Exposure to long wavelength light that improves aged mitochondrial function shifts acute cytokine expression in serum and the retina.

Aged mitochondrial function can be improved with long wavelength light exposure. This reduces cellular markers of inflammation and can improve system function from fly through to human. We have previously shown that with age there are increases in cytokine expression in mouse serum. Here, we ask what impact 670nm light has on this expression using a 40 cytokine array in blood serum and retina in C57Bl6 mice. 670nm exposure was delivered daily for a week in 12 month old mice. This shifted patterns of cytokine expression in both serum and retina inducing a selective increase. In serum examples of significant increases were found in IL (interleukins) 1α, IL-7, 10, 16, 17 along with TNF-α and CXCL (chemokines) 9 and 10. In retina the increases were again mainly in some IL's and CXCL's. A few cytokines were reduced by light exposure. Changes in serum cytokines implies that long wavelengths impact systemically even to unexposed tissues deep in the body. In the context of wider literature, increased cytokine expression may be protective. However, their upregulation by light merits further analysis as cytokines upregulation can also be negative and there are probably complex patterns of interaction in the dynamics of their expression.

ISCEV guidelines for calibration and verification of stimuli and recording instruments (2023 update).

This document developed by the International Society for Clinical Electrophysiology of Vision (ISCEV) provides guidance for calibration and verification of stimulus and recording systems specific to clinical electrophysiology of vision. This guideline provides additional information for those using ISCEV Standards and Extended protocols and supersedes earlier Guidelines. The ISCEV guidelines for calibration and verification of stimuli and recording instruments (2023 update) were approved by the ISCEV Board of Directors 01, March 2023.

Shifting patterns of cellular energy production (adenosine triphosphate) over the day and key timings for the effect of optical manipulation.

Mitochondria are optically responsive organelles producing energy for cell function via adenosine triphosphate (ATP). But ATP production appears to vary over the day. Here we use Drosophila melanogaster to reveal daily shifts in whole animal ATP production in a tight 24 hours' time series. We show a marked production peak in the morning that declines around midday and remains low through afternoon and night. ATP production can be improved with long wavelengths (>660 nm), but apparently not at all times. Hence, we treated flies with 670 nm light to reveal optimum times. Exposures at 670 nm resulted in a significant ATP increases and a shift in the ATP/adenosine diphosphate (ADP) ratio at 8.00 and 11.00, whilst application at other time points had no effect. Hence, light-induced ATP increases appear limited to periods when natural production is high. In summary, long wavelength influences on mitochondria are conserved across species from fly to human. Determining times for their administration to improve function in ageing and disease are of key importance. This study progresses this problem.

Near infrared spectroscopy reveals instability in retinal mitochondrial metabolism and haemodynamics with blue light exposure at environmental levels.

Blue light (~400-470 nm) is considered potentially detrimental to the retina but is present in natural environmental light. Mitochondrial density is highest in the retina, and they exhibit a prominent optical absorption around 420 nm arising from the Soret band of their porphyrins, including in cytochrome-c-oxidase in their respiratory chain. We examine the impact of continuous 420 nm at environmental energy levels on retinal mitochondrial metabolism and haemodynamics in vivo in real time using broadband near-infrared spectroscopy. One hour environmental exposure to 420 nm induces significant metabolic instability in retinal mitochondria and blood signals, which continues for up to 1 h post blue exposure. Porphyrins are important in mitochondrial adenosine triphosphate (ATP) production and cytochrome-c-oxidase is a key part of the electron transport chain through which this is achieved. Hence, environmental 420 nm likely restricts respiration and ATP production that may impact on retinal function.

Identifying impacts of air pollution on subacute asthma symptoms using digital medication sensors.

BACKGROUND: Objective tracking of asthma medication use and exposure in real-time and space has not been feasible previously. Exposure assessments have typically been tied to residential locations, which ignore exposure within patterns of daily activities. METHODS: We investigated the associations of exposure to multiple air pollutants, derived from nearest air quality monitors, with space-time asthma rescue inhaler use captured by digital sensors, in Jefferson County, Kentucky. A generalized linear mixed model, capable of accounting for repeated measures, over-dispersion and excessive zeros, was used in our analysis. A secondary analysis was done through the random forest machine learning technique. RESULTS: The 1039 participants enrolled were 63.4% female, 77.3% adult (>18) and 46.8% White. Digital sensors monitored the time and location of over 286 980 asthma rescue medication uses and associated air pollution exposures over 193 697 patient-days, creating a rich spatiotemporal dataset of over 10 905 240 data elements. In the generalized linear mixed model, an interquartile range (IQR) increase in pollutant exposure was associated with a mean rescue medication use increase per person per day of 0.201 [95% confidence interval (CI): 0.189-0.214], 0.153 (95% CI: 0.136-0.171), 0.131 (95% CI: 0.115-0.147) and 0.113 (95% CI: 0.097-0.129), for sulphur dioxide (SO2), nitrogen dioxide (NO2), fine particulate matter (PM2.5) and ozone (O3), respectively. Similar effect sizes were identified with the random forest model. Time-lagged exposure effects of 0-3 days were observed. CONCLUSIONS: Daily exposure to multiple pollutants was associated with increases in daily asthma rescue medication use for same day and lagged exposures up to 3 days. Associations were consistent when evaluated with the random forest modelling approach.

Weeklong improved colour contrasts sensitivity after single 670 nm exposures associated with enhanced mitochondrial function.

Mitochondrial decline in ageing robs cells of ATP. However, animal studies show that long wavelength exposure (650-900 nm) over weeks partially restores ATP and improves function. The likely mechanism is via long wavelengths reducing nanoscopic interfacial water viscosity around ATP rota pumps, improving their efficiency. Recently, repeated 670 nm exposures have been used on the aged human retina, which has high-energy demands and significant mitochondrial and functional decline, to improve vision. We show here that single 3 min 670 nm exposures, at much lower energies than previously used, are sufficient to significantly improve for 1 week cone mediated colour contrast thresholds (detection) in ageing populations (37-70 years) to levels associated with younger subjects. But light needs to be delivered at specific times. In environments with artificial lighting humans are rarely dark-adapted, hence cone function becomes critical. This intervention, demonstrated to improve aged mitochondrial function can be applied to enhance colour vision in old age.

Mitochondria are specifically vulnerable to 420nm light in drosophila which undermines their function and is associated with reduced fly mobility.

Increased blue light exposure has become a matter of concern as it has a range of detrimental effects, but the mechanisms remain unclear. Mitochondria absorb short wavelength light but have a specific absorbance at 420nm at the lower end of the human visual range. This 420nm absorption is probably due to the presence of porphyrin. We examine the impact of 420nm exposure on drosophila melanogaster mitochondria and its impact on fly mobility. Daily 15 mins exposures for a week significantly reduced mitochondrial complex activities and increased mitochondrial inner membrane permeability, which is a key metric of mitochondrial health. Adenosine triphosphate (ATP) levels were not significantly reduced and mobility was unchanged. There are multiple options for energy/time exposure combinations, but we then applied single 420nm exposure of 3h to increase the probability of an effect on ATP and mobility, and both were significantly reduced. ATP and mitochondrial membrane permeability recovered and over corrected at 72h post exposure. However, despite this, normal mobility did not return. Hence, the effect of short wavelengths on mitochondrial function is to reduce complex activity and increasing membrane permeability, but light exposure to reduce ATP and to translate into reduced mobility needs to be sustained.

Improved mitochondrial function corrects immunodeficiency and impaired respiration in neonicotinoid exposed bumblebees.

Neonicotinoid pesticides undermine pollinating insects including bumblebees. However, we have previously shown that mitochondrial damage induced by neonicotinoids can be corrected by 670nm light exposure. But we do not know if this protection extends to immunity or what the minimum effective level of 670nm light exposure is necessary for protection. We use whole body bee respiration in vivo as a metric of neonicotinoid damage and assess the amount of light exposure needed to correct it. We reveal that only 1 min of 670nm exposure is sufficient to correct respiratory deficits induced by pesticide and that this also completely repairs damaged immunocompetence measured by haemocyte counts and the antibacterial action of hemolymph. Further, this single 1 min exposure remains effective for 3-6 days. Longer exposures were not more effective. Such data are key for development of protective light strategies that can be delivered by relatively small economic devices placed in hives.

Locating oneself in the past to influence the present: Impacts of Neolithic landscapes on mental health well-being.

There are well-established links between mental health and the environment. Mental illness is a global issue, and international policies increasingly focus on promoting mental health well-being through community-based approaches, including non-clinical initiatives such as therapeutic landscapes and the use of heritage assets. However, the empirical evidence-base for the impact of such initiatives is limited. This innovative study, known as Human Henge, used a mixed-methods approach to investigate the impact of immersive experiences of prehistoric landscapes on the well-being of participants with mental health issues. Uniquely, the study followed participants for a year after their participation in the project to explore the long-term impact of their experiences on their mental well-being. Findings highlight that, overall, participants experienced improved mental health well-being from baseline to mid- and end-of programme (p = 0.01 & 0.003), as well as one-year post-programme (p = 0.03). Qualitative data indicated the reconnection of participants with local communities, and with other people, in ways that improved their mental health well-being. These data highlight the effectiveness of using heritage as a means of improving the well-being of people with mental health issues.

Optically Improved Mitochondrial Function Redeems Aged Human Visual Decline.

The age spectrum of human populations is shifting toward the older with larger proportions suffering physical decline. Mitochondria influence the pace of aging as the energy they provide for cellular function in the form of adenosine triphosphate (ATP) declines with age. Mitochondrial density is greatest in photoreceptors, particularly cones that have high energy demands and mediate color vision. Hence, the retina ages faster than other organs, with a 70% ATP reduction over life and a significant decline in photoreceptor function. Mitochondria have specific light absorbance characteristics influencing their performance. Longer wavelengths spanning 650->1,000 nm improve mitochondrial complex activity, membrane potential, and ATP production. Here, we use 670-nm light to improve photoreceptor performance and measure this psychophysically in those aged 28-72 years. Rod and cone performance declined significantly after approximately 40 years of age. 670-nm light had no impact in younger individuals, but in those around 40 years and older, significant improvements were obtained in color contrast sensitivity for the blue visual axis (tritan) known to display mitochondrial vulnerability. The red visual axis (protan) improved but not significantly. Rod thresholds also improved significantly in those >40 years. Using specific wavelengths to enhance mitochondrial performance will be significant in moderating the aging process in this metabolically demanding tissue.

Clinical and Molecular Characterization of Familial Exudative Vitreoretinopathy Associated With Microcephaly.

PURPOSE: Familial exudative vitreoretinopathy (FEVR) is a rare finding in patients with genetic forms of microcephaly. This study documents the detailed phenotype and expands the range of genetic heterogeneity. DESIGN: Retrospective case series. METHODS: Twelve patients (10 families) with a diagnosis of FEVR and microcephaly were ascertained from pediatric genetic eye clinics and underwent full clinical assessment including retinal imaging. Molecular investigations included candidate gene Sanger sequencing, whole-exome sequencing (WES), and whole-genome sequencing (WGS). RESULTS: All patients had reduced vision and nystagmus. Six were legally blind. Two probands carried bi-allelic LRP5 variants, both presenting with bilateral retinal folds. A novel homozygous splice variant, and 2 missense variants were identified. Subsequent bone density measurement identified osteoporosis in one proband. Four families had heterozygous KIF11 variants. Two probands had a retinal fold in one eye and chorioretinal atrophy in the other; the other 2 had bilateral retinal folds. Four heterozygous variants were found, including 2 large deletions not identified on Sanger sequencing or WES. Finally, a family of 2 children with learning difficulties, abnormal peripheral retinal vasculogenesis, and rod-cone dystrophy were investigated. They were found to have bi-allelic splicing variants in TUBGCP6. Three families remain unsolved following WES and WGS. CONCLUSIONS: Molecular diagnosis has been achieved in 7 of 10 families investigated, including a previously unrecognized association with LRP5. WGS enabled molecular diagnosis in 3 families after prior negative Sanger sequencing of the causative gene. This has enabled patient-specific care with targeted investigations and accurate family counseling.

The temporal sequence of improved mitochondrial function on the dynamics of respiration, mobility, and cognition in aged Drosophila.

Aging is associated with mitochondrial decline and reduced adenosine triphosphate (ATP) production leading to cellular dysfunction, but this is improved by long-wavelength light absorbed by cytochrome c oxidase, increasing cytochrome c oxidase activity, ATP production and improving metabolism, sensory motor function, and cognition. Yet, the sequence of these events is unknown. We give old flies a single 90-minute 670-nm pulse and measure temporal sequences of changes in respiration, ATP, motor, and cognitive ability. Respiration increased significantly 20 minutes after light initiation and remained elevated for 4 days. Measurable ATP increased at 1 hour, peaking at 3 hours, and then declined rapidly. Respiration improved before ATP increased, which indicates an early ATP sink. Flies explore environments stereotypically, which is lost with aging but is reestablished for 7 hours after light exposure. However, again, there are improvements before there are peaks in ATP production. Improved mobility and cognitive function persist after ATP levels return to normal. Hence, elevated ATP in age may initiate independent signaling mechanisms that result in improvements in aged metabolism and function.

A Quantitative and Qualitative Exploration of Photoaversion in Achromatopsia.

Purpose: Photoaversion (PA) is a disabling and ubiquitous feature of achromatopsia (ACHM). We aimed to help define the characteristics of this important symptom, and present the first published assessment of its impact on patients' lives, as well as quantitative and qualitative PA assessments. Methods: Molecularly confirmed ACHM subjects were assessed for PA using four tasks: structured survey of patient experience, novel quantitative subjective measurement of PA, visual acuities in differing ambient lighting, and objective palpebral aperture-related PA testing. Results: Photoaversion in ACHM was found to be the most significant symptom for a substantial proportion (38%) of patients. A novel subjective PA measurement technique was developed and demonstrated fidelity with more invasive paradigms without exposing often very photosensitive patients to brighter light intensities used elsewhere. An objective PA measurement was also refined for use in trials, indicating that higher light intensities than previously published are likely to be needed. Monocular testing, as required for trials, was also validated for the first time. Conclusions: This study offers new insights into PA in ACHM. It provides the first structured evidence of the great significance of this symptom to patients, suggesting that PA should be considered as an additional outcome measure in therapeutic trials. It also offers new insights into the characteristics of PA in ACHM, and describes both subjective and objective measures of PA that could be employed in clinical trials.

Feasibility of Deploying Inhaler Sensors to Identify the Impacts of Environmental Triggers and Built Environment Factors on Asthma Short-Acting Bronchodilator Use.

BACKGROUND: Epidemiological asthma research has relied upon self-reported symptoms or healthcare utilization data, and used the residential address as the primary location for exposure. These data sources can be temporally limited, spatially aggregated, subjective, and burdensome for the patient to collect. OBJECTIVES: First, we aimed to test the feasibility of collecting rescue inhaler use data in space-time using electronic sensors. Second, we aimed to evaluate whether these data have the potential to identify environmental triggers and built environment factors associated with rescue inhaler use and to determine whether these findings would be consistent with the existing literature. METHODS: We utilized zero-truncated negative binomial models to identify triggers associated with inhaler use, and implemented three sensitivity analyses to validate our findings. RESULTS: Electronic sensors fitted on metered dose inhalers tracked 5,660 rescue inhaler use events in space and time for 140 participants from 13 June 2012 to 28 February 2014. We found that the inhaler sensors were feasible in passively collecting objective rescue inhaler use data. We identified several environmental triggers with a positive and significant association with inhaler use, including: AQI, PM10, weed pollen, and mold. Conversely, the spatial distribution of tree cover demonstrated a negative and significant association with inhaler use. CONCLUSIONS: Utilizing a sensor to capture the signal of rescue inhaler use in space-time offered a passive and objective signal of asthma activity. This approach enabled detailed analyses to identify environmental triggers and built environment factors that are associated with asthma symptoms beyond the residential address. The application of these new technologies has the potential to improve our surveillance and understanding of asthma. Citation: Su JG, Barrett MA, Henderson K, Humblet O, Smith T, Sublett JW, Nesbitt L, Hogg C, Van Sickle D, Sublett JL. 2017. Feasibility of deploying inhaler sensors to identify the impacts of environmental triggers and built environment factors on asthma short-acting bronchodilator use. Environ Health Perspect 125:254-261; http://dx.doi.org/10.1289/EHP266.

Improving Mitochondrial Function Protects Bumblebees from Neonicotinoid Pesticides.

Global pollination is threatened by declining insect pollinator populations that may be linked to neonicotinoid pesticide use. Neonicotinoids over stimulate neurons and depolarize their mitochondria, producing immobility and death. However, mitochondrial function can be improved by near infrared light absorbed by cytochrome c oxidase in mitochondrial respiration. In flies, daily exposure to 670nm light throughout life increases average lifespan and aged mobility, and reduces systemic inflammation. Here we treat bumble bees with Imidacloprid a common neonicotinoid. This undermined ATP and rapidly induced immobility and reduced visual function and survival. Bees exposed to insecticide and daily to 670nm light showed corrected ATP levels and significantly improved mobility allowing them to feed. Physiological recordings from eyes revealed that light exposure corrected deficits induced by the pesticide. Overall, death rates in bees exposed to insecticide but also given 670nm light were indistinguishable from controls. When Imidacloprid and light exposure were withdrawn, survival was maintained. Bees and insects generally cannot see deep red light so it does not disturb their behaviour. Hence, we show that deep red light exposure that improves mitochondrial function, reverses the sensory and motor deficits induced by Imidacloprid. These results may have important implications as light delivery is economic and can be placed in hives/colonies.

Electroretinogram assessment of children with sensorineural hearing loss: implications for screening.

BACKGROUND: The guidelines of the National Deaf Children's Society recommend that children with sensorineural hearing loss (SNHL) be routinely screened for ophthalmological problems and suggest electroretinography (ERG) to exclude Usher syndrome. The present study reports the nature and prevalence of abnormal ERG findings in a cohort of children with SNHL undergoing ERG with the aim of identifying risk factors for the diagnosis of Usher syndrome. METHODS: The medical records of children (<18 years of age) with SNHL referred for ERG at Moorfields Eye Hospital, London, between January 2009 and December 2011 were retrospectively reviewed. Patients were included if they had been referred with SNHL by an audiological medicine consultant and the primary indication for electrodiagnostic testing was possible Usher syndrome. RESULTS: A total of 84 cases met inclusion criteria of which 13 (15%) had ERG findings showing rod-cone dysfunction consistent with a diagnosis of Usher syndrome. Two patients with retinal pigmentary changes had normal ERGs and were diagnosed with rubella retinopathy based on the clinical findings. Risk factor analysis showed that age of ≥8 years at the time of ERG, sex, and bilateral hearing loss were not predictive of a diagnosis of Usher syndrome. However, the presence of or referral for cochlear implants, having relevant symptoms and/or clinical signs consistent with a retinal dystrophy, and profound hearing loss were all highly predictive. CONCLUSIONS: ERG is a useful diagnostic tool in children with SNHL and should be performed in children with SNHL who have cochlear implants and/or have signs or symptoms of retinal dystrophy. A focused approach could have potential cost-saving benefit.

Mitochondrial decline precedes phenotype development in the complement factor H mouse model of retinal degeneration but can be corrected by near infrared light.

Mitochondria produce adenosine triphosphate (ATP), critical for cellular metabolism. ATP declines with age, which is associated with inflammation. Here, we measure retinal and brain ATP in normal C57BL/6 and complement factor H knockout mice (Cfh(-/-)), which are proposed as a model of age-related macular degeneration. We show a significant premature 30% decline in retinal ATP in Cfh(-/-) mice and a subsequent shift in expression of a heat shock protein that is predominantly mitochondrial (Hsp60). Changes in Hsp60 are associated with stress and neuroprotection. We find no differences in brain ATP between C57BL/6 and Cfh(-/-) mice. Near infrared (NIR) increases ATP and reduces inflammation. ATP decline in Cfh(-/-) mice was corrected with NIR which also shifted Hsp60 labeling patterns. ATP decline in Cfh(-/-) mice occurs before inflammation becomes established and photoreceptor loss occurs and may relate to disease etiology. However, ATP levels were corrected with NIR. In summary, we provide evidence for a mitochondrial basis for this disease in mice and correct this with simple light exposure known to improve mitochondrial function.

The eyes of the deep diving hooded seal (Cystophora cristata) enhance sensitivity to ultraviolet light.

The mammalian visual range is approximately 400-700 nm, although recent evidence suggests varying ultraviolet (UV) extensions in diverse terrestrial species. UV sensitivity may have advantages in the dim, blue light shifted environment experienced by submerged marine mammals. It may also be advantageous when seals are on land as UV is reflected by snow and ice but absorbed by fur, enhancing visual contrast. Here we show that the pelagic hooded seal (Cystophora cristata) has a highly UV permissive cornea and lens. Seals like other carnivores have a tapetum lucidum (TL) reflecting light back through the retina increasing sensitivity. The TL in this seal is unusual being white and covering almost the entire retina unlike that in other carnivores. Spectral reflectance from its surface selectively increases the relative UV/blue components >10 times than other wavelengths. Retinal architecture is consistent with a high degree of convergence. Enhanced UV from a large TL surface with a high degree of retinal convergence will increase sensitivity at a cost to acuity. UV electrophysiological retina responses were only obtained to dim, rod mediated stimuli, with no evidence of cone input. As physiological measurements of threshold sensitivity are much higher than those for psychophysical detection, these seals are likely to be more UV sensitive than our results imply. Hence, UV reflections from the TL will afford increased sensitivity in dim oceanic environments.

Near-infrared light increases ATP, extends lifespan and improves mobility in aged Drosophila melanogaster.

Ageing is an irreversible cellular decline partly driven by failing mitochondrial integrity. Mitochondria accumulate DNA mutations and reduce ATP production necessary for cellular metabolism. This is associated with inflammation. Near-infrared exposure increases retinal ATP in old mice via cytochrome c oxidase absorption and reduces inflammation. Here, we expose fruitflies daily to 670 nm radiation, revealing elevated ATP and reduced inflammation with age. Critically, there was a significant increase in average lifespan: 100-175% more flies survived into old age following 670 nm exposure and these had significantly improved mobility. This may be a simple route to extending lifespan and improving function in old age.