Age-associated changes in human tear proteome.

BACKGROUND: Prevalence of many eye and ocular surface diseases increases with age. While the clinical characteristics and pathophysiologic mechanisms of these conditions are often either known or extensively studied, the effects of normal aging on tear film and ocular surface have not been as widely researched. METHODS: In order to examine the effects of aging on tear fluid proteomics, tear fluid samples were collected preoperatively from 115 subjects undergoing strabismus or refractive surgery using glass microcapillary tubes. In addition to their refractive error or strabismus, the subjects did not have any other current, known eye diseases. The non-pooled samples were analysed using NanoLC-TripleTOF implementing a sequential window acquisition of all theoretical fragment ion spectra mass spectrometry, resulting in quantified data of 849 proteins. RESULTS: According to correlation results, 17 tear proteins correlated significantly with increased age and many of these proteins were connected to inflammation, immune response and cell death. According to enrichment analysis, growth and survival of cells decreased while immune response and inflammation increased with aging. We also discovered several well-known, activated and inhibited upstream regulators, e.g. NF-κB, which has been previously connected to aging in numerous previous studies. CONCLUSIONS: Overall, the results show the common age-dependent alterations in tear fluid protein profile, which demonstrate similar age-associated alterations of biological functions previously shown in other tissue and sample types.

[Acute angle-closure glaucoma triggered by epidemic nephropathy]. / Myyräkuumeen laukaisema akuutti sulkukulmaglaukooma.

Epidemic nephropathy, i.e. nephropatia epidemica is a febrile illness caused by the Puumala virus and involving a transient impairment in kidney function. Additional commonly experienced symptoms include headache, backache and limb pain, as well as drowsiness or restlessness and nausea. Visual disturbances appear in approx. one third of those affected with the disease. Blurring of vision is the most common problem. We describe a patient case in which a previously healthy woman contracted epidemic nephropathy causing ocular symptoms that were strong.

[Update on Current Care Guideline: Glaucoma]. / Avokulmaglaukooma.

The up-date of the Finnish Current Care Guideline for glaucoma is based primarily on systematic reviews searched up by March 2014. The recommendations are presented in nine tables, which are based on 95 graded statements with evidence summaries. The online availability (www.kaypahoito.fi) of the English translation of guideline and evidence summaries enables the verification of the evidence and recommendations. Ten external stakeholders gave a mean value of 1.8 (range of 1 = completely agree to 4 = completely disagree) for the structured questions (e.g. definitions, goals, questions, target users) and judged the evidence and the recommendations.

A prototype protocol for evaluating the real-world data set using a structured electronic health record in glaucoma.

PURPOSE: As the first step in monitoring and evaluating day-to-day glaucoma care, this study reports all real-world data recorded during the first full year after the implementation of a prototype for glaucoma-specific structured electronic healthcare record (EHR). METHODS: In 2019, 4618 patients visited Tays Medical Glaucoma Clinic at Tays Eye Centre, Tampere University Hospital, Finland, that serves a population of 0.53 M. Patient data were entered into a glaucoma-specific EHR by trained nurses to be checked by glaucoma specialists. Tays Eye Centre follows the Finnish Current Care Guideline for glaucoma in which glaucoma is defined using a '2 out of 3' rule, that is, ≥2 findings evaluated as glaucomatous in optic nerve head (ONH), retinal nerve fibre layer (RNFL) and visual field (VF). RESULTS: The clinical evaluations of ONH, RNFL and VF were recorded in 95%-100% of all eyes. ONH was evaluated as glaucomatous more often (44%) than RNFL (33%) and VF tests (30%). Progressive changes in any of the three tests were recorded in 35% of the '≥2/3 glaucoma group' compared to 2%-9% in the other groups. The mean IOP at visit was 15 mmHg. The mean target IOP was 17 mmHg, and it was recorded in 94% of eyes. CONCLUSION: The developed structured data presentation enables comparisons between different population-based real-world glaucoma data sets and glaucoma clinics. Compared to a data set from the UK, the proportion of glaucoma suspicion-related visits was smaller in Tays Eye Centre and test intervals were longer.

The Finnish current care guideline for open-angle glaucoma.

This article is an English translation of the 4th Finnish Current Care Guideline for diagnostics, treatment and follow-up of primary open-angle glaucoma, normal-tension glaucoma and pseudoexfoliative glaucoma. This guideline is based on systematic literature reviews and expert opinions with Finland's geographical and operational healthcare environment in mind.

Glaucoma progression in patients receiving intravitreal anti-VEGF treatment for neovascular age-related macular degeneration.

PURPOSE: The purpose of this study was to investigate how often glaucoma and neovascular age-related macular degeneration (nAMD) occur in the same patient and to evaluate whether glaucoma progression is faster in eyes treated with intravitreal anti-VEGF medications for nAMD. METHODS: This single-centre retrospective real-world data (RWD) consists of medical records of 6314 glaucoma and 2166 nAMD patients treated in 2008-2017 in Tays Eye Centre, Finland. To study glaucoma progression, changes in visual fields (mean deviation [MD], dB/year), IOP (mmHg/year) and fundus photographs (progression, yes/no) were compared in glaucoma eyes with and without anti-VEGF treatment for nAMD and ≥1 year follow-up. RESULTS: During the 10-year period, 147 patients with glaucoma received intravitreal anti-VEGF treatment for nAMD corresponding to 2% of glaucoma and 7% of nAMD patients. The mean change in MD was -0.70 dB/year (SD 1.8) vs. -0.27 dB/year (SD 1.7) (p = 0.027) in glaucoma eyes with (n = 37) and without (n = 4304) anti-VEGF injections, respectively. In patients with bilateral glaucoma and unilateral nAMD treated with anti-VEGF injections (n = 20), MD declined at -0.62 dB/year (SD 1.9) vs 0.33 dB/year (SD 1.5) (p = 0.654), and glaucoma progression was detected in 14/20 vs 10/20 (p = 0.219) fundus photographs in eyes with anti-VEGF treatment compared with their untreated fellow eyes. CONCLUSION: nAMD and glaucoma were found co-existing in the same eye at rates that were similar to the age-corrected prevalence of the two diseases in the general population. Our results suggest that intravitreal anti-VEGF treatment for nAMD may accelerate glaucoma progression.

Ten-year real-world outcomes of antivascular endothelial growth factor therapy in neovascular age-related macular degeneration using pro re nata regimen.

BACKGROUND/AIMS: To analyse long-term outcomes of antivascular endothelial growth factor (anti-VEGF) therapy for the treatment of neovascular age-related macular degeneration (nAMD) using pro re nata (PRN) regimen in a single-centre clinical practice. METHODS: All patients receiving intravitreal injection (IVI) for nAMD between 1 January 2008 and 31 December 2020 were searched from electronic medical records. All 3844 treatment-naïve eyes of 3008 patients were included with a total of 50 146 IVIs (87% bevacizumab) administered. Main outcome measures were mean change in visual acuity (VA) from baseline, proportion of eyes within 15 letters of baseline, proportion of eyes with VA ≥20/40 Snellen and ≤20/200 Snellen, number of annual visits and number of annual IVIs. RESULTS: The mean baseline VA was 55 Early Treatment Diabetic Retinopathy Study (ETDRS) letters and the mean change in VA from baseline was +2, +2, ±0, -2, -2 and -4 ETDRS letters at year 1, 2, 3, 5, 7 and 10, respectively. Proportions of eyes within 15 letters of baseline were 88%, 87%, 82%, 80%, 76% and 72% at the end of years 1, 2, 3, 5, 7 and 10, respectively. The median number of annual IVI was 6 at years 1-7 and 5 at year 10. The median number of annual total visits was 10 at year 1, 9 at years 2-7 and 8 at year 10, respectively. CONCLUSIONS: VA was maintained short-term and long-term with anti-VEGF therapy using PRN treatment regimen.

Immediate sequential bilateral cataract surgery: a 13-year real-life report of 56 700 cataract operations.

BACKGROUND/AIMS: To assess the frequency of immediate sequential bilateral cataract surgery (ISBCS) and endophthalmitis during 13-year period in Tays Eye Centre, Tampere University Hospital, Tampere, Finland. METHODS: All cataract surgeries performed between 1 January 2008 and 31 December 2020, and all endophthalmitis cases during the same period were searched from electronic patient records. Numbers and frequencies of ISBCS, and complications, including endophthalmitis and vitreous loss, were recorded and compared with unilateral operations. RESULTS: The study included 56 700 cataract surgeries in 34 797 patients of whom 39% (n=13 445) had ISBCS. The median age of the patients was 75 (IQR 68-80, range 0.08-99) years at the time of surgery. The proportion of ISBCS patients increased from 4.2% in 2008 to 46% in 2020. Vitreous loss occurred in 480 (0.9%) of cataract surgeries. There were no postoperative endophthalmitis after cataract surgery (n=0) during the 13-year period. CONCLUSION: The proportion of patients undergoing ISBCS increased from 4.2% in 2008 to 46% in 2020. No endophthalmitis were found to be associated with ISBCS.

Changes in incidence and severity of visual impairment due to glaucoma during 40 years - a register-based study in Finland.

PURPOSE: To report the incidence and severity of reported visual impairment (VI) due to glaucoma and the changes in them during the past 40 years in Finland. METHODS: A register-based study, in which the data were collected from the Finnish Register of Visual Impairment between 1980 and 2019. These data included 5819 visually impaired glaucoma patients, of which 61% were female. Visual impairment (VI) was classified according to the Finnish national definitions. The number of treated glaucoma patients in Finland was calculated using glaucoma medication reimbursement data available between 1986 and 2019 from the Social Insurance Institution of Finland registers. RESULTS: The incidence of reported VI due to glaucoma per 100 000 persons had increased from 2.3 in the 1980s to 3.4 in the 2010s. During the same time period, the incidence of reported VI per 10 000 treated glaucoma patients had decreased from 32 in the 1980s to 21 in the 2010s. Primary open-angle glaucoma (45%) was the main subtype for reported VI due to glaucoma. During the 40 years, the proportion of mild VI and the age at the onset of reported VI had increased. CONCLUSION: The incidence of reported VI due to glaucoma has increased during the 40 years, but the risk of treated glaucoma patients becoming visually impaired has decreased. Visual impairment (VI) also occurs at an older age. This is likely due to the earlier diagnoses and improved therapy. To prevent the unfavourable development of VI due to glaucoma among the ageing population in the future, all attempts need to be made to improve glaucoma care.

The effect of successful trabeculectomy on the ocular surface and tear proteomics-a prospective cohort study with 1-year follow-up.

PURPOSE: To report changes in the ocular surface and tear proteomics after discontinuation of chronic glaucoma medication. METHODS: Patients requiring trabeculectomy were recruited from the glaucoma clinic of Tampere University Hospital, Finland. Fifty-seven patients with previous history of anti-glaucomatous eye drops (8.1 ± 6.8 years) and having undergone a successful trabeculectomy were included in this report. Outcomes of interest were conjunctival redness grading, tear secretion (Schirmer I) and tear film proteomics (SWATH-MS) in addition to thorough clinical examination. The protocol included five time points: preoperative visit and postoperative visits at month 1, 3, 6 and 12. All parameters measured were compared to the corresponding preoperative levels of each individual eye. RESULTS: Conjunctival redness and irritation were significantly reduced during follow-up, while tear production remained unchanged. Protein profiles of the tear film indicated significant changes in the ocular surface. Lipid transport was increased while several pro-inflammatory proteins were consistently decreased after the surgery. CONCLUSION: Clinical signs as well as the proteomics results indicated that the trabeculectomy and resulting cessation of topical glaucoma medication were very beneficial to the ocular surface. The state of the conjunctiva improved throughout the 1-year follow-up while the levels of pro-inflammatory proteins decreased and lipid transport-associated functions were increased.

Local ocular renin-angiotensin-aldosterone system: any connection with intraocular pressure? A comprehensive review.

The renin-angiotensin system (RAS) is one of the oldest and most extensively studied human peptide cascades, well-known for its role in regulating blood pressure. When aldosterone is included, RAAS is involved also in fluid and electrolyte homeostasis. There are two main axes of RAAS: (1) Angiotensin (1-7), angiotensin converting enzyme 2 and Mas receptor (ACE2-Ang(1-7)-MasR), (2) Angiotensin II, angiotensin converting enzyme 1 and angiotensin II type 1 receptor (ACE1-AngII-AT1R). In its entirety, RAAS comprises dozens of angiotensin peptides, peptidases and seven receptors. The first mentioned axis is known to counterbalance the deleterious effects of the latter axis. In addition to the systemic RAAS, tissue-specific regulatory systems have been described in various organs, evidence that RAAS is both an endocrine and an autocrine system. These local regulatory systems, such as the one present in the vascular endothelium, are responsible for long-term regional changes. A local RAAS and its components have been detected in many structures of the human eye. This review focuses on the local ocular RAAS in the anterior part of the eye, its possible role in aqueous humour dynamics and intraocular pressure as well as RAAS as a potential target for anti-glaucomatous drugs.KEY MESSAGESComponents of renin-angiotensin-aldosterone system have been detected in different structures of the human eye, introducing the concept of a local intraocular renin-angiotensin-aldosterone system (RAAS).Evidence is accumulating that the local ocular RAAS is involved in aqueous humour dynamics, regulation of intraocular pressure, neuroprotection and ocular pathology making components of RAAS attractive candidates when developing new effective ways to treat glaucoma.

Comparison of Capillary and Schirmer Strip Tear Fluid Sampling Methods Using SWATH-MS Proteomics Approach.

Purpose: The purpose of this study was to examine the protein profile differences between capillary and Schirmer strip tear fluid samples. Methods: Both capillary and Schirmer strip tear samples were collected from 31 healthy participants at the same visit, and the samples were analyzed with nanoflow liquid chromatography coupled with time-of-flight mass spectrometer (NanoLC-MSTOF), implementing a sequential window acquisition of all theoretical fragment ion spectra mass spectrometry (SWATH-MS). Sample type-specific and combined spectral libraries were used to evaluate the differences between the sample types in protein expression levels and biological functions. Results: In proportion, more extracellular proteins connected to immune response were quantified from the capillary samples while Schirmer strip samples contained more intracellular proteins. The sample types yielded similar counts of quantified proteins when a combined spectral library including both sample types was implemented. The differential expression analysis between the sample types identified proteins increased in the capillary samples (e.g., immunoglobulins) and Schirmer strip samples (e.g., heat-shock proteins, annexins, and S100 proteins). Conclusions: Tear proteomics data originating from the same participants vary depending on whether the sample is collected with capillary or Schirmer strip, although there is also overlap between the two sample types when a combined spectral library is implemented in the SWATH-MS analysis. In discovery-based proteomics research of tear fluid, appropriate sampling method should be chosen carefully based on the research focus. Translational Relevance: Currently, there is no consensus on how the tear fluid sampling methods affect the resulting proteomics data, and hence, identification of the most suitable sampling methods for clinical researchers with varying research interests is important.

Angiotensin (1-7) reduces intraocular pressure in the normotensive rabbit eye.

PURPOSE: In the present study the effects of exogenous angiotensin II and its breakdown metabolite angiotensin (1-7) on the intraocular pressure (IOP) and on aqueous humor dynamics in normotensive rabbit eye were evaluated. METHODS: Male New Zealand White rabbits with normal IOP were used for intravitreous and topical administration of the test compounds. IOP was measured in conscious rabbits by pneumatonometer after topical anesthesia. Outflow measurements were made with a two-level constant pressure method in anesthetized animals. RESULTS: Angiotensin (1-7) administered intravitreously reduced IOP within 1 to 5 hours (P < 0.05). This effect was abolished by the selective angiotensin (1-7) antagonist A-779, and partially by the selective angiotensin II type 2 receptor antagonist PD123319. When olmesartan, an angiotensin II type 1 receptor blocker, was administered simultaneously with angiotensin (1-7), no antagonism was seen. Intravitreous administration of CGP42112 A, an angiotensin II type 2 receptor agonist, and angiotensin II did not significantly influence IOP, nor did topical administration of these compounds alter IOP. Angiotensin II significantly reduced outflow facility (P < 0.01) dose dependently, whereas angiotensin (1-7) had no effect. CONCLUSIONS: Angiotensin (1-7) is a biologically active vasodilatory and antiproliferative heptapeptide, and its vascular effects counteract those of angiotensin II. It reduces intraocular pressure possibly by a selective Mas receptor, without changing aqueous humor outflow facility in the normotensive rabbit eye.

A modified in vitro method for aqueous humor outflow studies in enucleated porcine eyes.

The aim of this study was to develop and test a short-term in vitro method for aqueous humour outflow studies using enucleated porcine eyes. The method used was a modification of two methods that have previously been used: whole eyes and anterior segment cultures. The advantage of the model used in this study was that the anterior part of the eye, including the anterior and posterior chambers, remained intact as in whole enucleated eyes, but neither iridotomia nor trephination through the cornea was needed. The deepening of the anterior chamber during perfusion was avoided by regulating the "vitreal" pressure. Test compounds were administered topically or intracamerally to an anatomically normal anterior chamber. Fresh porcine eyes (n = 48) were sectioned at the equator, and the vitreous mass was carefully removed. This anterior bisection was bound around a specific plastic chamber, thus creating a closed eye. The anterior chamber was perfused at a pressure of 15 mmHg. The mean outflow rate in the nonmedicated eye group was 3.7 +/- 0.20 microL/min (mean +/- standard error of the mean), and it increased by 18% during 9 h owing to a wash-out effect. Compounds known to enhance the aqueous outflow were used for testing the validity of the preparation.

A Single Drop in the Eye - Effects on the Whole Body?

INTRODUCTION: Although the local adverse effects of ophthalmic drugs, including allergic reactions, are well recognized, less is known about the systemic side- effects of eye drops, especially during pregnancy, breast-feeding and early childhood. Ophthalmologists should also be aware of unusual, in some cases even life-threatening, effects of commonly used eye drops. CONCLUSION: This brief review outlines the routes of systemic absorption and the kinetics of active components present in eye drops, and identifies the clinically relevant systemic adverse effects.

Many Faces of Renin-angiotensin System - Focus on Eye.

The renin-angiotensin system (RAS), that is known for its role in the regulation of blood pressure as well as in fluid and electrolyte homeostasis, comprises dozens of angiotensin peptides and peptidases and at least six receptors. Six central components constitute the two main axes of the RAS cascade. Angiotensin (1-7), an angiotensin converting enzyme 2 and Mas receptor axis (ACE2-Ang(1-7)-MasR) counterbalances the harmful effects of the angiotensin II, angiotensin converting enzyme 1 and angiotensin II type 1 receptor axis (ACE1-AngII-AT1R) Whereas systemic RAS is an important factor in blood pressure regulation, tissue-specific regulatory system, responsible for long term regional changes, that has been found in various organs. In other words, RAS is not only endocrine but also complicated autocrine system. The human eye has its own intraocular RAS that is present e.g. in the structures involved in aqueous humor dynamics. Local RAS may thus be a target in the development of new anti-glaucomatous drugs. In this review, we first describe the systemic RAS cascade and then the local ocular RAS especially in the anterior part of the eye.

Abnormal increase of intraocular pressure in fellow eye after severe ocular trauma: A case report.

BACKGROUND: An ocular injury can lead to secondary glaucoma in the traumatized eye in 3% to 20% of cases. Literature on the risk of developing elevated intraocular pressure in the nontraumatized fellow eye is scant. Clinicians treating ocular traumas should also bear in mind sympathetic ophthalmia, a rare bilateral granulomatous panuveitis following accidental or surgical trauma to 1 eye. CASE REPORT: We report a case of high-pressure glaucoma of the fellow eye without any signs of uveitis. The left eye of a 24-year-old man was injured in an inadvertent movement during a free-time table-tennis match. The eye was severely crushed, leading to blindness. His right eye developed medically uncontrolled high-pressure glaucoma only 1 month after the injury. CONCLUSION: To the best of our knowledge, there are no previous reports of post-traumatic glaucoma in the nontraumatized eye after open-globe injury.

Angiotensin(1-7) and ACE2, "The Hot Spots" of Renin-Angiotensin System, Detected in the Human Aqueous Humor.

BACKGROUND: The main purpose of the study was to establish whether essential components of the renin-angiotensin system (RAS) exist in the human aqueous humor. METHODS: Forty-five patients ≥ 60 (74±7) years of age undergoing cataract surgery at Tampere University Hospital were randomly selected for the prospective study. The exclusion criterion was the use of oral antihypertensive medicine acting via renin-angiotensin system. Aqueous humor samples were taken at the beginning of normal cataract extraction. The samples were frozen and stored at -80 °C. The concentrations of intraocular endogenous RAS components Ang(1-7), ACE2, and ACE1 were measured using ELISA. RESULTS: Concentration medians of Ang(1-7), ACE2, and ACE1 in the aqueous humor were: Ang(1-7) 4.08 ng/ml, ACE2 2.32 ng/ml and ACE1 0.35 ng/ml. The concentrations were significantly higher in glaucomatous than in non-glaucomatous eyes, ACE1 (p=0.014) and Ang(1-7) (p=0.026) vs non-glaucomatous eyes. CONCLUSIONS: Ang(1-7), ACE2 and ACE1 are found in the human aqueous humor. The observations are consistent with the conception that local tissue-RAS exists in the human eye and it might have a role in the control of intraocular pressure.

Local ocular renin-angiotensin system - a target for glaucoma therapy?

An active local intraocular renin-angiotensin system (RAS) has recently been shown to exist in the human eye, and evidence is now accumulating that antihypertensive drugs acting on RAS can also lower intraocular pressure. They seem also to work as neuroprotective agents against retinal ganglion cell loss in vivo; though no compounds are in ophthalmological use at present. Classically, the highly vasoconstrictive angiotensin II (Ang II) is the key peptide in the circulatory RAS. However, the final effect of RAS activation at tissue level is more complex, being based not only on the biological activity of Ang II but also on the activities of other products of angiotensinogen metabolism, often exerting opposite effects to Ang II action.

Angiotensin receptors in the eyes of arterial hypertensive rats.

PURPOSE: The aim of the present study was to determine whether the eye tissues of arterial hypertensive rats evince expression of angiotensin receptors (AT(1) and AT(2)) as well as the novel Mas receptor, whose endogenous ligand is vasorelaxing Angiotensin (1-7) [Ang (1-7)]. METHODS: Enucleated eyes from spontaneously hypertensive rats (SHR) and double transgenic rats harbouring human renin and angiotensinogen genes (dTGR) and their normotensive controls were used. Half of the rats were pretreated orally with an Angiotensin II (Ang II) type 1 receptor blocker (ARB). The eyes were snap-frozen in isopentane at -40 degrees and stored at -70 degrees for subsequent reverse transcriptase polymerase chain reaction (RT-PCR) analysis or in vitro autoradiography. RESULTS: The mRNA expression of AT(1a) and AT(2) as well as the novel Mas receptor was detected in all rat groups, being markedly higher in the retina than in the ciliary body. dTGR had significantly more receptors than SHR, but no direct relation to blood pressure level was seen. According to the autoradiography, treatment with ARB blocked a part of AT(1) receptors but had no clear effect on AT(2) receptors. CONCLUSION: The novel Mas receptor was found by RT-PCR in eye tissue for the first time. Its specific ligand, Ang (1-7), may be involved in the regulation of intraocular pressure--as recently demonstrated by us--and in the pathogenesis of retinal diseases as a counter-regulatory component for the vascular and proliferative actions of Ang II. The results suggest that the density of AT(1) receptors in the eye is independent of the blood pressure level of the animal.