Predicting Vision Loss In Healthy Aging With Manganese-Enhanced Mri Of The Rat Eye

In healthy aging, visual function declines throughout adulthood. Age-related changes in neuronal ion homeostasis -- specifically, increased Ca2+ influx through L-type voltage gated calcium channels (L-VGCCs) -- are believed to contribute to certain functional declines, but this possibility has not yet been tested in the neural retina. In young, mid- and old adult Long-Evans rats, we compared visual function (optokinetic tracking), as well as retinal physiology and eye morphology (Mn2+-enhanced MRI (MEMRI), which uses neuronal Mn2+ uptake as a marker of Ca2+ influx). We documented significant age-related decreases in visual performance and increases in retinal ion influx. We confirmed that Mn2+ uptake was regulated by L-VGCC using systemic and topical application of the L-VGCC antagonist nifedipine, and discovered an age-related change in sensitivity to L-VGCC blocker diltiazem. Based on Western blot studies, we find this sensitivity change to be consistent with the age-dependant appearance of drug-insensitive L-VGCC isoforms. Longitudinally, rats starting the study with relatively high retinal Mn2+ uptake, compared to other cohort members, experienced significantly greater declines in contrast sensitivity in the ~4.5 mo following MRI. Independent of that relationship, rats starting the study with relatively large eyes experienced significantly greater declines in contrast sensitivity. The latter finding suggests that particularly rapid juvenile or young-adult growth is a risk factor for particularly rapid senescence. Longitudinally, we found no evidence of retinal volume loss, and found that changes in retinal volume were not correlated with changes in visual function -- suggesting that age-related vision declines cannot be explained by neuron loss. In summary, our longitudinal studies identify two previously-unknown risk factors for age-related vision declines: rapid eye growth in early life, and age-related changes in L-VGCC-dependent retinal ion physiology

Carbogaseous spring waters, coldwater geysers and dry CO2 exhalations in the tectonic window of the Lower Engadine Valley, Switzerland

Abstract.: In the region of Scuol-Tarasp in the Lower Engadine Valley in the Eastern Swiss Alps, there are a variety of phenomena related to a geogenetic CO2 production, including carbogaseous mineral springs, previously active coldwater geysers and dry gas exhalations from the ground via mofettes. Previous isotopic studies revealed that the CO2 originates from the metamorphic decomposition of carbonate rocks in the crust. This paper presents an inventory of the springs, geysers and mofettes, and proposes a conceptual model on the regional gas and water circulation. Based on hydrochemical criteria, it was possible to identify six main groups of spring waters, three of which are carbogaseous mineral springs. Most of the carbogaseous springs and gas exhalations are bound to the Bündnerschiefer fractured aquifer. The different water types originate from mixing of groundwater and highly mineralised carbogaseous fluids from depth. Near-surface degassing of CO2 from the fluid phase creates the dry gas exhalations. CO2 and radon measurements in 178 soil boreholes suggest that the gas exhalations occur at a limited number of point-like anomalies, and there is no evidence for regionally important diffuse CO2 discharges from the groun

Refractive Development in the “ROP Rat”

Although retinopathy of prematurity (ROP) is clinically characterized by abnormal retinal vessels at the posterior pole of the eye, it is also commonly characterized by vascular abnormalities in the anterior segment, visual dysfunction which is based in retinal dysfunction, and, most commonly of all, arrested eye growth and high refractive error, particularly (and paradoxically) myopia. The oxygen-induced retinopathy rat model of ROP presents neurovascular outcomes similar to the human disease, although it is not yet known if the “ROP rat” also models the small-eyed myopia characteristic of ROP. In this study, magnetic resonance images (MRIs) of albino (Sprague-Dawley) and pigmented (Long-Evans) ROP rat eyes, and age- and strain-matched room-air-reared (RAR) controls, were examined. The positions and curvatures of the various optical media were measured and the refractive state (℞) of each eye estimated based on a previously published model. Even in adulthood (postnatal day 50), Sprague-Dawley and Long-Evans ROP rats were significantly myopic compared to strain-matched controls. The myopia in the Long-Evans ROP rats was more severe than in the Sprague-Dawley ROP rats, which also had significantly shorter axial lengths. These data reveal the ROP rat to be a novel and potentially informative approach to investigating physiological mechanisms in myopia in general and the myopia peculiar to ROP in particular

Swiss Marketing Leadership Studie 2016 : digitale Transformation im Marketing

Die meisten Schweizer Unternehmen haben verstanden, dass die Digitale Transformation das Marketing grundlegend verändert. Doch vielerorts fehlt es an strategischer Verankerung, Systematik und Ressourcen. Das Institut für Marketing Management der ZHAW School of Management hat am 8. September im Rahmen des Swiss CRM Forum seine diesjährige Swiss Marketing Leadership Studie vorgestellt. Die Befragung von 646 Schweizer Unternehmen zeigt, dass hierzulande ein grundlegendes Verständnis für die Veränderungen im Marketing vorhanden ist, welche die Digitale Transformation mit sich bringt. Allerdings befinden sich viele Unternehmen noch am Anfang des Transformationsprozesses. Auch nicht alle Unternehmen sehen die Entwicklung vornehmlich als Chance. Bisweilen fürchtet man eine Bedrohung des Status quo. Insgesamt zeigt sich, dass hierzulande noch viele Herausforderungen zu meistern sind, will man weiterhin im internationalen Wettbewerb mithalten können.­­ Kundenbeziehungsmanagement als Treiber: Bei B2C-Unternehmen geniesst die Digitale Transformation einen signifikant höheren Stellenwert als im B2B-Bereich. Insbesondere das Kundenbeziehungsmanagement gilt vielerorts als Katalysator der Entwicklung. Weniger ausgeprägt ist das Verständnis für den Wandel hingegen im Produktmanagement, wo entsprechende Methoden und Tools noch eine untergeordnete Rolle spielen. Zudem zeigt sich, dass kaum ein Unternehmen bisher ein ganzheitliches, toolbasiertes Product-Lifecycle-Management betreibt. Fachleute verzweifelt gesucht: Gemäss Studie planen Schweizer Unternehmen mehr denn je, in das Kundenbeziehungsmanagement zu investieren. Allerdings zeigen sich dabei grosse Unterschiede: Je reifer das Unternehmen bezüglich Digitalisierung, desto grösser die Bereitschaft für Investitionen. Ausserdem gibt es grosse branchenspezifische Unterschiede. Trotz teilweise reger Aktivität fehlt es jedoch an strategischer Verankerung, Systematik und vor allem Ressourcen. Entsprechende Budgets sind zwar vielerorts vorhanden, doch die Rekrutierung geeigneter Mitarbeitenden stellt eine grosse Herausforderung dar. Die Studie wurde in Zusammenarbeit mit zahlreichen Partnern aus der Privatwirtschaft realisiert

Unexpected spatial distribution of bubble rearrangements in coarsening foams

Foams are ideal model systems to study stress-driven dynamics, as stress-imbalances within the system are continuously generated by the coarsening process, which unlike thermal fluctuations, can be conveniently quantified by optical means. However, the high turbidity of foams generally hinders the detailed study of the temporal and spatial distribution of rearrangement events, such that definite assessments regarding their contribution to the overall dynamics could not be made so far. In this paper, we use novel light scattering techniques to measure the frequency and position of events within a large sample volume. As recently reported (A. S. Gittings and D. J. Durian, Phys. Rev. E, 2008, 78, 066313), we find that the foam dynamics is determined by two distinct processes: intermittent bubble rearrangements of finite duration and a spatially homogeneous quasicontinuous process. Our experiments show that the convolution of these two processes determines the age-dependence of the mean dynamics, such that relations between intermittent rearrangements and coarsening process can not be established by considering means. By contrast the use of the recently introduced photon correlation imaging technique (A. Duri, D. A. Sessoms, V. Trappe, and L. Cipelletti, Phys. Rev. Lett., 2009, 102, 085702) enables us to assess that the event frequency is directly determined by the strain-rate imposed by the coarsening process. Surprisingly, we also find that, although the distribution of successive events in time is consistent with a random process, the spatial distribution of successive events is not random: rearrangements are more likely to occur within a recently rearranged zone. This implies that a topological rearrangement is likely to lead to an unstable configuration, such that a small amount of coarsening-induced strain is sufficient to trigger another event

Quantitative mapping of ion channel regulation by visual cycle activity in rodent photoreceptors in

PURPOSE. To test the hypothesis that the extent of outer retina uptake of manganese, measured noninvasively with manganese-enhanced MRI (MEMRI), is a quantitative biomarker of photoreceptor ion channel regulation by visual cycle activity. METHODS. Four groups of animals were studied: control rats adapted to three different background light intensities, darkadapted control mice systemically pretreated with retinylamine, and dark-adapted mice with a nonsense mutation in exon 3 of the RPE65 gene (RPE65 rd12 ) with and without systemic 11-cis-retinal pretreatment. In all cases, rodents were anesthetized and studied with MEMRI 4 hours after manganese administration IP. Central retinal thickness and intraretinal ion channel regulation were measured from the MEMRI data. RESULT. No differences (P Ͼ 0.05) in retinal thickness were noted within any arm of this study. In rats, manganese uptake was inversely proportional to the background light intensity in the outer retina but not in the inner retina. Specific inhibition at the level of RPE65 activity, either acutely with retinylamine or chronically in RPE65 rd12 mice, similarly reduced (P Ͻ 0.05) outer retinal manganese uptake compared with that in control mice. In RPE65 rd12 mice, outer retinal manganese uptake returned to normal (P Ͼ 0.05) after 11-cis retinal treatment. Inner retinal uptake was supernormal (P Ͻ 0.05) in retinylaminetreated mice but normal in untreated or 11-cis treated RPE65 rd12 mice. CONCLUSIONS. The present data support measuring the extent of manganese uptake in the outer retina as an analytic noninvasive metric of visual cycle regulation of photoreceptor ion channel activity in vivo. (Invest Ophthalmol Vis Sci. 2009;50: 188050: -188550: ) DOI:10.116750: /iovs.08-2958 N ormal vision involves conversion of photons to electrical activity in the retina. In rod photoreceptors, this process starts when light interacts with rhodopsin (which consists of opsin and covalently bound 11-cis-retinal) to produce a cis-totrans isomerization. Through a series of signal transduction steps, this isomerization causes cyclic guanosine monophosphate (cGMP)-gated ion channels in rods, which are maximally opened in the dark, to close in a graded fashion depending on the light intensity. 1,2 Rhodopsin and 11-cis-retinal are regenerated via the visual cycle to produce fresh rhodopsin. A key step in the visual cycle involves retinal pigment epitheliumspecific protein 65 kDa (RPE65), an isomerase that converts all-trans retinol back to 11-cis-retinal. 3 Prolonged impairment of the visual cycle resulting in inhibited 11-cis-retinal production-for example, by long-term inhibition of RPE65 activitycan produce persistent build-up of unbound opsin to concentrations high enough to induce chronic channel closure, which is linked with photoreceptor degeneration. 4 New pharmaceutical and gene therapies are being developed to address abnormal visual cycle activity and associated retinal degeneration. As these treatment options enter clinical trials, there is a need for noninvasive metrics of abnormal visual cycle activity in focal retinal regions (to identify which locations are most likely to benefit from treatment intervention before overt retinal thinning is evident), and, after different dosage schedules and concentrations of treatments for visual cycle abnormalities, can prognostically measure local rescue efficacy in emerging retinopathy. 5 Currently, the electroretinogram (ERG) and optical coherence tomography (OCT) have been essential in documenting overall progression and treatment response for retinal dystrophy. Manganese-enhanced MRI (MEMRI) is a noninvasive method that allows for simultaneous measurement of regional retinal uptake of manganese ion (Mn 2ϩ , a strong MRI contrast agent and biomarker for regulation of ions such as calcium) colocalized with retinal thickness, after systemic injection of a modest and nontoxic amount of MnCl 2 . 6 -8 We have found that MEMRI is sensitive to the state of cGMP-gated channels, since significantly more manganese was taken up in the outer retina in dark-adapted rodents relative to that in light adapted rodents. In this study we tested the hypothesis that the extent of outer retina uptake of manganese is a quantitative biomarker of photoreceptor ion channel regulation by visual cycle activity. At intermediate light intensities, photoreceptors respond to background light levels with a proportionate closure of the ion cation channels. 1 It is not yet known if such a graded response is reflected in the extent of outer retinal manganese uptake in rodents. We also examined the sensitivity of MEMRI to specific inhibition of the visual cycle at the level of RPE65 that subsequently reduces 11-cis-retinal production, which is expected to result in a buildup of unbound opsin and closure of photoreceptor ion channels. 4,9,10 MEMRI was used to study darkadapted control mice and mice systemically pretreated with retinylamine. 9 A single application of retinylamine produces a long-lasting but impermanent inhibition of 11-cis-retinal production without associated retinal degeneration. 10,11 METHODS The animals were treated in accordance with the NIH Guide for the Care and Use of Laboratory Animals and the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research. In all cases, rats or mice were housed and maintained in a normal 12 hour/12 hour light/dark cycle. The day before the MRI experiment, rodents were placed and maintained in total darkness overnight. All procedures (e.g., weighing animals, injecting MnCl 2 , anesthesia for MRI, and MRI examination) were performed in dim red light, darkness, or the light level being studied. MnCl 2 was administered as an intraperitoneal injection to awake rats (44 mg/kg) or mice (66 mg/kg), as described previously (Roberts R, et al. IOVS 2008;43:ARVO E-Abstract 4926). 7,8 Different doses were necessary, since, in a preliminary study, the 44-mg/kg dose of MnCl 2 did not produce reliable contrast changes in the mouse retina (data not shown), possibly due to the relatively higher overall metabolic rate in the mouse. Instead, it was found empirically that a somewhat higher dose of manganese (66 mg/kg) produced more robust retinal contrast changes. In all cases, rodents were maintained awake in dark conditions for another 3.5 hours, anesthetized, and imaged (MEMRI study). Experimental Arms Light/Dark. Male albino control Sprague-Dawley (SD) rats (204 -276 g; mean age, 46 days) were examined with MEMRI after exposure to the following light intensities: 1.8 Ϯ 0.7 (n ϭ 10, mean Ϯ SEM), 51.3 Ϯ 11.7 (n ϭ 5), and 250.2 Ϯ 19.3 (n ϭ 6) lux. Light meter (traceable dual-range light meter; Control Co., Friendswood, TX) values were multiplied by 0.91 to correct fluorescent light values to the tungsten light calibration values. The intermediate light levels were produced by positioning the cage different distances from a 25-W fluorescent light bulb. Every hour after manganese administration, intensity readings were obtained at the brightest and dimmest portions of the cage and averaged; mean readings over the 4-hour time course (before the MEMRI experiment) were then averaged. Retinylamine. Two groups were studied in this arm of the study: noninjected C57BL/6 mice (n ϭ 8 males; 28 -33 g; mean age, 184 days) and C57BL/6 mice (n ϭ 6 males; 27-32 g; mean age, 184 days) treated with retinylamine (kind gift of Martin Golczak and Krzysztof Palczewski, Case Western Reserve University, Cleveland, OH). 9 For each treated mouse, retinylamine (0.5 mg) was dissolved in DMSO (100 L) and injected intraperitoneally. The next day, treated mice were briefly anesthetized with ether. Their eyes were dilated with 1 drop of atropine and they were allowed to fully wake up. They were then positioned close to laboratory lights (300 lux) for 4 hours to ensure the remaining rhodopsin levels were bleached. In all cases, the mice were dark adapted overnight, during the injection, and MEMRI examination. These two groups had similar extraocular muscle signal intensities (as reported in the results section) implying similar whole body handling of manganese (i.e., no DMSO effect). RPE65 rd12 . In this arm of the study, the following groups were examined with MEMRI: noninjected C57BL/6 mice (n ϭ 4 males; 26 -29 g; mean age, 90 days) and noninjected RPE65 rd12 on a C57BL/6 background (n ϭ 4 males; 16 -20 g; mean age, 35 days; Jackson Laboratories, Bar Harbor, ME). 11 Note that the 11-cis-retinal formulation and administration used in this study killed three other RPE65 rd12 mice and impaired systemic handling of manganese in three surviving RPE65 rd12 mice that required correction (vide infra). In all cases, the mice were dark adapted overnight, during the injection, and during the MEMRI examination. Note that C57BL/6 mice have the methionine amino acid at codon 450 of the RPE65 gene. 12 Manganese-Enhanced MRI. Immediately before the MRI experiment, each animal was anesthetized with urethane (36% solution, IP 0.083 mL/20 g animal weight, prepared fresh daily; Aldrich, Milwaukee, WI). In addition, some mice received an injection of xylazine (1-8 mg/kg, IP). In mice, urethane was found to increase respiratory frequency and thus motion artifacts on MEMRI. The addition of a small amount of the muscle relaxant xylazine helped to minimize these artifacts. To maintain the core temperature, a recirculating heated water blanket was used. Rectal temperatures were continuously monitored throughout each experiment, as previously described. 13 MRI data were acquired on a 4.7-T system (Avance; Bruker AXS, Madison, WI) using a two-turn transmit/receive surface coil (1.0 cm diameter) placed over the eye. Images were acquired with an adiabatic spin-echo imaging sequence (repetition time [TR] 14 A single transverse slice through the center of the eye (based on sagittal localizer images collected using the same adiabatic pulse sequence as just described) was obtained for each animal. Data Analysis Retinal Thickness. Whole retinal thicknesses were determined from each MEMRI-generated image as the radial distance between the anterior edge and the posterior edge of the retina at distances Ϯ 0.4 to 1 mm from the optic nerve. Layer-Specific Signal Intensity. Within each group, individual linearized retinas were averaged into a composite image and used for visual comparison purposes only. For quantitative analysis, signal intensities were analyzed using the program NIH IMAGE (developed by Wayne Rasband, National Institutes of Health, Bethesda, MD; available at http://rsb.info.nih.gov/ij/ index.html) and derived macros. Downloaded from iovs.arvojournals.org on 06/29/2019 tive of the inner and outer retina, respectively, and were analyzed as previously described. Statistical Analysis The retinal thicknesses were consistent with a normal distribution, and comparisons between groups were performed by unpaired two-tailed t-test. Comparison of retinal signal intensities and Mn 2ϩ ion enhancements were performed in a generalized estimating equation approach. RESULTS Background Light Intensit