Optoretinography measures the stimulus-evoked response of the photoreceptors using light. Current systems use adaptive optics (AO) to obtain cellular-level resolution and fast volume acquisitions, to be able to monitor a single cone’s response with sufficient sampling over time.
The systems are complex to operate and therefore are not ideal in the clinical setting, where ease-of-use and high throughput are desirable.
Here, we set out to explore if a less complex research-grade imaging system without AO could detect light-evoked changes in the retina when stimulus is applied.
The imaging system uses 100 kHz swept source for OCT and tracking laser scanning ophthalmoscope is coupled into the sample arm for active eye-tracking. This provides a correction signal for the OCT to minimize spurious phase noise from eye motion.
The stimulus is done with 555 nm LED (single flash and 10 Hz flicker) during OCT imaging. Obviously, the resolution is not the same without AO and signals are a collective response from tens of photoreceptors resulting in measurements of phase shift between scattering speckle fields rather than well-defined single reflections from within a photoreceptor.
Improper eye tracking can also negatively affect phase-sensitive imaging needed to observe ORG signals. The ability to observe any stimulus-evoked responses using standard OCT would make optoretinography more accessible to study human vision as well as novel functional biomarkers of retinal diseases.
Extraction of phase-based optoretinograms (ORG) from serial B-scans acquired over tens of seconds by mouse retinal raster scanning OCT system.
- Several specialized retinal optical coherence tomography (OCT) acquisition and processing methods have been recently developed to allow in vivo probing of light-evoked photoreceptors function, focusing on measurements in individual photoreceptors (rods and cones).
- Recent OCT investigations in humans and experimental animals have shown that the outer segments in dark-adapted rods and cones elongate in response to the visible optical stimuli that bleach fractions of their visual photopigment.
- We have previously successfully contributed to these developments by implementing OCT intensity-based “optoretinograms” (ORG), the paradigm of using near-infrared OCT (NIR OCT) to measure bleaching-induced back-scattering and/or elongation changes of photoreceptors in the eye in vivo.
- In parallel, several groups have successfully implemented phase-based ORGs, mainly in human studies, exploiting changes in the phases of back-scattered light.
- This allowed more sensitive observations of tiny alterations of photoreceptors structures. Applications of the phase-based ORG have been implemented primarily in high speed and cellular resolution AO-OCT systems that can visualize photoreceptor mosaic, allowing phase measurements of path length changes in outer segments of individual photoreceptors.
- The phase-based ORG in standard resolution OCT systems is much more demanding to implement and has not been explored extensively. This manuscript describes our efforts to implement a phase analysis framework to retinal images acquired with a standard resolution and raster scanning OCT system, which offers much lower phase stability than line-field or full-field OCT detection schemes due to the relatively slower acquisition speed.
- Our initial results showcase the successful extraction of phase-based ORG signal from the B-scans acquired at ∼100 Hz rate and its favorable comparison with intensity-based ORG signal extracted from the same data sets.
- We implemented the calculation of phase-based ORG signals using Knox-Thompson paths and modified signal recovery by adding decorrelation weights.
- The phase-sensitive ORG signal analysis developed here for mouse retinal raster scanning OCT systems could be in principle extended to clinical retinal raster scanning OCT systems, potentially opening doors for clinically friendly ORG probing.
Observation of Conditions Preceding Peak Indoor Air Volatile Org Compound Concentrations in Vapor Intrusion Studies.
- Temporal and spatial variability of indoor air volatile organic compound (VOC) concentrations can complicate vapor intrusion (VI) assessment and decision-making.
- Indicators and tracers (I&T) of VI, such as differential temperature, differential pressure, and indoor radon concentration, are low-cost lines of evidence to support sampling scheduling and interpretation of indoor air VOC sampling results. This study compares peak indoor air chlorinated VOC concentrations and I&T conditions before and during those peak events at five VI sites.
- The sites differ geographically and in their VI conceptual site models (CSM). Relative to site-specific baseline values, the results show that cold or falling outdoor temperatures, rising cross slab differential pressures, and increasing indoor radon concentrations can predict peak VOC concentrations.
- However, cold outdoor air temperature was not useful at one site where elevated shallow soil temperature was a better predictor. Correlations of peak VOC concentrations to elevated or rising barometric pressure and low wind speed were also observed with some exceptions.
- This study shows how the independent variables that control or predict peak indoor air VOC concentrations are specific to building types, climates, and VI CSMs. More I&T measurements at VI sites are needed to identify scenario-specific baseline and peak related I&T conditions to improve decision-making.
Proof of Pharmacology of Org 48775-0, a p38 MAP kinase inhibitor, in Healthy Volunteers.
To investigate safety, tolerability, pharmacokinetics and pharmacodynamics of the highly selective oral p38alpha/beta MAP kinase inhibitor Org 48775-0 in a first-in-human study.
In the SAD study, an oral dose of Org 48775-0 (0.3 mg to 600 mg) was evaluated in healthy males.
In the MAD study, dose levels of 30, 70 and 150 mg were dosed for six consecutive days, twice daily. Both studies were performed in a double-blind, randomized, placebo-controlled, cross-over fashion and evaluated pharmacokinetics, pharmacodynamics (ex vivo inhibition of LPS-induced TNFalpha release) and routine clinical and laboratory data.
Pharmacokinetic and pharmacodynamic parameters of Org 48775-0 were compared between healthy males and postmenopausal females, and the effect of a standardized fat meal was evaluated.
All adverse events observed in the SAD (16; dizziness and headache, diarrhoea, and catheter-related phlebitis) and MAD (43; mainly somnolence, dizziness, headache and nasopharyngitis) cohorts were mild, transient and completely reversible. Pharmacokinetics were linear up to single doses of 400 mg.
OrgFrontier? Plasma Membrane Isolation Kit
OrgFrontier? Viable/Non-Viable Cells Separation Kit
Median Tmax ranged from 0.5 to 1.8 hours, geometric mean for T1/2 from 7.0 to 14.4 hours. Org 48775-0 doses equal to and greater than 30 mg significantly inhibited LPS-induced TNFalpha release (42.3%; 95%CI=-65.2; -4.3) compared to placebo.
In the MAD study, Org 48775-0 treatment inhibited LPS-induced TNFalpha release during the entire steady state period.
Levels of inhibition amounted 30-75% for 30 mg, 53-80% for 70 mg, and 77-92% for 150 mg Org 48775-0.
Org 48775-0 has the capacity to significantly inhibit MAP kinase activity in humans, without safety concerns.