The Human Electro-oculogram: Interaction of Light and Alcohol

PURPOSE. To investigate the production of the voltage changes evoked in the retinal pigment epithelium (RPE) by light and alcohol and the interaction of these agents. METHODS. The eye movement potential in humans was intermittently recorded to standard horizontal excursions for long periods during which either retinal illumination was altered or ethyl alcohol was administered by the oral, intragastric, or intravenous route. In other experiments, both light and alcohol were administered. RESULTS. Alcohol and light produced near identical corneofundal voltage changes (positive and then negative) over more than 40 minutes. Differences in timing between alcohol and light increases are explicable by the delays in alcohol absorption. Weak background light suppressed the effect of light steps, and low levels of background alcohol suppressed the response to subsequent doses. Backgrounds of one agent did not affect the voltage changes caused by the other. Minimal alcohol effects were seen after administration of 1 g orally or 270 mg intravenously-that is, doses that produced undetectable changes in breath alcohol. The semisaturating oral dose was approximately 20 mg/kg. CONCLUSIONS. Alcohol and light act through separate pathways to form a final common pathway inside the RPE cell that is responsible for triggering the timing of the slow oscillatory changes of EOG voltage. The sensitivity and duration with which alcohol affects the RPE are comparable with the effect of melatonin or dopamine, although only the former interacts with light similarly to alcohol. Transient modulation of the acetylcholine (Ach) neuronal receptor occurs at similar sensitivity, but all other known actions of alcohol require higher concentrations than this RPE action. (Invest Ophthalmol Vis Sci. 2000;41:2722-2729 S ince the original descriptions of the electro-oculogram (EOG) in humans, 1-4 intraretinal microelectrode recordings 5-10 have elucidated the underlying mechanisms. Light adaptation of the retina changes the quantity of an unknown substance or substances, probably produced by photoreceptors, that diffuses to the apical processes of the retinal pigment epithelium (RPE) where it binds to membrane-bound chemical receptors. These then liberate an intracellular second messenger that ultimately depolarizes the basolateral surface of the RPE cells, causing a light-induced increase in the corneofundal potential (hereafter termed light rise), by increasing the chloride conductance. 11 The external and internal transmitters are unknown, as is the relationship between the transmitter concentration and the stereotyped voltage changes. Thus, the time course of the concentration changes of the external or the internal transmitter may determine the timing of the light rise and the subsequent oscillations. The EOG remains a useful clinical test, 12-18 because it offers an overview of the functioning of photoreceptors, subretinal space, and RPE, but because light is used to provoke the voltage changes, retinal and RPE dysfunction cannot be separated. Therefore, other agents, such as bicarbonate ions, acetazolamide, and hyperosmotic solutions, which act directly on the RPE, have been investigated. 18 -22 All have been found to cause a slow decrease in corneofundal potential. Previous experiments METHODS Subjects Three students aged 20 to 25 years and the authors (seventh decade) gave informed consent, and the experimental protocols complied with the Helsinki declaration. Recording Techniques Five-millimeter chloride-coated silver disc electrodes were placed on each temple, near the lateral canthi, and a similar earth electrode was placed on the forehead. The recording was bitemporal (i.e., the voltages were generated by both eyes). Standard 30°horizontal eye movements were made at two per From the Applie

The Electro-oculographic Responses to Alcohol and Light in a Series of Patients with Retinitis Pigmentosa

PURPOSE. Alcohol produces changes in the electro-oculogram (EOG) similar to those caused by light, but indirect evidence indicates that alcohol directly affects the retinal pigment epithelium (RPE). An investigation of the alcohol-induced increase (termed the alcohol rise in this study) in patients with disease of the photoreceptors was therefore of interest. METHODS. Standard EOGs were recorded after oral administration of alcohol in a group of patients with retinitis pigmentosa (RP). RESULTS. The average response of 17 patients to alcohol was a slow decrease of potential, which contrasts with the normal alcohol rise. In patients with considerable residual peripheral field, alcohol produced a small increase of voltage, followed by a prolonged decrease. The slower decrease in the EOG voltage was evident in patients with small fields and could be seen even in those who had lost all visual function. Light caused small increments of EOG voltage (termed light rises), again related to the field size. CONCLUSIONS. It is probable that the intracellular signaling system that causes the alcohol and light rises is lost in RP. (Invest Ophthalmol Vis Sci. 2000;41:2730 -2734 T he light-induced increase (termed light rise in this study) of the EOG is produced by the liberation of an unknown substance from the retina, which has been shown to affect second-messenger systems in the apical membrane of the RPE. 1,2 Results in a companion study 3 demonstrated that small oral doses of alcohol produce an effect on the EOG that is indistinguishable from that evoked by light, except for a delay due to the time required to absorb alcohol from the gut. The interactions between alcohol and light were investigated, and the inference from the results was that alcohol (similar to other agents) is able to alter the basolateral conductance of the RPE by a pathway that probably involves second messengers, but not the retina. 5 Because many of the photoreceptors in such retinas are nonfunctional, the failure to release a light rise substance is not surprising, and the EOG light rise is known to be greatly reduced. METHODS Seventeen patients were recruited by contacting the British Retinitis Pigmentosa Society, by letter and on its Web sites, and asking for volunteers, who were then given a written explanation of the proposed test, so they could provide informed consent. All the patients were under the care of specialist eye departments. One patient was excluded because he had bilateral cataract extraction with ocular implants. We did not accept patients under 18 years of age or those with other systemic conditions. The age range was between 22 and 74 years. The work was performed in accordance with the Declaration of Helsinki. Standard EOG recordings of 30°horizontal eye movements were made as described in a previous article, 3 except in the case of patients with very reduced vision, when the patients made extreme eye movements that were measured as 90°. The (ethyl) alcohol was administered after subjects fasted for more than 12 hours (0.3 g/kg, 20% wt/vol in water, drunk in 15 seconds). Other clinical tests (fields, electroretinograms [ERGs]) were performed in a standard fashion in patients with the best preserved vision to confirm clinical diagnoses. ERGs were elicited by equipment (a LED-powered miniganzfeld stimulus) similar to that already described

The multifocal pattern electroretinogram in glaucoma

AbstractBackground: The pattern ERG can be used to detect early glaucomatous change, because the response of cells in the inner retina from (typically) 20°–40° of area is reduced before perimetric abnormality is certain. The multifocal pattern electroretinogram (mfPERG) allows analysis of many local regions within this area. The aim of this study was to investigate whether in patients with presumed glaucoma the mfPERG permits diagnosis and discrimination from normals.Methods: Measurements on 25 age-related normal eyes were compared to those on 23 eyes with different stages of glaucoma. A RETIScan system was used to generate a stimulus pattern of 19 hexagons, each consisting of six triangles. The triangles pattern-reversed black to white at 75 Hz. Those 19 hexagons were grouped into three stimulus regions: a central field, a middle, and a peripheral ring. The complete array subtended 48° at the eye. The hexagons alternated between black and white, in a temporal pattern that followed a corrected binary m-sequence (length 512, 10 cycles with 39 s each). The amplitudes and latencies of positive responses at approximately 50 ms (P-50) and negative responses at approximately 95 ms (N-95) were analyzed.Results: In patients with glaucoma the P-50 and N-95 components of the mfPERG were significantly reduced for the central area and both outer rings compared to normal volunteers (p<0.001, Mann–Whitney-U). The most distinct reduction was observed for N-95 and the central ring. Changes in latencies were not conclusive. The reduction of the components increased with the stage of glaucoma. A predictive model for detecting early glaucomatous changes was designed based on P-50–N-95 with 88% sensitivity and 76% specificity.Conclusion: In glaucoma a marked reduction of components, especially centrally is observed in the mfPERG. This hints to an early involvement of central ganglion cells and may be useful for future functional tests

Intelligence and semen quality are positively correlated

Human cognitive abilities inter-correlate to form a positive matrix, from which a large first factor, called &apos;Spearman&apos;s g&apos; or general intelligence, can be extracted. General intelligence itself is correlated with many important health outcomes including cardio-vascular function and longevity. However, the important evolutionary question of whether intelligence is a fitnessrelated trait has not been tested directly, let alone answered. If the correlations among cognitive abilities are part of a larger matrix of positive associations among fitness-related traits, then intelligence ought to correlate with seemingly unrelated traits that affect fitness-such as semen quality. We found significant positive correlations between intelligence and 3 key indices of semen quality: log sperm concentration (r = .15, p = .002), log sperm count (r =.19, p b .001), and sperm motility (r = .14, p = .002) in a large sample of US Army Veterans. None was mediated by age, body mass index, days of sexual abstinence, service in Vietnam, or use of alcohol, tobacco, marijuana, or hard drugs. These results suggest that a phenotype-wide fitness factor may contribute to the association between intelligence and health. Clarifying whether a fitness factor exists is important theoretically for understanding the genomic architecture of fitness-related traits, and practically for understanding patterns of human physical and psychological health

Cryptographically Secure Information Flow Control on Key-Value Stores

We present Clio, an information flow control (IFC) system that transparently incorporates cryptography to enforce confidentiality and integrity policies on untrusted storage. Clio insulates developers from explicitly manipulating keys and cryptographic primitives by leveraging the policy language of the IFC system to automatically use the appropriate keys and correct cryptographic operations. We prove that Clio is secure with a novel proof technique that is based on a proof style from cryptography together with standard programming languages results. We present a prototype Clio implementation and a case study that demonstrates Clio's practicality.Comment: Full version of conference paper appearing in CCS 201

The ChromaTest, a digital color contrast sensitivity analyzer, for diabetic maculopathy: a pilot study

BACKGROUND: To assess the ability of the Chromatest in investigating diabetic maculopathy. METHOD: Patients with Type 2 diabetes and no concurrent ocular pathology or previous laser photocoagulation were recruited. Visual acuities were assessed followed by colour contrast sensitivity testing of each eye using Chromatest. Dilated fundoscopy with slit lamp biomicroscopy with 78 D lens was then performed to confirm the stage of diabetic retinopathy according to the Early Treatment Diabetic Retinopathy Study. RESULTS: 150 eyes in 150 patients were recruited into this study. 35 eyes with no previous laser photocoagulation were shown to have clinically significant macular oedema (CSMO) and 115 eyes with untreated non-proliferative diabetic retinopathy (NPDR) on fundus biomicroscopy. Statistical significant difference was found between CSMO and NPDR eyes for protan colour contrast threshold (p = 0.01). Statistical significance was found between CSMO and NPDR eyes for tritan colour contrast threshold (p = 0.0002). Sensitivity and specificity for screening of CSMO using pass-fail criterion for age matched TCCT results achieved 71% (95% confidence interval: 53-85%) and 70% (95% confidence interval: 60-78%), respectively. However, threshold levels were derived using the same data set for both training and testing the effectiveness since this was the first study of NPDR using the Chromatest CONCLUSION: The ChromaTest is a simple, cheap, easy to use, and quick test for colour contrast sensitivity. This study did not achieve results to justify use of the Chromatest for screening, but it reinforced the changes seen in tritan colour vision in diabetic retinopathy

Genetic determinants of heel bone properties: genome-wide association meta-analysis and replication in the GEFOS/GENOMOS consortium

Quantitative ultrasound of the heel captures heel bone properties that independently predict fracture risk and, with bone mineral density (BMD) assessed by X-ray (DXA), may be convenient alternatives for evaluating osteoporosis and fracture risk. We performed a meta-analysis of genome-wide association (GWA) studies to assess the genetic determinants of heel broadband ultrasound attenuation (BUA; n = 14 260), velocity of sound (VOS; n = 15 514) and BMD (n = 4566) in 13 discovery cohorts. Independent replication involved seven cohorts with GWA data (in silico n = 11 452) and new genotyping in 15 cohorts (de novo n = 24 902). In combined random effects, meta-analysis of the discovery and replication cohorts, nine single nucleotide polymorphisms (SNPs) had genome-wide significant (P < 5 × 10(-8)) associations with heel bone properties. Alongside SNPs within or near previously identified osteoporosis susceptibility genes including ESR1 (6q25.1: rs4869739, rs3020331, rs2982552), SPTBN1 (2p16.2: rs11898505), RSPO3 (6q22.33: rs7741021), WNT16 (7q31.31: rs2908007), DKK1 (10q21.1: rs7902708) and GPATCH1 (19q13.11: rs10416265), we identified a new locus on chromosome 11q14.2 (rs597319 close to TMEM135, a gene recently linked to osteoblastogenesis and longevity) significantly associated with both BUA and VOS (P < 8.23 × 10(-14)). In meta-analyses involving 25 cohorts with up to 14 985 fracture cases, six of 10 SNPs associated with heel bone properties at P < 5 × 10(-6) also had the expected direction of association with any fracture (P < 0.05), including three SNPs with P < 0.005: 6q22.33 (rs7741021), 7q31.31 (rs2908007) and 10q21.1 (rs7902708). In conclusion, this GWA study reveals the effect of several genes common to central DXA-derived BMD and heel ultrasound/DXA measures and points to a new genetic locus with potential implications for better understanding of osteoporosis pathophysiology

Evaluation of individual and ensemble probabilistic forecasts of COVID-19 mortality in the United States

Short-term probabilistic forecasts of the trajectory of the COVID-19 pandemic in the United States have served as a visible and important communication channel between the scientific modeling community and both the general public and decision-makers. Forecasting models provide specific, quantitative, and evaluable predictions that inform short-term decisions such as healthcare staffing needs, school closures, and allocation of medical supplies. Starting in April 2020, the US COVID-19 Forecast Hub (https://covid19forecasthub.org/) collected, disseminated, and synthesized tens of millions of specific predictions from more than 90 different academic, industry, and independent research groups. A multimodel ensemble forecast that combined predictions from dozens of groups every week provided the most consistently accurate probabilistic forecasts of incident deaths due to COVID-19 at the state and national level from April 2020 through October 2021. The performance of 27 individual models that submitted complete forecasts of COVID-19 deaths consistently throughout this year showed high variability in forecast skill across time, geospatial units, and forecast horizons. Two-thirds of the models evaluated showed better accuracy than a naïve baseline model. Forecast accuracy degraded as models made predictions further into the future, with probabilistic error at a 20-wk horizon three to five times larger than when predicting at a 1-wk horizon. This project underscores the role that collaboration and active coordination between governmental public-health agencies, academic modeling teams, and industry partners can play in developing modern modeling capabilities to support local, state, and federal response to outbreaks

The United States COVID-19 Forecast Hub dataset

Academic researchers, government agencies, industry groups, and individuals have produced forecasts at an unprecedented scale during the COVID-19 pandemic. To leverage these forecasts, the United States Centers for Disease Control and Prevention (CDC) partnered with an academic research lab at the University of Massachusetts Amherst to create the US COVID-19 Forecast Hub. Launched in April 2020, the Forecast Hub is a dataset with point and probabilistic forecasts of incident cases, incident hospitalizations, incident deaths, and cumulative deaths due to COVID-19 at county, state, and national, levels in the United States. Included forecasts represent a variety of modeling approaches, data sources, and assumptions regarding the spread of COVID-19. The goal of this dataset is to establish a standardized and comparable set of short-term forecasts from modeling teams. These data can be used to develop ensemble models, communicate forecasts to the public, create visualizations, compare models, and inform policies regarding COVID-19 mitigation. These open-source data are available via download from GitHub, through an online API, and through R packages