ABSTRACT.Purpose: The aim of this study was to assess the effect of a single drop of hyaluronic acid on tear film thickness (TFT) in healthy subjects. Methods: Sixteen healthy subjects (eight male/eight female) aged between 20 and 36 years were included in this randomized, double-masked placebocontrolled study. One eye received a single dose of hyaluronic acid (Olixia pure â ; Croma Pharma, Korneuburg, Austria) eye drops, and the fellow eye received physiologic saline solution as placebo control. The study eye was chosen randomly. TFT as measured with a custom-built Fourier-domain optical coherence tomography (FD-OCT) system was the main outcome variable and measured before and every 10 min until 1 hr after topical administration. Results: Baseline TFT was 4.8 AE 0.5 lm in the study eye and 5.0 AE 0.4 lm in the control eyes. Hyaluronic acid significantly increased TFT (p = 0.008 versus placebo) with a maximum effect 10 min after instillation (13.9 AE 11.9%). Post hoc analysis revealed that an increase in TFT was seen until 30 min after administration compared to placebo. Data in the placebo group show high reproducibility with an intraclass correlation coefficient of 0.93 and a coefficient of variation of 5.4 AE 3.3%. Conclusion: The data of this study indicate that hyaluronic acid increases TFT for as long as 30 min in healthy subjects. In addition, our data provide evidence that our custom-built OCT system is capable of measuring residence time of lubricants on the ocular surface.

Purpose In the recent years several systems for the measurement of retinal oxygen saturation became commercially available. These systems rely on spectral analysis of the light reflected and scattered at the fundus. To measure the validity of the obtained results is difficult, because no gold standard method for the measurement of retinal oxygen saturation exists. We measured oxygen saturation in patients with reduced arterial oxygen saturation due to chronic obstructive pulmonary disease (COPD) and correlated data obtained in retinal arteries with systemic oxygen saturation values. Methods Eleven patients with COPD were included in this study and two identical study days were scheduled. The patients were in need of long term oxygen therapy to reach normal values for the oxygen saturation. Retinal arterial oxygen saturation was studied using spectral analysis of fundus photos using the Retinal Vessel Analyzer (Imedos®). Systemic oxygen saturation was studied with a pulse oximeter. The measurements were repeated 20 minutes after the oxygen therapy was paused. Results On day one systemic oxygen saturation in patients with COPD was 93 ± 4% and 86 ± 6% with and without oxygen therapy, respectively. Retinal arterial oxygen saturation was 91 ± 5% and 87 ± 6%, respectively (similar findings on day two). The correlation between systemic and retinal oxygen saturation was high (Day 1: r=0.68, p=0.023; Day 2: r=0.91,b p=0.001). In addition we found a high correlation coefficient of the change in oxygen saturation values (Day 1: r=0.88, p=<0.001; Day 2: r=0.67, p=0.047). Conclusion Our data indicate that measurements of arterial retinal oxygen saturation using the Retinal Vessel Analyzer show adequate validity.

Background/aims Concerning healthcare approaches, a paradigm change from reactive medicine to predictive approaches, targeted prevention, and personalisation of medical services is highly desirable. This raises demand for biomarker signatures that support the prediction and diagnosis of diseases, as well as monitoring strategies regarding therapeutic efficacy and supporting individualised treatments. New methodological developments should preferably rely on non-invasively sampled biofluids like sweat and tears in order to provide optimal compliance, reduce costs, and ensure availability of the biomaterial. Here, we have thus investigated the metabolic composition of human tears in comparison to finger sweat in order to find biofluid-specific marker molecules derived from distinct secretory glands. The comprehensive investigation of numerous biofluids may lead to the identification of novel biomarker signatures. Moreover, tear fluid analysis may not only provide insight into eye pathologies but may also be relevant for the prediction and monitoring of disease progression and/ or treatment of systemic disorders such as type 2 diabetes mellitus. Methods Sweat and tear fluid were sampled from 20 healthy volunteers using filter paper and commercially available Schirmer strips, respectively. Finger sweat analysis has already been successfully established in our laboratory. In this study, we set up and evaluated methods for tear fluid extraction and analysis using high-resolution mass spectrometry hyphenated with liquid chromatography, using optimised gradients each for metabolites and eicosanoids. Sweat and tears were systematically compared using statistical analysis. As second approach, we performed a clinical pilot study with 8 diabetic patients and compared them to 19 healthy subjects. Results Tear fluid was found to be a rich source for metabolic phenotyping. Remarkably, several molecules previously identified by us in sweat were found significantly enriched in tear fluid, including creatine or taurine. Furthermore, other metabolites such as kahweol and various eicosanoids were exclusively detectable in tears, demonstrating the orthogonal power for biofluid analysis in order to gain information on individual health states. The clinical pilot study revealed that many endogenous metabolites that have previously been linked to type 2 diabetes such as carnitine, tyrosine, uric acid, and valine were indeed found significantly up-regulated in tears of diabetic patients. Nicotinic acid and taurine were elevated in the diabetic cohort as well and may represent new biomarkers for diabetes specifically identified in tear fluid. Additionally, systemic medications, like metformin, bisoprolol, and gabapentin, were readily detectable in tears of patients. Conclusions The high number of identified marker molecules found in tear fluid apparently supports disease development prediction, developing preventive approaches as well as tailoring individual patients’ treatments and monitoring treatment efficacy. Tear fluid analysis may also support pharmacokinetic studies and patient compliance control.

The widely expressed and poly-specific ABC transporters breast cancer resistance protein (ABCG2) and P-glycoprotein (ABCB1) are co-localized at the blood-brain barrier (BBB) and have shown to limit the brain distribution of several clinically used ABCB1/ABCG2 substrate drugs. It is currently not known to which extent these transporters, which are also expressed at the blood-retinal barrier (BRB), may limit drug distribution to the human eye and whether the ABCG2 reduced-function single-nucleotide polymorphism (SNP) Q141K (c.421C &gt; A) has an impact on retinal drug distribution. Ten healthy male volunteers (five subjects with the c.421CC and c.421CA genotype, respectively) underwent two consecutive positron emission tomography (PET) scans after intravenous injection of the model ABCB1/ABCG2 substrate [11C]tariquidar. The second PET scan was performed with concurrent intravenous infusion of unlabelled tariquidar to inhibit ABCB1 in order to specifically reveal ABCG2 function.In response to ABCB1 inhibition with unlabelled tariquidar, ABCG2 c.421C &gt; A genotype carriers showed significant increases (as compared to the baseline scan) in retinal radiotracer influx K1 (+62 ± 57%, p = 0.043) and volume of distribution VT (+86 ± 131%, p = 0.043), but no significant changes were observed in subjects with the c.421C &gt; C genotype. Our results provide the first evidence that ABCB1 and ABCG2 may together limit the distribution of systemically administered ABCB1/ABCG2 substrate drugs to the human retina. Functional redundancy between ABCB1 and ABCG2 appears to be compromised in carriers of the c.421C &gt; A SNP who may therefore be more susceptible to transporter-mediated drug-drug interactions at the BRB than non-carriers.

We compare the focal structure–function correlation of structural measurements of peripapillary retinal nerve fiber layer thickness (RNFL‐T) using optical coherence tomography (OCT), capillary density (CD) measurements using OCT‐angiography (OCT‐A), or a combination of both, with visual field deviation (VFD) in early to advanced glaucoma. Primary open angle glaucoma patients (n = 46, mean ± SD age: 67 ± 10 years; VF mean deviation: −10.41 ± 6.76 dB) were included in this cross‐sectional study. We performed 30–2 standard automated perimetry OCT (3.5‐mm diameter ring scan) and 15°×15° OCT‐A (superficial vascular complex slab). Based on a nerve fiber trajectory model, each VF test spot was assigned to an OCT‐A wedge and an OCT ring‐sector. Two univariate linear models (Mv and Mt) using either CD‐based vascular (Mv) or RNFL‐T–based thickness information (Mt) and one multivariate model using both (Mv:t) were compared in their associations with measured focal VFD, which were higher for the multivariate model Mv:t (mean ± SD correlation coefficient: 0.710 ± 0.086) than for either nested model (0.627 ± 0.078 for Mv and 0.578 ± 0.095 for Mt). Using a focal visual field approach, the combination of RNFL‐T and CD showed better structure–function correlations than thickness or vascular information only.

Vascular changes and alterations of oxygen metabolism are suggested to be implicated in multiple sclerosis (MS) pathogenesis and progression. Recently developed in vivo retinal fundus imaging technologies provide now an opportunity to non-invasively assess metabolic changes in the neural retina. This study was performed to assess retinal oxygen metabolism, peripapillary capillary density (CD), large vessel density (LVD), retinal nerve fiber layer thickness (RNFLT) and ganglion cell inner plexiform layer thickness (GCIPLT) in patients with diagnosed relapsing multiple sclerosis (RMS) and history of unilateral optic neuritis (ON). 16 RMS patients and 18 healthy controls (HC) were included in this study. Retinal oxygen extraction was modeled using O2 saturations and Doppler optical coherence tomography (DOCT) derived retinal blood flow (RBF) data. CD and LVD were assessed using optical coherence tomography (OCT) angiography. RNFLT and GCIPLT were measured using structural OCT. Measurements were performed in eyes with (MS+ON) and without (MS-ON) history for ON in RMS patients and in one eye in HC. Total oxygen extraction was lowest in MS+ON (1.8 ± 0.2 μl O2/min), higher in MS-ON (2.1 ± 0.5 μl O2/min, p = 0.019 vs. MS+ON) and highest in HC eyes (2.3 ± 0.6 μl O2/min, p = 0.002 vs. MS, ANOVA p = 0.031). RBF was lower in MS+ON (33.2 ± 6.0 μl/min) compared to MS-ON (38.3 ± 4.6 μl/min, p = 0.005 vs. MS+ON) and HC eyes (37.2 ± 4.7 μl/min, p = 0.014 vs. MS+ON, ANOVA p = 0.010). CD, LVD, RNFLT and GCIPL were significantly lower in MS+ON eyes. The present data suggest that structural alterations in the retina of RMS patients are accompanied by changes in oxygen metabolism, which are more pronounced in MS+ON than in MS-ON eyes. Whether these alterations promote MS onset and progression or occur as consequence of disease warrants further investigation.Clinical Trial Registration:ClinicalTrials.gov registry, NCT03401879.

Intrinsic optical signals constitute a noninvasive biomarker promising the objective assessment of retinal photoreceptor function. We employed a commercial optical coherence tomography (OCT) system and an OCT signal model for evaluation of optical path length (OPL) changes in the temporal outer retina of five healthy subjects during light adaptation. Data were acquired at 30 time points, in ambient light and during long duration stimulation with white light, and analyzed, employing a signal model based on the sum of seven Gaussian curves corresponding to all relevant anatomical structures of the outer retina. During light stimulation, mean OPL between rod outer segment tips (ROST) and the retinal pigment epithelium (RPE) decreased by 21.4 ± 3.5%. Further, OPL between the external‐limiting membrane (ELM) and the RPE decreased by 5.2 ± 0.9% versus baseline, while OPL between ELM and ROST showed an initial decrease by 2.1 ± 1.6% versus baseline and, thereafter, increased by 2.8 ± 2.1% versus baseline. Thus, the presented approach allowed for assess to dynamic changes in the outer retina in response to light. The change in the subretinal space occurring in the context of light adaptation could be measured using a standard OCT platform and a dedicated signal model.

The aim of the present study was to assess retinal oxygen metabolism in patients with type II diabetes and different stages of non-proliferative diabetic retinopathy (DR) and compare these findings to healthy controls. For this purpose, 67 patients with type II diabetes and 20 healthy controls were included in this cross-sectional study. 34 patients had no, 15 had mild and 18 had moderate to severe DR. Retinal oxygen saturation in arteries and veins was measured using the oxygen module of the Retinal Vessel Analyzer (RVA). Total retinal blood flow (TFBF) was measured using a custombuilt Doppler optical coherence tomography system. Retinal oxygen extraction was calculated out of retinal oxygen saturation and TRBF. Arteriovenous difference in oxygen saturation was highest in healthy subjects (34.9±7.5%), followed by patients with no DR (32.5±6.3%) and moderate to severe DR (30.3±6.5%). The lowest values were found in patients with mild DR (27.3±8.0%, p=0.010 vs. healthy subjects). TRBF tended to be higher in patients with no DR (40.1±9.2µl/min) and mild DR (41.8±15.0µl/min) compared to healthy subjects (37.2±5.7µl/min) and patients with moderate to severe DR (34.6±10.4µl/min). Retinal oxygen extraction was the highest in healthy subjects (2.24±0.57µl O2/min), followed by patients with no DR (2.14±0.6µl O2/min), patients with mild DR (1.90±0.77µl O2/min) and patients with moderate to severe DR (1.78±0.57µl O2/min, p=0.040 vs. healthy subjects). These results indicate that retinal oxygen metabolism is altered in patients with type II diabetes. Further, retinal oxygen extraction decreases with increasing severity of DR.