Retinal Architecture in ​\u3cem\u3eRGS9-\u3c/em\u3e and ​\u3cem\u3eR9AP\u3c/em\u3e-Associated Retinal Dysfunction (Bradyopsia)

Purpose To characterize photoreceptor structure and mosaic integrity in subjects with RGS9- and R9AP-associated retinal dysfunction (bradyopsia) and compare to previous observations in other cone dysfunction disorders such as oligocone trichromacy. Design Observational case series. Methods setting: Moorfields Eye Hospital (United Kingdom) and Medical College Wisconsin (USA). study population: Six eyes of 3 subjects with disease-causing variants in RGS9 or R9AP. main outcome measures: Detailed retinal imaging using spectral-domain optical coherence tomography and confocal adaptive-optics scanning light ophthalmoscopy. Results Cone density at 100 μm from foveal center ranged from 123 132 cones/mm2to 140 013 cones/mm2. Cone density ranged from 30 573 to 34 876 cones/mm2 by 600 μm from center and from 15 987 to 16,253 cones/mm2 by 1400 μm from center, in keeping with data from normal subjects. Adaptive-optics imaging identified a small, focal hyporeflective lesion at the foveal center in both eyes of the subject with RGS9-associated disease, corresponding to a discrete outer retinal defect also observed on spectral-domain optical coherence tomography; however, the photoreceptor mosaic remained intact at all other observed eccentricities. Conclusions Bradyopsia and oligocone trichromacy share common clinical symptoms and cannot be discerned on standard clinical findings alone. Adaptive-optics imaging previously demonstrated a sparse mosaic of normal wave-guiding cones remaining at the fovea, with no visible structure outside the central fovea in oligocone trichromacy. In contrast, the subjects presented in this study with molecularly confirmed bradyopsia had a relatively intact and structurally normal photoreceptor mosaic, allowing the distinction between these disorders based on the cellular phenotype and suggesting different pathomechanisms

Prognostication in Stargardt disease using Fundus Autofluorescence: Improving Patient Care

PURPOSE: To explore fundus autofluorescence (FAF) imaging as an alternative to electroretinogram (ERG), as a non-invasive, quick, and readily interpretable method to predict disease progression in Stargardt disease (STGD). DESIGN: Retrospective case series of patients who attended Moorfields Eye Hospital (London, UK). SUBJECTS: Patients with STGD who met the following criteria were included: (i) biallelic disease-causing variants in ABCA4, (ii) ERG testing performed inhouse with an unequivocal ERG group classification, and (iii) ultra-widefield (UWF) FAF imaging performed up to 2 years before or after the ERG. METHODS: Patients were divided into three ERG groups based on retinal function and three FAF groups according to the extent of the hypoautofluorescence and their retinal background appearance. FAF imaging of 30 and 55° were also subsequently reviewed. MAIN OUTCOME MEASURES: ERG/FAF concordance and its association with baseline visual acuity and genetics. RESULTS: 234 patients were included in the cohort. 170 patients (73%) had the same ERG and FAF group, 33 (14%) had a milder FAF than ERG group, and 31 (13%) had a more severe FAF than ERG group. Children under the age of 10 (n=23) had the lowest ERG/FAF concordance, 57% (9 out of the 10 with discordant ERG/FAF had milder FAF than ERG), and adults with adult onset had the highest (80%). Missense genotypes were more commonly seen in the mildest phenotypes. In 97% and 98% of the cases, respectively, 30° and 55° FAF imaging matched with the group defined by UWF FAF. CONCLUSIONS: We demonstrate that FAF imaging is an effective modality to determine the extent of retinal involvement and thereby inform prognostication, by comparing FAF to the current gold standard of ERG testing to determine retinal involvement and thereby prognosis. In 80% of patients in our large molecularly proven cohort we were able to predict if the disease was confined to the macula or also affected the peripheral retina. Children assessed at a young age, with at least one null variant, early disease onset, and/or poor initial VA may have wider retinal involvement than predicted by FAF alone and/or progress to a more severe FAF phenotype over time

Soil biocrusts affect metabolic response to hydration on dunes in west Queensland, Australia

Soil biocrusts, formed from communities of microbes and their extracellular products are a common feature of dryland soil surfaces. Biocrust organisms are only intermittently metabolically active, but due to their ubiquity they make a significant contribution to the carbon cycle. Quantification of the controls and insights into the interlinked process of photosynthesis and respiration are essential to enhancing our understanding of the carbon cycle in the world’s drylands. Yet, there have been relatively few field studies investigating controls on both biocrust photosynthesis and respiration. We undertook field-based experiments at two dune sites during the dry season in Diamantina National Park in Queensland, Australia to determine how biocrust hydration and illumination affect soil CO2 flux and photosynthesis. Static chambers and an infra-red gas analyser were used to quantify soil CO2 flux, and a fluorometer and a CFImager were used to determine a range of photosynthetic parameters in the field and laboratory respectively. When dry, biocrust photosynthetic activity was not detected and soil CO2 flux was very low irrespective of biocrust cover. Hydration led to a large and immediate increase in CO2 flux, which was more pronounced in the presence of biocrusts and on the dune with thinner biocrusts. Hydration also initiated the onset of photosynthesis in some biocrusts, which was greatest under low light conditions and sustained with further hydration. There were only infrequent periods of net CO2 uptake to the soil, occurring when CO2 uptake due to photosynthetic activity was less than background soil CO2 flux. Chlorophyll fluorescence imaging indicated biocrust spatial heterogeneity was evident at the cm scale where microtopography creates a myriad of environments for different crust organisms. Our findings demonstrate that biocrusts are highly spatially heterogenetic at both landscape and small scale, which suggests the maintenance of biocrust spatial diversity is likely to be key to imparting resilience to changing climate and disturbance. As well as reaffirming the importance of biocrusts for the carbon cycle in dryland dune soils the study demonstrates that biocrust respiration and photosynthesis respond differently to hydration and shading. This adds an unpredictability to the distribution of soil carbon stocks and the gaseous exchanges of CO2 between the surface and atmosphere. Future changes to precipitation and increased temperatures are likely to reduce soil moisture across much of the Australian interior and consequently biocrusts may experience a decline in biomass, structure, and function which could have significant repercussions beyond carbon stocks.Natural Environment Research Counci

Rescue of the MERTK phagocytic defect in a human iPSC disease model using translational read-through inducing drugs.

Inherited retinal dystrophies are an important cause of blindness, for which currently there are no effective treatments. In order to study this heterogeneous group of diseases, adequate disease models are required in order to better understand pathology and to test potential therapies. Induced pluripotent stem cells offer a new way to recapitulate patient specific diseases in vitro, providing an almost limitless amount of material to study. We used fibroblast-derived induced pluripotent stem cells to generate retinal pigment epithelium (RPE) from an individual suffering from retinitis pigmentosa associated with biallelic variants in MERTK. MERTK has an essential role in phagocytosis, one of the major functions of the RPE. The MERTK deficiency in this individual results from a nonsense variant and so the MERTK-RPE cells were subsequently treated with two translational readthrough inducing drugs (G418 & PTC124) to investigate potential restoration of expression of the affected gene and production of a full-length protein. The data show that PTC124 was able to reinstate phagocytosis of labeled photoreceptor outer segments at a reduced, but significant level. These findings represent a confirmation of the usefulness of iPSC derived disease specific models in investigating the pathogenesis and screening potential treatments for these rare blinding disorders

Cognitive and disease-modifying effects of 11ß-hydroxysteroid dehydrogenase type 1 inhibition in male Tg2576 mice, a model of Alzheimer's disease

Chronic exposure to elevated levels of glucocorticoids has been linked to age-related cognitive decline and may play a role in Alzheimer's disease. In the brain, 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) amplifies intracellular glucocorticoid levels. We show that short-term treatment of aged, cognitively impaired C57BL/6 mice with the potent and selective 11β-HSD1 inhibitor UE2316 improves memory, including after intracerebroventricular drug administration to the central nervous system alone. In the Tg2576 mouse model of Alzheimer's disease, UE2316 treatment of mice aged 14 months for 4 weeks also decreased the number of β-amyloid (Aβ) plaques in the cerebral cortex, associated with a selective increase in local insulin-degrading enzyme (involved in Aβ breakdown and known to be glucocorticoid regulated). Chronic treatment of young Tg2576 mice with UE2316 for up to 13 months prevented cognitive decline but did not prevent Aβ plaque formation. We conclude that reducing glucocorticoid regeneration in the brain improves cognition independently of reduced Aβ plaque pathology and that 11β-HSD1 inhibitors have potential as cognitive enhancers in age-associated memory impairment and Alzheimer's dementia

Assessing Retinal Structure In Complete Congenital Stationary Night Blindness and Oguchi Disease

Purpose To examine retinal structure and changes in photoreceptor intensity after dark adaptation in patients with complete congenital stationary night blindness and Oguchi disease. Design Prospective, observational case series. Methods We recruited 3 patients with complete congenital stationary night blindness caused by mutations in GRM6, 2 brothers with Oguchi disease caused by mutations in GRK1, and 1 normal control. Retinal thickness was measured from optical coherence tomography images. Integrity of the rod and cone mosaic was assessed using adaptive optics scanning light ophthalmoscopy. We imaged 5 of the patients after a period of dark adaptation and examined layer reflectivity on optical coherence tomography in a patient with Oguchi disease under light- and dark-adapted conditions. Results Retinal thickness was reduced in the parafoveal region in patients with GRM6 mutations as a result of decreased thickness of the inner retinal layers. All patients had normal photoreceptor density at all locations analyzed. On removal from dark adaptation, the intensity of the rods (but not cones) in the patients with Oguchi disease gradually and significantly increased. In 1 Oguchi disease patient, the outer segment layer contrast on optical coherence tomography was 4-fold higher under dark-adapted versus light-adapted conditions. Conclusions The selective thinning of the inner retinal layers in patients with GRM6 mutations suggests either reduced bipolar or ganglion cell numbers or altered synaptic structure in the inner retina. Our finding that rods, but not cones, change intensity after dark adaptation suggests that fundus changes in Oguchi disease are the result of changes within the rods as opposed to changes at a different retinal locus

Methanogen activity and microbial diversity in Gulf of Cádiz mud volcano sediments

The Gulf of Cádiz is a tectonically active continental margin with over sixty mud volcanoes (MV) documented, some associated with active methane (CH4) seepage. However, the role of prokaryotes in influencing this CH4 release is largely unknown. In two expeditions (MSM1-3 and JC10) seven Gulf of Cádiz MVs (Porto, Bonjardim, Carlos Ribeiro, Captain Arutyunov, Darwin, Meknes, and Mercator) were analyzed for microbial diversity, geochemistry, and methanogenic activity, plus substrate amended slurries also measured potential methanogenesis and anaerobic oxidation of methane (AOM). Prokaryotic populations and activities were variable in these MV sediments reflecting the geochemical heterogeneity within and between them. There were also marked differences between many MV and their reference sites. Overall direct cell numbers below the SMTZ (0.2–0.5 mbsf) were much lower than the general global depth distribution and equivalent to cell numbers from below 100 mbsf. Methanogenesis from methyl compounds, especially methylamine, were much higher than the usually dominant substrates H2/CO2 or acetate. Also, CH4 production occurred in 50% of methylated substrate slurries and only methylotrophic CH4 production occurred at all seven MV sites. These slurries were dominated by Methanococcoides methanogens (resulting in pure cultures), and prokaryotes found in other MV sediments. AOM occurred in some slurries, particularly, those from Captain Arutyunov, Mercator and Carlos Ribeiro MVs. Archaeal diversity at MV sites showed the presence of both methanogens and ANME (Methanosarcinales, Methanococcoides, and ANME-1) related sequences, and bacterial diversity was higher than archaeal diversity, dominated by members of the Atribacterota, Chloroflexota, Pseudomonadota, Planctomycetota, Bacillota, and Ca. “Aminicenantes.” Further work is essential to determine the full contribution of Gulf of Cádiz mud volcanoes to the global methane and carbon cycles

Clinical and Epidemiologic Research Efficacy and Prognostic Factors of Response to Carbonic Anhydrase Inhibitors in Management of Cystoid Macular Edema in Retinitis Pigmentosa

Citation: Liew G, Moore AT, Webster AR, Michaelides M. Efficacy and prognostic factors of response to carbonic anhydrase inhibitors in management of cystoid macular edema in retinitis pigmentosa. Invest Ophthalmol Vis Sci. 2015;56:1531-1536. DOI:10.1167/iovs.14-15995 PURPOSE. To determine the efficacy and prognostic factors associated with carbonic anhydrase inhibitors (CAI) in the treatment of cystoid macular edema (CME) in retinitis pigmentosa (RP). METHODS. This was a cohort study of 81 subjects who were assessed before and after treatment. Spectral-domain optical coherence tomography (SD-OCT) was used to quantify CME. A reduction of at least 11% in central subfield (CSF) thickness was defined as objective evidence of response. RESULTS. In the 125 eyes that received topical dorzolamide, 40.0% demonstrated a response to treatment with a mean reduction in OCT CSF thickness of 105 lm (95% confidence interval [CI]: 82, 128). Mean starting visual acuity (VA) increased from 6/15 to 6/12 after a median time on treatment of 3.0 months. In patients prescribed oral acetazolamide, 28.1% of eyes (41.2% of patients) showed improvement in mean OCT CSF thickness of 115 lm (95% CI: 52, 177) over a median treatment interval of 4.0 months. Visual acuity improved from 6/15 to 6/ 12. Eyes that responded to topical dorzolamide were more likely to have autosomal recessive than autosomal dominant RP (44.6% vs. 23.3%, P ¼ 0.02), and a higher mean baseline OCT CSF than eyes that did not respond (P ¼ 0.02). CONCLUSIONS. We report that 40.0% of eyes (53.1% of patients) showed an objective improvement in CME after treatment with topical dorzolamide and 28.1% of eyes (41.2% of patients) after treatment with oral acetazolamide. Autosomal recessive RP and greater initial central retinal thickness predicted response to treatment with topical dorzolamide