinus, respectively. Laser Doppler flowmetry was used to measure choroidal blood flow in one group, and ciliary blood flow in a second group. A servonull micropressure system was used to measure EVP in a third group. The protocol for all three groups entailed varying MAP mechanically with occluders on the aorta and vena cava. RESULTS. The OVP and IOP relationship correlated linearly (r ϭ 0.99) during mechanical manipulation of MAP. EVP also correlated well with OVP (r ϭ 0.9). Resistance calculations based on choroidal and ciliary blood flows and the pressure gradients indicate active adjustment of arterial resistance and passive changes in venous resistance in response to changing MAP in both circulations. CONCLUSIONS. The rabbit orbital venous sinus permits continuous measurements of OVP. The present findings show that OVP is not static and suggest that OVP may play an important role in IOP homeostasis and ocular hemodynamics. (Invest Ophthalmol Vis Sci. 2002;43:3728 -3734) B ecause the veins draining the eye are small or difficult to reach without disturbing the eye and orbit, measurements of venous pressure outside the eye are not performed routinely. However, as the downstream recipient of conventional aqueous outflow and the efflux of the ocular circulations, the orbital venous system's physiology is intertwined with aqueous dynamics and ocular hemodynamics. In the case of the episcleral veins, the episcleral venous pressure (EVP) is the pressure head that must be overcome for aqueous passage through the trabecular pathway, and so the EVP is acknowledged as a key determinant of steady state intraocular pressure (IOP). 1 However, although EVP is often measured in studies of drug effects on aqueous dynamics, 2 it has rarely been manipulated experimentally, aside from studies of pseudofacility. 3 In contrast to EVP and aqueous dynamics, the effects of orbital venous pressure (OVP) on ocular hemodynamics are less clear. To the best of the authors' knowledge, the only information in the literature comes from the study by Bill 4 in which the blood flow from a cannulated vortex vein was measured as the cannula pressure was varied while holding IOP constant at different levels. Otherwise, we are aware of no studies in which blood flow in an ocular circulation was measured while OVP was varied or measured. Given the paucity of information about OVP, we sought a method to measure it. We found that the rabbit's skull offers a unique opportunity to measure OVP by direct cannulation of the orbital venous sinus through the posterior supraorbital foramen. This article presents the results of continuous measurements of OVP, EVP, IOP, mean arterial pressure (MAP), and choroidal and ciliary blood flows. The relationships between these parameters obtained during mechanical manipulation of MAP over a wide range show that OVP is not static and that it may play an important role in ocular hydrodynamics. METHODS All animal procedures were approved by the Institutional Animal Care and Use Committee and conducted in accordance with the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research. At the end of the experiment, all animals were killed with an overdose of anesthetic without regaining consciousness. Animal Preparation New Zealand albino rabbits (2-3 kg, n ϭ 25) of both sexes were housed for 1 to 3 days in the vivarium with access to food and water ad libitum before the experiments. The animals were anesthetized with pentobarbital sodium (30 mg/kg, intravenously, supplemented as needed) and paralyzed with gallamine triethiodide (1 mg/kg) to eliminate eye movement. The animals were intubated through a tracheotomy and ventilated with room air. Expired PCO 2 was monitored (Normocap 200; Datex, Tewksbury, MA) and maintained at 40 to 45 mm Hg. A heating pad was used to maintain normal body temperature (38 -39°C). All intravenous injections were given through cannulas placed in the marginal ear veins. The right eye and the right orbital venous sinus were used in all experiments. To estimate the ocular arterial pressure (AP) and ensure the adequacy of anesthesia, a catheter was inserted into the right ear artery and connected to a pressure transducer positioned at the same height above the heart as the eye. After the initial surgical preparation, the animals were mounted in a stereotaxic head holder, and the right eye was cannulated with a 23-gauge needle inserted into the vitreous cavity through the pars plana to measure the IOP with a pressure transducer. To avoid the rabbit ocular trauma response 5 and release of prostaglandins, 6,7 the right eye was anesthetized topically with lidocaine before cannulation and care was taken not to disturb the cornea and anterior chamber. Measurement of OVP The orbital venous sinus covers most of the backside of the rabbit eye

Pericyte-derived cells participate in optic nerve scar formation

Introduction: Pericytes (PCs) are specialized cells located abluminal of endothelial cells on capillaries, fulfilling numerous important functions. Their potential involvement in wound healing and scar formation is achieving increasing attention since years. Thus, many studies investigated the participation of PCs following brain and spinal cord (SC) injury, however, lacking in-depth analysis of lesioned optic nerve (ON) tissue. Further, due to the lack of a unique PC marker and uniform definition of PCs, contradicting results are published.Methods: In the present study the inducible PDGFRβ-P2A-CreERT2-tdTomato lineage tracing reporter mouse was used to investigate the participation and trans-differentiation of endogenous PC-derived cells in an ON crush (ONC) injury model, analyzing five different post lesion time points up to 8 weeks post lesion.Results: PC-specific labeling of the reporter was evaluated and confirmed in the unlesioned ON of the reporter mouse. After ONC, we detected PC-derived tdTomato+ cells in the lesion, whereof the majority is not associated with vascular structures. The number of PC-derived tdTomato+ cells within the lesion increased over time, accounting for 60–90% of all PDGFRβ+ cells in the lesion. The presence of PDGFRβ+tdTomato- cells in the ON scar suggests the existence of fibrotic cell subpopulations of different origins.Discussion: Our results clearly demonstrate the presence of non-vascular associated tdTomato+ cells in the lesion core, indicating the participation of PC-derived cells in fibrotic scar formation following ONC. Thus, these PC-derived cells represent promising target cells for therapeutic treatment strategies to modulate fibrotic scar formation to improve axonal regeneration

Radius‐Maumenee syndrome: A case series with a long‐term follow‐up

Abstract The aim of the case series is to highlight the surgical challenges experienced like failed intervention, choroidal effusion, a postoperative cystoid macular oedema, and describe treatment options for Radius‐Maumenee syndrome. Authors reported on 3 bilateral cases of Radius‐Maumenee syndrome which underwent medical treatment, trabeculectomy with Mitomycin C, implantation with XEN45, Ahmed glaucoma valve, Baerveldt glaucoma implant, and cyclophotocoagulation

Mid- and Longterm Experiences with the Boston-Keratoprosthesis. The Cologne and Salzburg Perspective

Background Eyes with severe corneal opacifications and insufficient prognosis for high-risk corneal transplantation can be considered for the implantation of a Boston-keratoprosthesis. Since 2013, this technique of artificial corneal replacement is provided to high-risk eyes at the Department of Ophthalmology, University of Cologne and for 9 years at the University of Salzburg. In the meantime, a type I Boston keratoprosthesis (BI-KPro) has been implanted in 24 eyes in Cologne and in 28 eyes in Salzburg. Methods In this article, results and complications according to BI-KPro are discussed, both from the literature in PubMed, as well as from our own experiences. Results Twenty-four eyes of 22 patients had been provided with a BI-KPro since September 2013, of which only one keratoprosthesis could not be obtained thus far, and an increase in visual acuity could be achieved in 23 eyes (96%). On average, 1.5 revisions per eye were required during the postoperative course. Since 2007, a BI-KPro has been implanted in 28 eyes in Salzburg. In 62% (16 of 26 eyes), visual acuity increased postoperatively, with a complication rate of 81% in a longer follow-up period. In both cohorts, the spectrum of complications ranged from retroprosthetic membrane formation, to secondary glaucoma, to infectious keratitis with or without graft melting, to vitritis, to endophthalmitis. Conclusion The range of possible complications according to BI-KPro is broad, but the BI-KPro represents currently the most widely used form of artificial corneal replacement in high-risk eyes and leads to visual improvement in most patients

Leukotriene Signaling as a Target in α-Synucleinopathies

Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) are two common types of α-synucleinopathies and represent a high unmet medical need. Despite diverging clinical manifestations, both neurodegenerative diseases share several facets of their complex pathophysiology. Apart from α-synuclein aggregation, an impairment of mitochondrial functions, defective protein clearance systems and excessive inflammatory responses are consistently observed in the brains of PD as well as DLB patients. Leukotrienes are lipid mediators of inflammatory signaling traditionally known for their role in asthma. However, recent research advances highlight a possible contribution of leukotrienes, along with their rate-limiting synthesis enzyme 5-lipoxygenase, in the pathogenesis of central nervous system disorders. This review provides an overview of in vitro as well as in vivo studies, in summary suggesting that dysregulated leukotriene signaling is involved in the pathological processes underlying PD and DLB. In addition, we discuss how the leukotriene signaling pathway could serve as a future drug target for the therapy of PD and DLB