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Ocular infections vary greatly in severity. Studies have tried to identify certain patterns related to the ocular microbiome in the studied populations in order to identify risk populations, new treatments and prophylaxis guidelines. However, it is critical to determine which antibiotics should be used in various situations and where alternatives to antibiotics are appropriate. Results of many studies show that high levels of antibiotic resistance in ophthalmology and multidrug resistance continue to be a reality and a challenge today. Iodine-povidone and chlorhexidine are two major antiseptics used in ophthalmology. It is hoped that future reports show good results without the use of antibiotics will encourage ophthalmologists to limit the use of topical antibiotics, reducing the rate of antimicrobial resistance.

Introduction: Alzheimer’s disease (AD) and age-related eye diseases pose an increasing burden as the world’s population ages. However, there is limited understanding on the association of AD/cognitive impairment, no dementia (CIND) with age-related eye diseases. Methods: In this cross-sectional, memory clinic-based study of multiethnic Asians aged 50 and above, participants were diagnosed as AD (n = 216), cognitive impairment, no dementia (CIND) (n = 252), and no cognitive impairment (NCI) (n = 124) according to internationally accepted criteria. Retinal photographs were graded for the presence of age-related macular degeneration (AMD) and diabetic retinopathy (DR) using standard grading systems. Multivariable-adjusted logistic regression models were used to determine the associations between neurological diagnosis and odds of having eye diseases. Results: Over half of the adults had at least one eye disease, with AMD being the most common (60.1%; n = 356), followed by DR (8.4%; n = 50). After controlling for age, sex, race, educational level, and marital status, persons with AD were more likely to have moderate DR or worse (OR = 2.95, 95% CI = 1.15–7.60) compared with NCI. In the fully adjusted model, the neurological diagnosis was not associated with AMD (OR = 0.75, 95% CI = 0.45–1.24). Conclusion: Patients with AD have an increased odds of having moderate DR or worse, which suggests that these vulnerable individuals may benefit from specific social support and screening for eye diseases. Agency for Science, Technology and Research (A*STAR) Nanyang Technological University National Medical Research Council (NMRC) National Research Foundation (NRF) Published version This study was supported by the National Medical Research Council (CG/C010A/2017_SERI, OFIRG/0048/2017, OFLCG/004c/2018, TA/MOH-000249-00/2018, MOHOFIRG20nov-0014, and NMRC/CG2/004b/2022-SERI), National Research Foundation Singapore (NRF2019- THE002-0006 and NRF-CRP24-2020-0001), A∗ STAR (A20H4b0141), the Singapore Eye Research Institute and Nanyang Technological University [SERI-NTU Advanced Ocular Engineering (STANCE) Program], the Duke-NUS Medical School [Duke-NUS-KP(Coll)/2018/0009A], and the SERI-Lee Foundation (LF1019-1) Singapore. The sponsor or funding organization had no role in the design or conduct of this research.

Objective: To compare total retinal oxygen extraction between patients with primary open-angle glaucoma (POAG) and healthy control subjects. Design: A prospective, single-center, cross-sectional, case–control study performed at the Medical University of Vienna. Subjects: Forty patients with POAG and 40 age- and sex-matched control subjects. Methods: Total retinal blood flow was measured using Doppler optical coherence tomography (OCT). Retinal arterial and venous oxygen saturation was measured using reflectance spectroscopy. From these parameters, oxygen content in the retinal arterial and venous circulation as well as total retinal oxygen extraction were calculated. Results: Total retinal blood flow was lower in POAG (25.2 ± 6.7 µL/min) as compared to healthy control subjects (35.6 ± 8.3 µL/min, p < 0.001). Retinal arterial oxygen content was not different between the two groups (0.18 ± 0.01 mL(O2)/mL in both groups, p < 0.761), but retinal venous oxygen content was higher in POAG (0.15 ± 0.01 mL(O2)/mL) than in healthy controls (0.14 ± 0.01 mL(O2)/mL p < 0.001). Accordingly, retinal oxygen extraction was reduced in POAG (0.8 ± 0.3 µL(O2)/min as compared to healthy controls: 1.4 ± 0.4 µL(O2)/min, p < 0.001). There was a significant association between total retinal blood flow and total retinal oxygen extraction with measures of structural and functional damage (p < 0.001 each). Conclusions: This study indicates that POAG is associated with a reduction in total retinal oxygen extraction linked to structural and functional damage of the disease. Since the technology is non-invasive, it allows for longitudinal studies investigating to which degree low retinal oxygen extraction is linked to the progression of the disease.

To evaluate machine learning (ML) approaches for structure-function modeling to estimate visual field (VF) loss in glaucoma, models from different ML approaches were trained on optical coherence tomography thickness measurements to estimate global VF mean deviation (VF MD) and focal VF loss from 24-2 standard automated perimetry. The models were compared using mean absolute errors (MAEs). Baseline MAEs were obtained from the VF values and their means. Data of 832 eyes from 569 participants were included, with 537 Asian eyes for training, and 148 Asian and 111 Caucasian eyes set aside as the respective test sets. All ML models performed significantly better than baseline. Gradient-boosted trees (XGB) achieved the lowest MAE of 3.01 (95% CI: 2.57, 3.48) dB and 3.04 (95% CI: 2.59, 3.99) dB for VF MD estimation in the Asian and Caucasian test sets, although difference between models was not significant. In focal VF estimation, XGB achieved median MAEs of 4.44 [IQR 3.45-5.17] dB and 3.87 [IQR 3.64-4.22] dB across the 24-2 VF for the Asian and Caucasian test sets and was comparable to VF estimates from support vector regression (SVR) models. VF estimates from both XGB and SVR were significantly better than the other models. These results show that XGB and SVR could potentially be used for both global and focal structure-function modeling in glaucoma.

The superior orbital apex syndrome is a relatively uncommon complication of midface maxillofacial trauma. The clinical symptoms consist in ophthalmoplegia, palpebral ptosis, exophthalmia, fixed mydriasis, retrobulbar pain and supraorbital nerve hypoesthesia by involvement of the third (oculomotor nerve), fourth (trochlear), fifth (trigeminal) and sixth nerve (abducens). If there is involvement of the optical nerve, the syndrome is termed - orbital apex syndrome. In this article, we will present the case of a 33-years old male, victim of human aggression with traumatic superior orbital apex syndrome. We discuss details of diagnosis and surgical treatment. We will make, also, a review of literature on this subject. Even if the actual therapeutic algorithm is currently a matter of controversy, the generally accepted therapy plane initiated with a high dose of corticosteroids. Fine slice CT scan examination is mandatory for the correct planning. If the CT scan reveals a highly displaced maxillo-zygomatic complex fracture with or without orbital blow-out fracture, we recommend early surgical intervention after the resolving of the periorbital hematoma within 5 to 10 days ideally if concomitant intracranial injury or other conditions permit it. The early restoration of the orbital anatomy and volume will create the basis for cranial nerve decompression and function at the level of superior orbital fissure.

Retinal imaging has been proposed as a biomarker for neurological diseases such as multiple sclerosis (MS). Recently, a technique for non-invasive assessment of the retinal microvasculature called optical coherence tomography angiography (OCTA) was introduced. We investigated retinal microvasculature alterations in participants with relapsing–remitting MS (RRMS) without history of optic neuritis (ON) and compared them to a healthy control group. The study was performed in a prospective, case–control design, including 58 participants (n = 100 eyes) with RRMS without ON and 78 age- and sex-matched control participants (n = 136 eyes). OCTA images of the superficial capillary plexus (SCP), deep capillary plexus (DCP) and choriocapillaris (CC) were obtained using a commercial OCTA system (Zeiss Cirrus HD-5000 Spectral-Domain OCT with AngioPlex OCTA, Carl Zeiss Meditec, Dublin, CA). The outcome variables were perfusion density (PD) and foveal avascular zone (FAZ) features (area and circularity) in both the SCP and DCP, and flow deficit in the CC. MS group had on average higher intraocular pressure (IOP) than controls (P P = 0.003) and decreased PD in DCP (P P = 0.004). Deep FAZ was significantly larger (P = 0.005) and less circular (P P > 0.186). Our study indicates that there are microvascular changes in the macular parafoveal retina of RRMS patients without ON, showing increased PD in SCP and decreased PD in DCP. Further studies with a larger cohort of MS patients and MRI correlations are necessary to validate retinal microvascular changes as imaging biomarkers for diagnosis and screening of MS.

Importance: Deep learning (DL) networks require large data sets for training, which can be challenging to collect clinically. Generative models could be used to generate large numbers of synthetic optical coherence tomography (OCT) images to train such DL networks for glaucoma detection. Objective: To assess whether generative models can synthesize circumpapillary optic nerve head OCT images of normal and glaucomatous eyes and determine the usability of synthetic images for training DL models for glaucoma detection. Design, Setting, and Participants: Progressively growing generative adversarial network models were trained to generate circumpapillary OCT scans. Image gradeability and authenticity were evaluated on a clinical set of 100 real and 100 synthetic images by 2 clinical experts. DL networks for glaucoma detection were trained with real or synthetic images and evaluated on independent internal and external test data sets of 140 and 300 real images, respectively. Main Outcomes and Measures: Evaluations of the clinical set between the experts were compared. Glaucoma detection performance of the DL networks was assessed using area under the curve (AUC) analysis. Class activation maps provided visualizations of the regions contributing to the respective classifications. Results: A total of 990 normal and 862 glaucomatous eyes were analyzed. Evaluations of the clinical set were similar for gradeability (expert 1: 92.0%; expert 2: 93.0%) and authenticity (expert 1: 51.8%; expert 2: 51.3%). The best-performing DL network trained on synthetic images had AUC scores of 0.97 (95% CI, 0.95-0.99) on the internal test data set and 0.90 (95% CI, 0.87-0.93) on the external test data set, compared with AUCs of 0.96 (95% CI, 0.94-0.99) on the internal test data set and 0.84 (95% CI, 0.80-0.87) on the external test data set for the network trained with real images. An increase in the AUC for the synthetic DL network was observed with the use of larger synthetic data set sizes. Class activation maps showed that the regions of the synthetic images contributing to glaucoma detection were generally similar to that of real images. Conclusions and Relevance: DL networks trained with synthetic OCT images for glaucoma detection were comparable with networks trained with real images. These results suggest potential use of generative models in the training of DL networks and as a means of data sharing across institutions without patient information confidentiality issues. Agency for Science, Technology and Research (A*STAR) Nanyang Technological University National Medical Research Council (NMRC) National Research Foundation (NRF) Published version This work was funded by grants from the National Medical Research Council (grants CG/C010A/2017_SERI, OFLCG/004c/2018-00, MOH-000249-00, MOH-000647-00, MOH-001001-00, MOH-001015-00, MOH-000500-00, and MOH-000707-00), National Research Foundation Singapore (grants NRF2019-THE002-0006 and NRF-CRP24-2020-0001), A*STAR (grant A20H4b0141), the Singapore Eye Research Institute & Nanyang Technological University (SERI-NTU Advanced Ocular Engineering [STANCE] Program), and the SERI-Lee Foundation (grant LF1019-1) in Singapore.

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.

Bariatric surgery is an emerging therapeutic approach for obese type 2 diabetes mellitus (T2DM) patients, with proven benefits for achieving target glucose control and even remission of diabetes. However, the effect of bariatric surgery upon diabetic retinopathy is still a subject of debate as some studies show a positive effect while others raise concerns about potential early worsening effects. We performed a systematic review, on PubMed, Science Direct, and Web of Science databases regarding the onset and progression of diabetic retinopathy in obese T2DM patients who underwent weight-loss surgical procedures. A total of 6375 T2DM patients were analyzed. Most cases remained stable after bariatric surgery (89.6%). New onset of diabetic retinopathy (DR) was documented in 290 out of 5972 patients (4.8%). In cases with DR at baseline, progression was documented in 50 out of 403 (12.4%) and regression in 90 (22.3%). Preoperative careful preparation of hemoglobin A1c (HbA1c), blood pressure, and lipidemia should be provided to minimize the expectation of DR worsening. Ophthalmologic follow-up should be continued regularly in the postoperative period even in the case of diabetic remission. Further randomized trials are needed to better understand the organ-specific risk factors for progression and provide personalized counseling for T2DM patients planned for bariatric surgery.

Background: Optical coherence tomography (OCT) is a retinal imaging system that may improve the diagnosis of multiple sclerosis (MS) persons, but the evidence is currently equivocal. To assess whether compensating the peripapillary retinal nerve fiber layer (pRNFL) thickness for ocular anatomical features as well as the combination with macular layers can improve the capability of OCT in differentiating non-optic neuritis eyes of relapsing-remitting MS patients from healthy controls. Methods: 74 MS participants (n = 129 eyes) and 84 age- and sex-matched healthy controls (n = 149 eyes) were enrolled. Macular ganglion cell complex (mGCC) thickness was extracted and pRNFL measurement was compensated for ocular anatomical factors. Thickness measurements and their corresponding areas under the receiver operating characteristic curves (AUCs) were compared between groups. Results: Participants with MS showed significantly thinner mGCC, measured and compensated pRNFL (p ≤ 0.026). Compensated pRNFL achieved better performance than measured pRNFL for MS differentiation (AUC, 0.75 vs 0.80; p = 0.020). Combining macular and compensated pRNFL parameters provided the best discrimination of MS (AUC = 0.85 vs 0.75; p < 0.001), translating to an average improvement in sensitivity of 24 percent for differentiation of MS individuals. Conclusion: The capability of OCT in MS differentiation is made more robust by accounting OCT scans for individual anatomical differences and incorporating information from both optic disc and macular regions, representing markers of axonal damage and neuronal injury, respectively. Agency for Science, Technology and Research (A*STAR) Nanyang Technological University National Medical Research Council (NMRC) National Research Foundation (NRF) Published version This work was funded by grants from the National Medical Research Council (CG/C010A/2017_SERI; OFIRG/0048/2017; OFLCG/004c/2018; TA/MOH-000249-00/2018 MOH-OFIRG20nov-0014 and NMRC/CG2/004b/2022-SERI), National Research Foundation Singapore (NRF2019-THE002-0006 and NRF-CRP24-2020-0001), A*STAR (A20H4b0141), the Singapore Eye Research Institute & Nanyang Technological University (SERI-NTU Advanced Ocular Engineering (STANCE) Program), the Duke-NUS Medical School (Duke-NUS-KP(Coll)/2018/0009A), and the SERI-Lee Foundation (LF1019-1) Singapore.

BACKGROUND. Odontogenic rhinosinusal suppurations have a high potential for major ocular-orbital and cerebral complications because of the presence of anaerobic bacteria flora, with continuity, contiguity and haematogenous propagation mechanisms. This pathology is often diagnosed in other departments than ENT such as ophthalmology, neurosurgery or OMF surgery. MATERIAL AND METHODS. We present three clinical cases of odontogenic rhinosinusal suppurations with major complications: a 36-year-old patient with odontogenic pansinusitis complicated with orbital phlegmon and cerebral frontal lobe abscess; a 19-year-old patient with complicated maxillary-ethmoidal-frontal sinusitis complicated with frontal subdural empyema and frontal bone osteomyelitis (with a history of craniofacial trauma one year before); a 66-year-old patient with odontogenic maxillary-ethmoidal sinusitis complicated with orbital apex syndrome. RESULTS. The treatment was surgical, by external approach, with endoscopic nasal control, in interdisciplinary teams. We have associated massive antibiotic therapy. Surgical drainage for complicated rhinosinusitis should be done in emergency, within the first 24 hours after admission, according to guidelines. The bacteriological examination for aerobic and anaerobic flora can guide the diagnosis - two cases associated maxillo-ethmoidal aspergilloma lesions. The evolution of the cases was favourable. CONCLUSION. Interdisciplinary teams have successfully solved these complicated odontogenic rhinosinusal suppurations. Two of the cases were admitted and cured within 2 weeks, in the context of very hot weather, which exacerbated dormant dental infections.

Age-related macular degeneration is a chronic and progressive disease of the retina that occurs with increasing frequency with age, representing the leading cause of irreversible blindness in patients over 50 years of age. The loss of visual perception occurs due to neovascular proliferation. Antivascular endothelial growth factors revolutionized the treatment of exudative age-related macular degeneration. Our aim was to assess the systemic safety of intravitreal administration of ranibizumab, bevacizumab, or aflibercept in patients with neovascular age-related macular degeneration. The study was conducted and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) checklist. The primary outcomes included: all-cause death and all serious systemic adverse events. We calculated the incidence of systemic adverse events, relative risk of the outcomes, and 95% confidence intervals. This review included representative outcome data on 12,292 participants from 24 trials, which included both men and women aged 50 years or older with neovascular age-related macular degeneration. In bevacizumab-treated patients, the most frequent systemic adverse event in our analysis was nonocular hemorrhage. In ranibizumab-treated patients, systemic adverse events were not dose-dependent. The number of systemic adverse events was similar in patients treated with ranibizumab (4.73%) or with aflibercept (4.76%). This meta-analysis did not find any statistically significant difference regarding the occurrence of death or other serious systemic adverse events such as treatment-emergent hypertension, myocardial infarction, stroke, or nonocular hemorrhage after intravitreal use of antivascular endothelial growth factors.

Docetaxel is a very effective chemotherapeutic agent for the treatment of metastatic or locally advanced breast cancer. Epiphora (hyperlacrimation) has been shown to be the most common eye condition in patients receiving docetaxel-based chemotherapy. This symptom does not decrease visual acuity, but decreases the quality of life. Daily activities (reading, working on the computer, watching TV, and so on) are affected, with patients complaining about an alteration of daily life with the appearance of this symptom. The mechanism by which epiphora occurs is considered to be the canalicular stenosis, but the trials on the subject failed to reach statistical significance. The objective of this scoping review is to determine whether there is a treatment regimen-dependent relationship between docetaxel administration and the presence of epiphora in women with breast cancer. The inclusion criteria were met by 10 trials, from which one was excluded owing to data selection biases. Accordingly, nine studies were evaluated quantitatively and qualitatively in the present review. We included subjects with docetaxel as single treatment or docetaxel in combination with other chemotherapy compounds. The occurrence of epiphora among subjects treated with docetaxel, regardless of the therapeutic regimen used, was statistically significant (p = 0.005). The proportion of patients with epiphora after weekly administration of docetaxel (54 out of 131 subjects, 41.22%) was different compared with that of those who received docetaxel at three week intervals (112 out of 325 subjects, 34.15%), but the difference between the two was not statistically significant (p = 0.732). The present study demonstrates that epiphora occurs more frequently in patients receiving weekly docetaxel-based chemotherapy than those taking the three-weekly regimen, but the difference is not statistically significant. Ophthalmologic assessment of all patients starting this treatment is recommended. The causal relationship between canalicular stenosis and epiphora is not fully elucidated as long as this ocular symptom occurs in women who do not have stenosis of the lacrimal system. Further well-designed trials are required to bring new insights into the mechanisms of epiphora pathogenesis in subjects treated with docetaxel.

International audience; Exfoliation syndrome (XFS) is the commonest known risk factor for secondary glaucoma and a significant cause of blindness worldwide. Variants in two genes, LOXL1 and CACNA1A have been previously associated with XFS. To further elucidate the genetic basis of XFS, we collected a global sample of XFS cases to refine the association at LOXL1, which previously showed inconsistent results between populations,and to identify new variants associated with XFS. We identified a rare, protective allele at LOXL1 (p.407Phe, OR= 25, P=2.9 x 10-14) through deep resequencing of XFS cases and controls from 9 countries. This variant results in increased cellular adhesion strength compared to the wild-type (p.407Tyr) allele. A genome-wide association study (GWAS) of XFS cases and controls from 24 countries followed by replication in 18 countries identified seven genome-wide significant loci (P < 5 x 10-8). Index variants at the new loci map to chromosomes 13q12 (POMP), 11q23.3 (TMEM136), 6p21 (AGPAT1), 3p24 (RBMS3) and 5q23 (near SEMA6A). These findings provide biological insights into the pathology of XFS, and highlight a potential role for naturally occurring rare LOXL1 variants in disease biology.

Aim: The aim of this paper was to describe the possible implications of topical (ocular) administration of Metamizole on vascular reactivity of the iris in Wistar rats. No other study regarding its topical use was found. Methods: Male adult Wistar rats were anaesthetized with Ketamine 100 mg /kg body weight - injected intraperitoneally - while maintaining spontaneous respiration and the blink reflex. After selecting the area of interest (long posterior ciliary artery - LPCA), manual adjustments of the image magnitude, clarity, and brightness were made, and the experiment began. The image recording lasted 10 minutes. Results: Metamizole induced a slight vasoconstriction that started with the initial moment for all the doses used. After the topical administration of Metamizole, we did not observe an increase of the vascular diameter of LPCA in a dose dependent manner. The saline solution used as a negative control did not modify the vessel diameter. Conclusions: Metamizole (dipyrone) is a non-opioid drug, which is commonly used in human and veterinary medicine. It is the most popular first-line analgesic in various populations. In some cases, this agent is still incorrectly classified as a non-steroidal anti-inflammatory drug. The high analgesic efficacy of metamizole, as well as its spasmolytic effect, makes it a very important pharmaceutical agent that could be used in the therapy of various eye disorders in humans and in animals. Abbreviations: COX = Cyclooxygenase; LPCA = Long Posterior Ciliary Artery; PRP = panretinal photocoagulation; PDR = proliferative diabetic retinopathy; Sec = second(s); VSPR = very severe non proliferative diabetic retinopathy.

Purpose To compare the effect of a single drop of different lubricant eye gels on tear film thickness (TFT) as measured with ultrahigh-resolution optical coherence tomography (UHR-OCT) in patients with mild-to-moderate dry eye disease (DED). Methods The study followed a randomized, single-masked, observer-blinded parallel group design. Patients received a single dose of either unpreserved trehalose 3% + hyaluronic acid 0.15% (TH), hyaluronic acid 0.2% (HA) or polyethylene glycol 0.4% + propylene glycol 0.3% (PP) eye drops. In total, 60 patients were included and TFT was measured using a custom-built UHR-OCT system. Results The mean TFT at baseline was 3.5 ± 0.7 μm. There was a significant difference in the time–course of TFT between the three groups (p = 0.001 between groups). Ten minutes after instillation, TFT increased by 155.8 ± 86.6%, 65.7 ± 71.5% and 33.4 ± 19.6% in the PP, TH and HA group, respectively (p

DOI: https://doi.org/10.3126/nepjoph.v10i2.20464 The focus of this review is the role of endocannabinoid system in ocular and systemic circulation. By critically examining preclinical and clinical research, we explore the cannabinoid receptors localization and vascular implications as well as their interaction with other anti-inflammatory drugs. The objective is to transfer knowledge on the use of cannabinoids, specifically their effect on ocular circulation and intraocular pressure, and provide a better understanding of the endocannabinoid system complexity in modulating local and systemic circulations in order to identify potential uses and limitations of cannabinoid-based therapeutics. Keywords: Cannabinoids, endocannabinoid system, ocular vascularisation, vasorelaxation, glaucoma

There is evidence that choroidal blood flow (ChBF) is regulated in a complex way during changes in ocular perfusion pressure (OPP). We hypothesized that ChBF regulates better in response to changes in mean arterial pressure (MAP) than in intraocular pressure (IOP).Eighteen volunteers (mean age, 26 years) were recruited for a randomized, three-way crossover design. MAP was varied via isometric exercise. IOP was either kept normal or elevated by 10 or 20 mm Hg by using a suction cup. Subfoveal ChBF was measured continuously for 8 minutes with laser Doppler flowmetry and OPP was calculated as 2/3*MAP-IOP. For data analysis, values from all subjects were pooled according to either IOP or MAP values, and correlation analyses were done.When data were grouped according to IOP, no correlation was observed between ChBF and MAP, but ChBF was lower the higher the IOP (P0.001). When data were grouped according to MAP, a significant correlation was found between ChBF and IOP (P0.001). When data were pooled according to IOP, the correlation between ChBF and OPP was weaker (P0.05). The OPP at which ChBF significantly increased from baseline was 61.3% ± 4.9% without suction cup, 65.2% ± 3.5% when IOP was increased by 10 mm Hg, and slightly lower when IOP was increased by 20 mm Hg (56.3% ± 4.8%, P = 0.07), but this effect did not reach the level of significance.The present study provides further evidence that the regulation of ChBF during changes in OPP is controlled by complex mechanisms in humans and has less capacity to adapt to IOP elevation than to MAP increase.

IMPORTANCE Exfoliation syndrome is a systemic disorder characterized by progressive accumulation of abnormal fibrillar protein aggregates manifesting clinically in the anterior chamber of the eye. This disorder is the most commonly known cause of glaucoma and a major cause of irreversible blindness. OBJECTIVE To determine if exfoliation syndrome is associated with rare, protein-changing variants predicted to impair protein function. DESIGN, SETTING, AND PARTICIPANTS A 2-stage, case-control, whole-exome sequencing association study with a discovery cohort and 2 independently ascertained validation cohorts. Study participants from 14 countries were enrolled between February 1999 and December 2019. The date of last clinical follow-up was December 2019. Affected individuals had exfoliation material on anterior segment structures of at least 1 eye as visualized by slit lamp examination. Unaffected individuals had no signs of exfoliation syndrome. EXPOSURES Rare, coding-sequence genetic variants predicted to be damaging by bioinformatic algorithms trained to recognize alterations that impair protein function. MAIN OUTCOMES AND MEASURES The primary outcome was the presence of exfoliation syndrome. Exome-wide significance for detected variants was defined as P < 2.5 x 10(-6). The secondary outcomes included biochemical enzymatic assays and gene expression analyses. RESULTS The discovery cohort included 4028 participants with exfoliation syndrome (median age, 78 years [interquartile range, 73-83 years]; 2377 [59.0%] women) and 5638 participants without exfoliation syndrome (median age, 72 years [interquartile range, 65-78 years]; 3159 [56.0%] women). In the discovery cohort, persons with exfoliation syndrome, compared with those without exfoliation syndrome, were significantly more likely to carry damaging CYP39A1 variants (1.3% vs 0.30%, respectively; odds ratio, 3.55 [95% CI, 2.07-6.10]; P = 6.1 x 10(-7). This outcome was validated in 2 independent cohorts. The first validation cohort included 2337 individuals with exfoliation syndrome (median age, 74 years; 1132 women; n = 1934 with demographic data) and 2813 individuals without exfoliation syndrome (median age, 72 years; 1287 women; n = 2421 with demographic data). The second validation cohort included 1663 individuals with exfoliation syndrome (median age, 75 years; 587 women; n = 1064 with demographic data) and 3962 individuals without exfoliation syndrome (median age, 74 years; 951 women; n = 1555 with demographic data). Of the individuals from both validation cohorts, 5.2% with exfoliation syndrome carried CYP39A1 damaging alleles vs 3.1% without exfoliation syndrome (odds ratio, 1.82 [95% CI, 1.47-2.26]; P < .001). Biochemical assays classified 34 of 42 damaging CYP39A1 alleles as functionally deficient (median reduction in enzymatic activity compared with wild-type CYP39A1, 94.4%[interquartile range, 78.7%-98.2%] for the 34 deficient variants). CYP39A1 transcript expression was 47% lower (95% CI, 30%-64% lower; P < .001) in ciliary body tissues from individuals with exfoliation syndrome compared with individuals without exfoliation syndrome. CONCLUSIONS AND RELEVANCE In this whole-exome sequencing case-control study, presence of exfoliation syndrome was significantly associated with carriage of functionally deficient CYP39A1 sequence variants. Further research is needed to understand the clinical implications of these findings. National Research Foundation of SingaporeNational Research Foundation, Singapore [NRF-NRFI2018-01]; US National Eye Institute of the National Institutes of Health [R01 EY020928, P30 EY014104, UM1 CA186107, U01 CA167552, EY015473]; Glaucoma Research Foundation of Canada [X052, CIRG17may053]; National Medical Research Council of SingaporeNational Medical Research Council, Singapore The study was funded by grant NRF-NRFI2018-01 from the National Research Foundation of Singapore. Additional support was provided by grants R01 EY020928, P30 EY014104, UM1 CA186107, U01 CA167552, and EY015473 from the US National Eye Institute of the National Institutes of Health, funding from the Glaucoma Research Foundation of Canada, and grants X052 and CIRG17may053 from the National Medical Research Council of Singapore.

Mucosal malignant melanoma is an extremely rare tumor of the nose, with an aggressive character, low prognosis and frequent recurrences. The authors present a case of a 60-year-old male patient, diagnosed five years ago with adenoid cystic carcinoma, for which he had surgery and radiotherapy, who was admitted in our Clinic with unilateral epistaxis and obstruction of the nasal cavity. Clinical exam revealed an obstructive polypoidal bleeding mass of the left nasal cavity. Biopsy was performed and the histopathological exam showed malignant mucosal melanoma. Wide local endoscopic surgery was practiced for two times in the last two years, and for now, there is no recurrence. Malignant melanomas are tumors with high mortality rate, which necessitate an early diagnosis and immediate treatment.

Purpose: Abnormal autoregulation of optic nerve head blood flow (ONHBF) has been postulated to play an important role in primary open‐angle glaucoma (POAG). We used laser Doppler flowmetry (LDF) to estimate quantitatively the ONHBF and compared ONHBF autoregulation between glaucoma patients and healthy controls during isometric exercise. Methods: Forty patients with POAG and 40 healthy age‐ and sex‐matched subjects underwent three periods of isometric exercise, each consisting of 2 min of handgripping. Optic nerve head blood flow (ONHBF) was measured continuously using LDF. Systemic blood pressure, intraocular pressure and ocular perfusion pressure were assessed in all participants. Results: Isometric exercise was associated with an increase in ocular perfusion pressure during all handgripping periods in both groups (p < 0.001). However, there was no change in ONHBF in either group. Three of the glaucoma patients and two of the healthy subjects showed a consistent 10% decrease in blood flow during isometric exercise, in spite of an increase in their blood pressure. This difference between groups was not significant (p = 0.61). Four other glaucoma subjects showed a consistent increase in blood flow of more than 10% during isometric exercise, whereas this was not seen in healthy subjects (p = 0.035). Conclusion: This study suggests that abnormal ONHBF autoregulation is more often seen in patients with POAG than healthy control subjects. The relationship to the glaucoma disease process is currently unknown and requires further investigation. Published version

Purpose. This randomized, observer-masked, crossover study investigated the effect of two hyaluronic acid/trehalose-based containing formulations, with different physical properties, on the signs and symptoms in patients with moderate to severe dry eye disease (DED). Methods. In one group, patients received a mixture of sodium hyaluronate and trehalose (HT, Thealoz Duo®) for use during the day. In the other group, patients received a more viscous formulation consisting of hyaluronic acid, trehalose, and carbomer (HTC-gel, Thealoz Duo Gel) to use pro re nata. Both groups used HTC-gel before going to bed. Clinical standard tests for DED were performed at the beginning and end of each one-week period. Further, patient satisfaction including quality of sleep was assessed using a visual analogue scale. Results. Corneal fluorescein and conjunctival lissamine green staining scores decreased, and tear breakup time (BUT) increased for both groups (p<0.001 each). Mean instillation frequency was 3.1 ± 2.6 drops/day when using HT and 1.9 ± 2.2 drops/day when using HTC-gel (p=0.02). A significant improvement in the quality of sleep was observed with both treatments (p=0.01). Conclusions. Our results show improvement in signs and symptoms of DED in both groups. While instillation of HTC-gel resulted in a lower instillation frequency, both formulations of trehalose showed good clinical efficacy. This trial is registered with NCT02980913.

Aims/hypothesis The aim of this study was to compare retinal oxygen extraction in individuals with diabetes with no or mild non-proliferative diabetic retinopathy and healthy age- and sex-matched volunteers. Methods A total of 24 participants with type 1 diabetes and 24 healthy age- and sex-matched volunteers were included in this cross-sectional study. Retinal oxygen extraction was measured by combining total retinal blood flow measurements using a custom-built bi-directional Doppler optical coherence tomography system with measurements of oxygen saturation using spectroscopic reflectometry. Based on previously published mathematical modelling, the oxygen content in retinal vessels and total retinal oxygen extraction were calculated. Results Total retinal blood flow was higher in diabetic participants (46.4 ± 7.4 μl/min) than in healthy volunteers (40.4 ± 5.3 μl/min, p = 0.002 between groups). Oxygen content in retinal arteries was comparable between the two groups, but oxygen content in retinal veins was higher in participants with diabetes (0.15 ± 0.02 ml O2/ml) compared with healthy control participants (0.13 ± 0.02 ml O2/ml, p

The aim of the present study was to investigate regulation of blood flow (BF) in the optic nerve head (ONH) and a peripapillary region (PPR) during an isometric exercise-induced increase in ocular perfusion pressure (OPP) using laser speckle flowgraphy (LSFG) in healthy subjects. For this purpose, a total of 27 subjects was included in this study. Mean blur rate in tissue (MT) was measured in the ONH and in a PPR as well as relative flow volume (RFV) in retinal arteries (ART) and veins (VEIN) using LSFG. All participants performed isometric exercise for 6 minutes during which MT and mean arterial pressure were measured every minute. From these data OPP and pressure/flow curves were calculated. Isometric exercise increased OPP, MTONH and MTPRR. The relative increase in OPP (78.5 ± 19.8%) was more pronounced than the increase in BF parameters (MTONH: 18.1 ± 7.7%, MTPRR: 21.1 ± 8.3%, RFVART: 16.5 ±12.0%, RFVVEIN: 17.7 ± 12.4%) indicating for an autoregulatory response of the vasculature. The pressure/flow curves show that MTONH, MTPRR, RFVART, RFVVEIN started to increase at OPP levels of 51.2 ± 2.0%, 58.1 ± 2.4%, 45.6 ± 1.9% and 45.6 ± 1.9% above baseline. These data indicate that ONHBF starts to increase at levels of approx. 50% increase in OPP: This is slightly lower than the values we previously reported from LDF data. Signals from the PPR may have input from both, the retina and the choroid, but the relative contribution is unknown. In addition, retinal BF appears to increase at slightly lower OPP values of approximately 45%. LSFG may be used to study ONH autoregulation in diseases such as glaucoma. Trial Registration: ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT02102880","term_id":"NCT02102880"}}NCT02102880

Purpose. To compare changes in intraocular pressure (IOP), axial eye length (AEL), and refractive outcome in primary open-angle glaucoma patients undergoing cataract surgery and trabeculectomy in dependence of the sequence of surgeries. Materials and Methods. We retrospectively analysed 48 eyes. The changes in refraction, intraocular pressure, and axial eye length were analysed after surgery. In group A (21 subjects), phacoemulsification was performed before trabeculectomy, and in group B (27 subjects), trabeculectomy was performed before phacoemulsification with a minimum time span between interventions of 6 months. Results. The reduction in IOP and the decrease in AEL after trabeculectomy were significant after 6 and 12 months postsurgery (p<0.001 each). The decrease in AEL was 0.42 ± 0.11% at 6 months after surgery and 0.40 ± 0.13% after 12 months from surgery; this decrease in AEL was comparable between the groups. The refractive outcome was significantly different between the groups (group A: 0.35 ± 0.75 dpt, group B: −0.05 ± 0.36 dpt, p=0.018); in group A, trabeculectomy caused a hyperopic shift of 0.34 ± 0.44 dpt (p=0.002) at 12 months postsurgery. Conclusion. IOP reduction after trabeculectomy causes AEL shortening. The effect on refractive outcome depends on the sequence of surgeries. Better refractive outcome is achieved if phacoemulsification is performed after trabeculectomy.

The development and increase use of the endoscopic techniques in endonasal surgery has encouraged the practice of endoscopic dacryocystorhinostomy as a trustworthy alternative to external dacryocystorhinostomy. The purpose of the present paper is to provide another insight into transnasal endoscopic dacryocystorhinostomy by proposing the fitting, at the end of the intervention, of a conformational stent model with aspiration made out of medical silicone similar to a Montgomery tube.

In the choroid, there is evidence that blood flow does not only depend on ocular perfusion pressure (OPP), but also on absolute mean arterial pressure (MAP) and intraocular pressure (IOP). The present study included 40 healthy subjects to investigate whether such behavior is also found in the optic nerve head (ONH). The ONH blood flow (ONHBF) was studied using laser Doppler flowmetry during a separate increase in IOP and MAP as well as during a combined elevation. Mean arterial pressure was increased by isometric exercise and IOP by the suction method. During both, the change in ONHBF was less pronounced than the change in OPP indicating autoregulation. Correlation analysis was performed for the combined experiments after pooling all data according to IOP and MAP values. A correlation between ONHBF and MAP was found at IOPs 25 mm Hg ( P25 mm Hg ( P=0.79). Optic nerve head blood flow and IOP were significantly correlated ( P

Purpose: The aim of the study was to compare the diameter of the central retinal artery (CRA) between patients with diabetes mellitus and healthy subjects in vivo. CRA diameters were calculated from retinal haemodynamic parameters measured with noninvasive measurement techniques. Methods: Sixteen patients with type 1 diabetes with no or mild diabetic retinopathy and 16 age-matched healthy controls were included in this study. Total retinal blood flow was assessed by combining bidirectional laser Doppler velocimetry in all veins entering the optic disc with measurements of retinal vessel diameters using a Dynamic Vessel Analyser. Blood flow velocity in the CRA was measured with colour Doppler imaging (CDI). The diameter of the CRA in the optic nerve was then calculated for each subject using the individual ocular haemodynamic data. Results: Calculated CRA diameters were significantly larger in patients with diabetes (180 ± 13 μm) compared with healthy controls (166 ± 10 μm, p = 0.001). No significant differences were found in retinal blood flow, retinal artery or vein diameters or mean flow velocity of the CRA. Conclusion: The data of the present study show increased calculated CRA diameter in patients with type 1 diabetes with no or mild retinopathy. Blood flow velocity measurements in retrobulbar vessels using CDI need to be interpreted with caution in terms of retinal blood flow, because no information about vessel diameters is obtained by this technique.

Ocular blood flow dysregulation has been implicated in the pathogenesis of glaucoma. Whereas the effect of single antiglaucoma substances on ocular blood flow has been addressed in various experiments, evidence for fixed combinations is sparse. In the present study, we set out to compare the effects of latanoprost 0.005%/timolol 0.5% (LT) fixed combination and brimonidine 0.2%/timolol 0.5% (BT) fixed combination on intraocular pressure (IOP) and ocular blood flow.In the present study, which followed a randomized, double-masked 2-way crossover design, 16 patients with primary open-angle glaucoma and 2 patients with ocular hypertension were included. The patients underwent a 6-week treatment with LT and a 6-week treatment with BT after a washout for previous antiglaucoma medication. Optic nerve head blood flow (ONHBF) was measured using laser Doppler flowmetry; retrobulbar flow velocities were measured using color Doppler imaging in the ophthalmic artery, the central retinal artery, and the posterior ciliary arteries. IOP was measured at 8 AM, 12 PM, and 4 PM.The mean baseline IOP was 25.3±2.8 mmHg. Both drugs were equally effective in reducing IOP (LT: -35.0%±10.0%; BT: -33.6%±8.8%, P=0.463 between groups). In addition, no difference in ocular perfusion pressure was observed between the 2 treatment groups (P=0.1, between groups). Neither LT nor BT altered ONHBF (P=0.4, baseline vs. treatment) and no effect on flow velocities in the retrobulbar vessels was seen with either of the 2 treatments.In the present study, a 6-week treatment with LT or BT was equally effective in reducing IOP. In addition, none of the administered drugs induced a significant effect on ocular blood flow parameters.

Purpose To analyze regulation of subfoveal choroidal blood flow (FLOW) during isometric exercise in healthy subjects in dependence of intraocular pressure (IOP), mean arterial pressure (MAP), ocular perfusion pressure (OPP), age, sex, fasting glucose, cholesterol, triglycerides, creatinine, and C-reactive protein levels and hematocrit. Methods We retrospectively analyzed results obtained in 261 healthy subjects who underwent a period of 6 minutes of isometric exercise during which FLOW was measured continuously and MAP was measured every minute. From these data, OPP and choroidal pressure/flow curves were calculated. Subjects were grouped into tertiles with regard to the dependent variables, and pressure/flow relationships were compared. Results Choroidal blood flow started to increase at OPP values of approximately 65% dependent on the MAP/IOP tertile. A significant increase of FLOW from baseline was noted at 67.7 ± 2.1% in the lowest MAP tertile, at 67.7 ± 2.0% in the second MAP tertile, and at 61.8 ± 2.0% in the highest MAP tertile (P = 0.01). At the three IOP levels, FLOW started to increase at an OPP increase of 69.8 ± 2.1%, 70.1 ± 2.2%, and 65.4 ± 1.9% above baseline, respectively (P = 0.03). Choroidal pressure/flow curves were independent of the other variables. Conclusions The present analysis indicates that FLOW regulation during isometric exercise is dependent on absolute MAP as well as IOP levels. This indicates that regulation depends on pressure levels at both the arterial and the venous side of the choroidal circulation and highlights the complexity of FLOW regulation during changes in OPP that cannot be simply characterized by classical autoregulation models.

Multiple drug resistance requires a flexible approach to find medicines able to overcome it. One method could be the exposure of existing medicines to UV laser beams to generate active photoproducts against bacteria and/or malignant tumors.The interaction of Chlorpromazine (CPZ) (irradiated with 266 nm pulsed laser beams) was studied at concentrations of 10 mg/ml and 20 mg/ ml in ultrapure water, with pseudotumors of rabbits eyes.The use of CPZ water solution exposed to 266 nm in the treatment of pseudotumor tissues produced on rabbit eyes showed that treatment results depend on initial (before irradiation) CPZ concentration and exposure time. At this stage, one could not specify which out of the generated photoproducts, individual or as a group, was/were efficient in pseudotumor cure but overall effects were observable. Application of CPZ irradiated solutions on rabbit eyes pseudotumors seemed to produce a faster recovery of tissues with respect to control, untreated eyes.Histologic findings in the treated tissues showed a good anti-inflammatory response. The results obtained open perspectives to fight MDR and/or development of pseudotumoral processes with substances that were not initially made for this purpose (non-antibiotics, for instance).

Purpose: An adequate oxygenation and perfusion is essential for the function of the inner retina. Recently, several techniques for the measurement of retinal oxygen saturation became available. We set out to evaluate reproducibility of the measurements using a modified Retinal Vessel Analyzer. Methods: A total of 20 healthy female and male subjects aged between 18 and 35 years (22.9 ± 3.9; mean ± SD) were included. The measurement of retinal oxygen saturation with the retinal oximeter employed in this study is based on optical reflectometry using the different absorption characteristics of oxygenated and deoxygenated haemoglobin. The intraclass correlation coefficients and the coefficients of variation (CV) for test–retest, short-term as well as day-to-day measurements were calculated. Results: The intraclass correlation coefficients were between 0.91 and 0.94 for retinal branch arteries and between 0.84 and 0.88 for retinal branch veins. In retinal arteries, we calculated a test–retest CV of 3.24 ± 3.18% for oxygen saturation measurements. In retinal veins, data were slightly less reproducible with a CV of 4.92 ± 3.57%. Short-term reproducibility of both measurement cycles on each study day was in the same range (CV in retinal arteries: 2.91 ± 2.42% and CV in retinal veins: 4.76 ± 3.14%). The day-to-day coefficient of variation was slightly higher (CV in retinal arteries: 3.97 ± 2.87% and CV in retinal veins: 6.18 ± 3.36%). Conclusion: The reproducibility of haemoglobin oxygen saturation measurements using the retinal oximeter is acceptable. Further studies on the validity of the obtained results are, however, required.

Cerebral and retinal blood flow are dependent on local neuronal activity. Several studies quantified the increase in cerebral blood flow and oxygen consumption during activity. In the present study we investigated the relation between changes in retinal blood flow and oxygen extraction during stimulation with diffuse luminance flicker and the influence of breathing gas mixtures with different fractions of O2 (FiO2; 100% 15% and 12%). Twenty-four healthy subjects were included. Retinal blood flow was studied by combining measurement of vessel diameters using the Dynamic Vessel Analyser with measurements of blood velocity using laser Doppler velocimetry. Oxygen saturation was measured using spectroscopic reflectometry and oxygen extraction was calculated. Flicker stimulation increased retinal blood flow (57.7 ± 17.8%) and oxygen extraction (34.6 ± 24.1%; p

Ocular melanoma is a rare malignancy found in clinical practice. In this paper, we present a case of highly aggressive ocular melanoma, which was surgically removed at the Department of Ophthalmology and diagnosed at the Department of Pathology, Emergency University Hospital, Bucharest, Romania, using conventional histopathological techniques. Uveal melanoma, a subset of ocular melanoma, has a distinct behavior in comparison to cutaneous melanoma and has a widely divergent prognosis. Approximately half of patients with ocular melanoma will develop metastatic disease, predominantly with hepatic, pulmonary or cerebral location, over a 10 to 15 years period. No systemic therapy was associated with an evident clinical outcome for patients with advanced disease and overall survival rate remains poor.

Glaucoma is a group of diseases involving the optic nerve and associated structures, which is characterized by progressive visual field loss and typical changes of the optic nerve head (ONH). The only known treatment of the disease is reduction of intraocular pressure (IOP), which has been shown to reduce glaucoma progression in a variety of large-scale clinical trials. Nowadays, a relatively wide array of topical antiglaucoma drugs is available, including prostaglandin analogues, carbonic anhydrase inhibitors, beta-receptor antagonists, adrenergic agonists, and parasympathomimetics. In clinical routine, this allows for individualized treatment taking risk factors, efficacy, and safety into account. A major challenge is related to adherence to therapy. Sustained release devices may help minimize this problem but are not yet available for clinical routine use. Another hope arises from non-IOP-related treatment concepts. In recent years, much knowledge has been gained regarding the molecular mechanisms that underlie the disease process in glaucoma. This also strengthens the hope that glaucoma therapy beyond IOP lowering will become available. Implementing this concept with clinical trials remains, however, a challenge.

Primary open-angle glaucoma (POAG) represents the most common form of a heterogeneous group of glaucomatous optic neuropathies which are a worldwide cause of irreversible blindness. Immune dysregulation and the genetic background are considered important risk factors. The influence on susceptibility to POAG of single nucleotide polymorphisms (SNPs) of tumor necrosis factor-α (TNF-α) was intensively studied, mostly on Asian population. We investigated the possible association of two TNF-α SNPs (-308G/A and -857C/T) with susceptibility to POAG and its clinical characteristics. A case-control association study of aforementioned TNF-α SNPs was performed on 197 POAG patients (divided into two subgroups: high-tension and normal-tension glaucoma - HTG/ NTG) versus 208 ethnically matched controls. This is the first study performed on Romanian population. No significant differences were found in terms of allelic frequencies, genotype distribution of the studied SNPs, or their haplotypes between POAG and healthy control groups. In the subgroup analysis, TT genotype of TNF-α -857T-allele was found to be associated with higher values of central corneal thickness (CCT) in NTG subgroup (p-value 0.032). In order to confirm the association between -857C/T SNP of TNF-α and CCT in NTG subgroup of POAG patients, additional studies on different populations should be performed.

PURPOSE Beneficial effects of dietary supplements in age-related macular degeneration (AMD) are related to antioxidative properties. In the Age-Related Eye Disease Study 1 (AREDS 1), a reduced progression to late stage AMD was found using vitamin C, E, zinc, and β-carotene. We showed previously that the AREDS 1 formulation restores the O2-induced retinal vasoconstrictor response of retinal vessels in a human endotoxin (lipopolysaccharide [LPS]) model. METHODS We hypothesized that the abnormal O2-induced retinal red blood cell (RBC) flow response can be modulated by a different formulation (vitamin C, E, and zinc, lutein/zeaxanthin, selenium, taurine, Aronia extract, and omega-3 free fatty acids). A total of 43 healthy subjects was included in this randomized, double masked, placebo-controlled parallel group study. The reactivity of retinal arterial and venous diameter, RBC velocity, and flow to 100% O2 breathing was investigated in the absence and presence of 2 ng/kg LPS. Between the two study days was a 14-day period of daily dietary supplement intake. RESULTS The decrease in retinal arterial diameter, RBC velocity, and flow during 100% O2 breathing was diminished significantly after LPS infusion. Dietary supplement intake for 14 days almost restored the response of retinal hemodynamic parameters to 100% O2 after LPS administration. This effect was significant for retinal arterial diameter (P = 0.03 between groups), and RBC velocity and flow (each P < 0.01 between groups). CONCLUSIONS The present data indicate restoring of the RBC flow response to 100% O2 after LPS administration. This is likely due to an amelioration of endothelial dysfunction resulting from oxidative stress, a factor involved in AMD pathophysiology. (ClinicalTrials.gov number, NCT00914576.).

Animal experiments indicate that the inner retina keeps its oxygen extraction constant despite systemic hypoxia. For the human retina no such data exist. In the present study we hypothesized that systemic hypoxia does not alter inner retinal oxygen extraction. To test this hypothesis we included 30 healthy male and female subjects aged between 18 and 35 years. All subjects were studied at baseline and during breathing 12% O2 in 88% N2 as well as breathing 15% O2 in 85% N2. Oxygen saturation in a retinal artery (SO2art) and an adjacent retinal vein (SO2vein) were measured using spectroscopic fundus reflectometry. Measurements of retinal venous blood velocity using bidirectional laser Doppler velocimetry and retinal venous diameters using a Retinal Vessel Analyzer (RVA) were combined to calculate retinal blood flow. Oxygen and carbon dioxide partial pressure were measured from earlobe arterialized capillary blood. Retinal blood flow was increased by 43.0 ± 23.2% ( P < 0.001) and 30.0 ± 20.9% ( P < 0.001) during 12% and 15% O2 breathing, respectively. SO2art as well as SO2vein decreased during both 12% O2 breathing (SO2art: −11.2 ± 4.3%, P < 0.001; SO2vein: −3.9 ± 8.5%, P = 0.012) and 15% O2 breathing (SO2art: −7.9 ± 3.6%, P < 0.001; SO2vein: −4.0 ± 7.0%, P = 0.010). The arteriovenous oxygen difference decreased during both breathing periods (12% O2: −28.9 ± 18.7%; 15% O2: −19.1 ± 16.7%, P < 0.001 each). Calculated oxygen extraction did, however, not change during our experiments (12% O2: −2.8 ± 18.9%, P = 0.65; 15% O2: 2.4 ± 15.8%, P = 0.26). Our results indicate that in healthy humans, oxygen extraction of the inner retina remains constant during systemic hypoxia.

Pentoxifylline, a nonselective phosphodiesterase inhibitor, shows vasodilator effects in certain vascular beds and reduces blood viscosity. We have previously shown that under states of vasoconstriction an interaction between circulating erythrocytes and leukocytes may play a role in the control of blood flow. The reason for this observation is not entirely clear but may be related to a mechanical interaction between red and white blood cells. In the present study we hypothesized that pentoxifylline may alter this interaction during oxygen-induced vasoconstriction.24 healthy male subjects participated in this double masked, randomized, placebo-controlled 2 way cross over trial. In order to increase white blood cell count (WBC) count, 300 μg of G-CSF was administered intravenously. Vasoconstriction of retinal vessels was induced by oxygen inhalation. 400mg of pentoxifylline or placebo was infused at two different study days. White blood cell flux was assessed with the blue-field entoptic technique. Vessel calibers were measured with a dynamic vessel analyzer (DVA) and red blood cell velocity (RBCV) was determined with laser Doppler velocimetry (LDV). Retinal blood flow was calculated based on retinal vessel diameters and RBCV.Administration of G-CSF induced a significant increase in WBC, both in the placebo and the pentoxifylline group (p0.01 for both groups). Retinal vessel diameter, RBCV, calculated retinal blood flow and white blood cell flow were not altered by administration of pentoxifylline. Hyperoxia induced a pronounced decrease in retinal blood flow parameters. No difference was observed between groups during oxygen breathing in vessel diameters (p=0.54), RBCV (p=0.34), calculated retinal blood flow (p=0.3) and white blood cell flow (p=0.26).Our data indicate that short time administration of pentoxifylline does not alter the oxygen-induced effect on ocular blood flow parameters during leukocytosis. Whether long-term treatment could improve retinal blood flow under states of vasoconstriction remains to be investigated.