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Cell-penetrating peptides (CPPs) hold great promise for intracellular delivery of therapeutic proteins. However, endosomal entrapment of transduced cargo is a major bottleneck hampering their successful application. While developing a transducible zinc finger protein-based artificial transcription factor targeting the expression of endothelin receptor A, we identified interaction between the CPP and the endosomal membrane or endosomal entanglement as a main culprit for endosomal entrapment. To achieve endosomal disentanglement, we utilized endosome-resident proteases to sever the artificial transcription factor from its CPP upon arrival inside the endosome. Using this approach, we greatly enhanced the correct subcellular localization of the disentangled artificial transcription factor, significantly increasing its biological activity and distribution in vivo. With rational engineering of proteolytic sensitivity, we propose a new design principle for transducible therapeutic proteins, helping CPPs attain their full potential as delivery vectors for therapeutic proteins.

Retinal vein occlusion (RVO) is a common vascular disease of the retina; however, the pathogenesis of RVO is still unclear. Branch RVO (BRVO) commonly occurs at the arteriovenous crossing and it was formerly believed that the diseased artery mechanically compresses the vein. However, it has been reported that the retinal vein runs deep beneath the artery at the arteriovenous crossing in eyes with an arterial overcrossing, and the venous lumen often appears to be preserved, even at the arteriovenous crossing, as shown by optical coherence tomography. Paques et al. [1] found venous nicking without arteriovenous contact using adaptive optics imaging. Thus, we investigated the potential role of a dysregulation of the retinal vein. While the pathogenesis of retinal vein occlusion (RVO) is still unclear, systemic hypertension and increased level of endothelin-1 (ET-1) are known risk factors (Flammer and Konieczka, 2015) [2]. We focused on the behavior of retinal veins in spontaneous hypertensive rats (SHR). Then, one of the retinal veins became exceptionally constricted and was nearly occluded (Fig. 1), and the chorioretinal blood flow significantly decreased in the retinas of SHRs following the intravenous injection of ET-1. In addition, immunoreactivity to ET-A receptor was higher in SHR retinas than in control (WKY; Wistar Kyoto rat) retinas (Fig. 2). The protein levels of ET-A receptor and HIF-1 were also significantly higher in SHR retinas than in WKY retinas (Fig. 3). We observed vasoactivity of retinal veins; a retinal venous constriction (Kida et al., 2018) [3]. This supports the hypothesis that ET-1 can constrict retinal veins, thus increasing retinal venous pressure, and that ET-1 may even contribute to the pathogenesis of RVO.

Purpose The pathomechanism leading to retinal vein occlusion (RVO) is unclear. Mechanical compression, thrombosis, and functional contractions of veins are discussed as the reasons for the increased resistance of venous outflow. We evaluated changes in the retinal venous pressure (RVP) following intravitreal injection of anti-vascular endothelial growth factor (VEGF) agent to determine the effect on RVO-related macular edema. Methods Twenty-six patients with RVO-related macular edema (16 branch RVOs [BRVOs] and 10 central RVOs [CRVOs], age 72.5 ± 8.8 years) who visited our hospital were included in this prospective study. Visual acuity (VA), intraocular pressure (IOP), central retinal thickness (CRT) determined by macular optical coherence tomography, and RVP measured using an ophthalmodynamometer were obtained before intravitreal injection of ranibizumab (IVR) and 1 month later. Results Comparison of the BRVOs and CRVOs showed that VA was significantly improved by a single injection in BRVOs (P < 0.0001; P = 0.1087 for CRVOs), but CRT and RVP were significantly decreased without significant difference in IOP after the treatment in both groups (P < 0.0001). Conclusion The anti-VEGF treatment resulted in a significant decrease in the RVP, but the RVP remained significantly higher than the IOP. An increased RVP plays a decisive role in the formation of macula edema, and reducing it is desirable.

Flammer syndrome describes the predisposition for an altered reaction of the blood vessels to stimuli such as coldness, emotional stress, and / or hypoxia - together with a group of additional signs and symptoms. The essential component of Flammer syndrome is primary dysregulation of blood vessels.

This case report introduces a female patient, who since her teenager age evidently suffers from Flammer syndrome (FS) as the clearly defined sub-optimal health condition. Further, the patient has experienced collateral pathological conditions which primarily might be linked to the family (genetic) predisposition, but the development of which could be synergistically promoted by the FS-phenotype. The facts are thoroughly analysed and consequent hypotheses are presented, which are indicative for highly desirable predictive diagnostics and targeted preventive measures to be created based on the accurate interpretation of the individualised patient profile. The authors emphasise the great clinical relevance of the FS and field-related research.

Purpose Whilst the pathogenesis of retinal vein occlusion (RVO) is still unclear, systemic hypertension and increased level of endothelin-1 (ET-1) are known risk factors. Therefore, we studied the influence of ET-1 on the retinal veins in hypertensive rats. Methods We focused on the behavior of retinal veins in spontaneous hypertensive rats (SHR). To determine whether ET-1 was associated with the blood flow in eyes of SHRs, the chorioretinal blood flow in the rats was assessed using laser speckle flowgraphy (LSFG-Micro, Softcare, Fukuoka, Japan) before and after an intravenous injection of ET-1 under general anesthesia. In addition, retinas from SHRs and age-matched normotensive Wistar-Kyoto rats (WKYs) were removed, and retinal sections were immunostained for the ET-A and ET-B receptors. The protein levels of both ET-1 receptors and hypoxia-inducible factor 1 (HIF-1) in the retinal tissues were also determined by western blot analysis. Results One of the retinal veins became exceptionally constricted and was nearly occluded, and the chorioretinal blood flow significantly decreased in the retinas of SHRs following the injection of ET-1. Immunoreactivity to ET-A receptor was higher in SHR retinas than in WKY retinas. The protein levels of ET-A receptor and HIF-1 were also significantly higher in SHR retinas than in WKY retinas. Conclusions An increase of ET-1 in circulating blood leads to the local constriction of retinal veins and this effect is accentuated in hypertensive rats by an upregulation of ET-A receptor. It is plausible that such a constriction of retinal veins increases retinal venous pressure, and may even contribute to the pathogenesis of RVO.

This review describes the clinical and basic research that led to the description of Flammer syndrome. It is narrated from a personal perspective. This research was initiated by the observation of an increased long-term fluctuation of visual fields in a subgroup of glaucoma patients. As these patients had strikingly cold hands, peripheral blood flow was tested with a capillary microscopy, and vasospastic syndrome (VS) was diagnosed. Further studies on these patients revealed frequently weakened autoregulation of ocular blood flow and increased flow resistivity in retroocular vessels. Their retinal vessels were more rigid and irregular and responded less to flickering light. Holistic investigation demonstrated low blood pressure, silent myocardial ischaemia, altered beat-to-beat variation, altered gene expression in the lymphocytes, slightly increased plasma endothelin level and increased systemic oxidative stress. This combination of signs and symptoms was better described by the term primary vascular dysregulation (PVD) than by VS. Subsequent studies showed additional symptoms frequently related to PVD, such as low body mass index, cold extremities combined with slightly increased core temperature, prolonged sleep onset time, reduced feelings of thirst, increased sensitivity to smell and also for certain drugs and increased retinal venous pressure. To better characterise this entire syndrome, the term Flammer syndrome (FS) was introduced. Most subjects with FS were healthy. Nevertheless, FS seemed to increase the risk for certain eye diseases, particularly in younger patients. This included normal-tension glaucoma, anterior ischaemic optic neuropathy, retinal vein occlusions, Susac syndrome and central serous chorioretinopathy. Hereditary diseases, such as Leber’s optic neuropathy or retinitis pigmentosa, were also associated with FS, and FS symptoms and sings occurred more frequent in patients with multiple sclerosis or with acute hearing loss. Further research should lead to a more concise definition of FS, a precise diagnosis and tools for recognizing people at risk for associated diseases. This may ultimately lead to more efficient and more personalised treatment.

Das Flammer-Syndrom (FS) beschreibt den Phanotyp von Menschen mit einer Pradisposition fur eine veranderte Reaktion der Blutgefase auf Stimuli wie Kalte, emotionellen Stress oder grose Hohe. Haufige Symptome sind: kalte Hande und/oder Fuse, tiefer Blutdruck, verlangerte Einschlafzeit, reduziertes Durstgefuhl, gesteigerte Empfindlichkeit fur Geruche, Schmerzen, Vibrationen und gewisse Medikamente. Menschen mit FS sind im Allgemeinen strebsam und erfolgreich, aber auch perfektionistisch und teils grublerisch. Haufige Zeichen sind: veranderte Genexpression, verlangerter Flussstillstand in den Nagelfalzkapillaren nach Kalteprovokation, verminderte Autoregulation der okularen Durchblutung, reduzierte Gefaserweiterung auf Flickerlichtstimulation. Der retinale Venendruck ist im Mittel hoher und die Astrozyten sind haufiger aktiviert. FS ist haufiger bei Frauen als bei Mannern, haufiger bei dunnen als bei dicken und bei jungen als bei alten Menschen, haufiger bei Akademikern als bei Nichtakademikern. Es ist sehr selten bei Menschen mit Berufen im Freien. Es ist assoziiert mit Normaldruckglaukom, okularen Gefasverschlussen, Retinitis pigmentosa, multipler Sklerose, Tinnitus und seltener sogar mit Horsturzen.

There is substantial research on the vasoactive peptide endothelin (ET)-1 in physiology, as well as in pathology. In fact, pathologically elevated levels of ET-1 have been found in several disease states, such as various cardiovascular diseases, different cancers, some neurodegenerative disorders, as well as in diabetes. Here, we describe and discuss ET-1, its importance in different diseases, and the potential therapeutic effects of ET-traps in the treatment of these diseases. Previous in vitro and in vivo research (in the diabetes disease space) demonstrated that ET-traps potently and significantly prevent the induction of different markers of diabetes-related pathology. This included induction of extracellular matrix (ECM) proteins (collagen 4α1 and fibronectin), which are pathologically elevated in diabetes. The ET-traps prevented induction of these and brought a significant return to non-diabetic levels. We also discuss the merits of using ET-traps over the currently used endothelin receptor antagonists (ERAs) and previously used therapeutic antibodies.

Background: To measure the retinal venous pressure (RVP) in both eyes of patients with unilateral central retinal vein occlusions and to compare these values to controls. Methods: The study included 31 patients with unilateral central retinal vein occlusions (CRVO) and 31 controls who were matched by age, sex, and systemic disease. RVP was measured in all patients bilaterally by means of contact lens ophthalmodynamometry, and the RVP measurements of the affected and unaffected eyes of patients were compared to the RVPs of controls. Ophthalmodynamometry is done by applying an increasing pressure on the eye via a contact lens. The minimum force required to induce a venous pulsation is called ophthalmodynamometric force (ODF). The RVP is defined and calculated as the sum of ODF and intraocular pressure (IOP) [RVP = ODF + IOP]. Results: The RVP group means ± SD were as follows: patient's affected eyes (45.0 ± 11.6mmHg), patient's unaffected eyes (38.0 ± 11.1mmHg) ,and (17.7 ± 6.7mmHg) in the eyes of controls. The values of RVP, even in the patients unaffected eyes, were significantly higher than in the eyes of controls (P

The second leading cause of blindness in humans – glaucoma is a multi-factorial disease; risk factors known are highly complex. A genetic component plays a role in the glaucoma pathology as well as internal and external stress factors suggesting epi/genetic patho mechanisms of the disease. Liquid biopsy analyses have been demonstrated as relevant for detecting a specific glaucoma signature in Flammer Syndrome phenotype. Multiomic approach has been proven as being of great utility for predictive diagnosis of glaucoma and patient stratification, further, providing information for potential multi-target treatments tailored to the person. The chapter highlights the omic-technologies and comprehensive molecular biological output for innovative PPPM strategies in glaucoma research with a potential to improve medical services in the area.

There are modern trends in medical research, such as molecular biology, molecular genetics and animal experiments. This is taking an ever greater role in industrial research, but also at universities, with consequences for the filling of positions and the distribution of funds. This is also reflected in the number of publications. While this undoubtedly has many advantages and has also brought much medical progress, there are important aspects in medicine for which other approaches are needed. By means of the discovery of Flammer Syndrome, we would like to show that alternative research methods are also important and have a right to exist. Important on the long road to the discovery of Flammer Syndrome were the observations on individual patients, a holistic approach and interdisciplinary cooperation.

Herewith we introduce a selected patient case, who evidently demonstrates Flammer syndrome signs and symptoms which might be strongly indicative for predictive diagnostic approaches and targeted preventive measures, if a correct interpretation would be made well in time. A self-report is presented.

Purpose: We set out to evaluate alterations of the therapeutic target genes KIT (CD 117), EGFR, and HER-2 in human retinoblastoma. Methods: Ninety-five formalin-fixed, paraffin-embedded retinoblastomas were brought into a tissue microarray (TMA) format. Immunohistochemistry was performed to analyze the expression of CD117, EGFR, and HER-2. Fluorescence in situ hybridization (FISH) was utilized for detection of EGFR amplifications. Three tumors with strong CD117 positivity were sequenced for KIT exon 11 mutations. Results: Detectable CD117 expression was seen in 19% of all interpretable cases. Sequence analysis of the three tumors with the strongest CD117 expression revealed no mutations. EGFR was positive in 14% of all cases. No EGFR amplification was observed by FISH, however. All tumors were negative for HER-2 expression. Conclusions: Our data suggest that selected cases of retinoblastoma may be candidates for anti-EGFR and imatinib mesylate (STI571) therapy

Purpose: To analyse short-term variability of systemic blood pressure and choroidal blood flow in glaucoma patients, and compare them with ocular hypertensive patients and controls. Subjects and methods: Thirty untreated patients with primary open-angle glaucoma (POAG), 25untreated patients with ocular hypertension (OHT) and 50healthy controls without local therapy were included in the study. Continuous 5-minute measurements of arterial systemic blood pressure (SBP) by Finometer and choroidal blood flow (CBF) by laser Doppler flowmetry were obtained. Variability of SBP and CBF was analysed by means of coefficient of variation and analyzed in ANOVA model. Linear regression analysis was performed on parameters of morphological (nerve fiber layer thickness) and functional glaucomatous damage (visual field) on one side, and between SBP and CBF on the other side. Results: ANOVA model demonstrated significant differences in variability between the groups (p = 0.003); post-hoc analysis specified a significantly higher short-term variability of both the blood pressure and choroidal blood flow in POAG patients (coefficients of variation: 3.33% ± 1.05% and 3.90% ± 2.17% respectively) than in healthy controls (coefficient of variation: 2.57% ± 0.80% and 2.94% ± 1.52% respectively). No significant differences were found for OHT patients. Conclusions: POAG patients without local therapy demonstrate an increased short-term BP and CBF variability

Purpose: This study was performed in an attempt to gain more information on whether the 30Hz-flicker mfERG indeed provides a sensitive measure of dysfunction in patients with primary open-angle glaucoma (POAG) as has been suggested previously. Methods: Eighteen POAG patients with visual field defects (MD>2.2dB) and glaucomatous optic neuropathies as well as 10 control subjects underwent mfERG recording as follows: 30Hz-flicker mfERG, LED stimulus screen, 61 hexagons, L max: 180cd/m2, L min: 0cd/m2, recording time: ∼5min, filter setting: 10-200Hz. The 30Hz response (also called the fundamental or the first harmonic response (1HW) and the second harmonic wave at 60Hz (2HW) were analysed as an overall response and in quadrants, as well as in 4 small neighbouring areas per quadrant. The patients' mfERGs were compared to those of the control group and to the mean defect values (MD) of the corresponding quadrants of the Octopus perimetry. Results: Neither in the overall response, nor in the quadrants, nor in the smaller areas examined did amplitudes and phases of the 1HW and the 2HW or the amplitude ratio of the 2HW to the 1HW (DFT-ratio) differ from the controls (P>0.05—ANOVA). There was no significant correlation between mfERG values and the MD (Spearman-test, Bonferroni). Conclusion: Thus, the 30Hz-flicker mfERG does not seem to be sensitive enough to separate glaucoma patients from normal

We aimed to immunohistochemically examine the expression of KIT (CD 117) in human posterior uveal melanoma and to analyze KIT-positive tumors for gene mutations. Brought into a tissue microarray (TMA) format were 101 formalin-fixed, paraffin-embedded posterior uveal melanomas. Immunohistochemistry was performed using the polyclonal anti-CD117 antibody from Dako (A4502). In ten selected KIT-positive tumors, exons 2, 8, 9, 11, 13 and 17 were sequenced. Of the 101 cases, 89 (88%) could be evaluated on the TMAs. Immunohistochemistry for CD 117 was weakly positive in 5 cases (6%), moderately positive in 10 cases (12%) and strongly positive in 57 cases (69%). No KIT mutations were detected in the analyzed exons. In conclusion, human posterior uveal melanoma frequently expresses CD117 at high levels. Although KIT mutations could not be found, it appears justified to investigate the utility of imatinib mesylate in the treatment of these patients.

Purpose: Oxidative stress plays an important role in the pathogenesis of glaucomatous optic neuropathy. One indirect measure of oxidative stress is the quantification of DNA breaks by comet assay. This study aims to quantify single-stranded DNA (ss-DNA) breaks in circulating leukocytes of glaucoma patients treated with Ginkgo biloba and Nifedipine and compare results with an untreated group. Design: Retrospective clinical study. Participants: Sixty patients with bilateral open-angle glaucoma. Methods: The following groups (n = 20) were retrospectively compared: Primary open-angle glaucoma (POAG) patients without any systemic treatment; POAG patients treated with 5 mg of Nifedipine daily; POAG patients treated with 120 mg of Ginkgo biloba daily. The damage to ss-DNA was quantified as tail-moment by comet assay. Main outcome measures: Damage to single-stranded DNA (ss-DNA) quantified as tail moment in three groups of patients. Results: Patients treated with Ginkgo biloba and Nifedipine exerted a significant...

Protein quality control is essential for maintaining mitochondrial fidelity. Proteins damaged by reactive oxygen species necessitate quality control to prevent mitochondrial dysfunction connected to aging and neurodegeneration. Here we report a role for the AAA ATPase p97/VCP and the proteasome in the quality control of oxidized mitochondrial proteins under low oxidative stress as well as normal conditions. Proteasomal inhibition and blocking p97-dependent protein retrotranslocation interfered with degradation of oxidized mitochondrial proteins. Thus, ubiquitin-dependent, p97-, and proteasome-mediated degradation of oxidatively damaged proteins plays a key role in maintaining mitochondrial fidelity and is likely an important defense mechanism against aging and neurodegeneration.

Objective: visual disorders are among the earliest symptoms of Alzheimer’s disease. It is, however, still controversial as to whether Alzheimer’s disease impairs colour vision. In this study, colour vision of Alzheimer’s disease patients was tested using the Ishihara test and the PV-16 choice test. The latter test, primarily designed for children, was chosen in order to avoid problems due to cognitive decline. Methods: 26 patients with mild to severe Alzheimer’s disease (M:F=5:21; mean age: 80"9 years, range: 53–95 years) and 25 controls (M:F=5:20; mean age 80"10 years, range: 56–100 years) were rated after undergoing complete neuro-ophthalmologic examination. Results: the Alzheimer’s disease patients made significantly more unspecific errors in the Ishihara test (P=0.02) and in the PV-16 choice test (P=0.0008) than the controls. No relation between test performance and severity of Alzheimer’s disease was found. Conclusions: Alzheimer’s disease patients have an unspecific colour vision deficiency independent of the severity of the disease.

Purpose: The aim of this study was to analyze predictors of long-term glaucoma progression. Patients and Methods: We followed 17 primary open angle glaucoma patients (POAG) and 25 ocular hypertensives (OHT) over three years, with regular follow-up examinations of both eyes every 6 months. Glaucoma damage was quantified by optical coherence tomography (retinal nerve fiber layer – OCT RNFL) and by perimetry. Corneal and hand temperature (infrared thermometer), corneal hysteresis, pachymetry and ocular pulse amplitude (OPA) readings were taken at baseline, and applanatory intraocular pressure and retinal vessel analysis recordings were made at baseline and follow-up visits. Forward-stepwise multiple regression analysis was performed. Results: With OCT-RNFL progression as the dependent variable, the model selected initial diagnosis (OHT less probable of progressing), baseline RNFL thickness, retinal arterial and venous diameter and arterial flicker response as significant damage predictors. For visual field damage progression, these were: corneal temperature, OPA, initial diagnosis and venous flicker response (all p Conclusion: Initial damage and vascular factors are strong predictors of future glaucoma progression.

Diurnal cycle variations in body-heat loss and heat production, and their resulting core body temperature (CBT), are relatively well investigated; however, little is known about their variations across the menstrual cycle under ambulatory conditions. The main purpose of this study was to determine whether menstrual cycle variations in distal and proximal skin temperatures exhibit similar patterns to those of diurnal variations, with lower internal heat conductance when CBT is high, i.e. during the luteal phase. Furthermore, we tested these relationships in two groups of women, with and without thermal discomfort of cold extremities (TDCE). In total, 19 healthy eumenorrheic women with regular menstrual cycles (28-32 days), 9 with habitual TDCE (ages 29 ± 1.5 year; BMI 20.1 ± 0.4) and 10 controls without these symptoms (CON: aged 27 ± 0.8 year; BMI 22.7 ± 0.6; p

Background Information. Meningothelial cells (MECs) are the cellular components of the meninges protecting the brain and as such provide important barrier function for the central nervous system building the interface between neuronal tissue and the cerebrospinal fluid (CSF). MECs were previously shown to be involved in the clearance of waste products from the CSF and in maintaining the optic nerve microenvironment. In addition, MECs are involved in immunological processes in the brain by secretion of pro-inflammatory cytokines in response to various pathologically relevant stress conditions. Results. In this study, we analysed the uptake of latex beads as well as bacteria by human MECs using flow cytometric analyses. We found that MECs are highly active phagocytes able of ingesting large amounts of latex beads, as well as Gram-positive and Gram-negative bacteria. Phagocytic activity of MECs was sensitive to nocodazole and cytochalasin D treatment to a varying degree depending on particle composition. Interestingly, Gram-positive bacteria such as Staphylococcus aureus are more readily taken up compared with Gram-negative Escherichia coli. In addition, pre-treatment of MECs with lipopolysaccharide (LPS) or phorbol-12-myristate-13-acetate (PMA) enhanced S. aureus uptake, whereas PMA but not LPS was effective in enhancing E. coli uptake. Conclusions. Thus, MECs are highly active facultative phagocytes likely important for the maintenance of CSF homeostasis and host defence in the central nervous system especially against Gram-positive bacteria. Additional supporting information may be found in the online version of this article at the publisher’s web-site

Hintergrund: Analyse der Pulsamplitude der Netzhautvenen bei Glaukompatienten. Patienten und Methoden: Bewegungen der 2 (in der Nahe und entfernt von der Papille) inferotemporalen Venensegmente von je 500 Mikrometer Lange wurden mittels des Retinal Vessel Analyzers wahrend 30 Sekunden aufgenommen. Eine selbst entwickelte Software wurde eingesetzt, um das zeitliche Verhalten des Venendurchmessers zu erforschen. Eine durchschnittliche Wellenform wurde aufgrund der Fourier-Analyse bestimmt. Der Unterschied zwischen dem hochsten und tiefsten Durchmesser wurde bei 25 Glaukomaugen mit 25 Kontrollprobanden verglichen. Ergebnisse: Die Pulsamplitude bei gesunden Probanden war hoher als in Glaukomaugen: in der Papillennahe betrug sie, relativ zur Baseline, jeweils 2,6 ± 2,1 % und 1,4 ± 0,8 % (t-Test, p = 0,009). Weiter von der Papille waren die Werte jeweils 1,7 ± 1,0 % und 1,1 ± 0,5 % (p = 0,01) Schlussfolgerungen: Netzhautvenen in Glaukompatienten weisen verminderte Pulsamplituden im Vergleich zu gesunden Kontrollaugen auf; ein Hinweis fur den gestorten Venenabfluss und erhohten intraluminalen Druck.

Es ist schon lange bekannt, dass ein erhohter Augendruck Ursache fur das Glaukom ist. Somit konzentriert sich auch die klassische Glaukomtherapie auf die Senkung des Augeninnendrucks (IOD). Dies hat nun, da es oft nicht ausreicht und es bei masigem oder normalem Augendruck zu Schaden kommen kann, das Bedurfnis nach neuen therapeutischen Ansatzen eroffnet. Es mussen auch andere Risikofaktoren (auser des Augendrucks) fur den Glaukomschaden mitverantwortlich sein, die man behandeln sollte. Ein solcher Risikofaktor ist z.B die gestorte Regulation der Durchblutung. Wenn der Augendruck oder der Blutdruck schwankt, kann das Auge normalerweise die Durchblutung durch Selbstregulation konstant halten. Ist diese Regulierung gestort, kommt es zu einer instabilen Sauerstoffversorgung, was zu oxidativem Stress und somit zum Glaukomschaden fuhrt. Wahrend sich einige dieser Therapien noch in der experimentellen Phase befinden, werden andere bereits im klinischen Alltag eingesetzt. Eine primare vaskulare Dysregulation (PVD) und die daraus resultierende, veranderte Autoregulation in der Augendurchblutung (OBF) konnen mit Magnesium und – bei ausbleibendem Effekt – mit niedrig dosierten Kalziumantagonisten besser behandelt werden. Starke nachtliche Blutdruckabfalle konnen anfangs durch erhohte Salz- und Flussigkeitsaufnahme und – falls das nicht genugt – in einem weiteren Schritt mit Fludrocortison vermieden werden. Oxidativer Stress (bedingt durch instabile Sauerstoffversorgung) sollte mit Nahrungsmitteln mit antioxidativer Wirkung, die reich an Polyphenol-Flavonoiden (wie Tee, Kaffee und Rotwein) oder an Anthocyanosiden (z. B. in Heidelbeeren) sind, reguliert werden. Ginkgo biloba schutzt die Mitochondrien des Sehnervs vor oxidativem Stress. Experimentell kann die glaukomatose Optikusneuropathie (GON) durch Hemmung der Aktivierung der Astrozyten verhindert werden. Diese konnen einerseits mechanisch aktiviert werden und durch die Blockade der epidermalen Wachstumsfaktorrezeptoren gehemmt werden. Anderseits konnen die Astrozyten biochemisch durch gesteigerte Endothelinproduktion mobilisiert werden und entsprechend mit sog. Endothelinblockern aufgehalten werden. Auch Stickstoffmonoxid-Synthase-2-(NOS-2-)Hemmer verhindern die Glaukomentwicklung. Die Hemmung der Matrix-Metalloproteinase-9 (MMP-9) beugt der Apoptose retinaler Ganglienzellen und der Gewebeumbildung vor.

The vasculature of the eye and the heart share several common characteristics. The easily accessible vessels of the eye are therefore-to some extent-a window to the heart. There is interplay between cardiovascular functions and risk factors and the occurrence and progression of many eye diseases. In particular, arteriovenous nipping, narrowing of retinal arteries, and the dilatation of retinal veins are important signs of increased cardiovascular risk. The pressure in the dilated veins is often markedly increased due to a dysregulation of venous outflow from the eye. Besides such morphological criteria, functional alterations might be even more relevant and may play an important role in future diagnostics. Via neurovascular coupling, flickering light dilates capillaries and small arterioles, thus inducing endothelium-dependent, flow-mediated dilation of larger retinal vessels. Risk factors for arteriosclerosis, such as dyslipidaemia, diabetes, or systemic hypertension, are also risk factors for eye diseases such as retinal arterial or retinal vein occlusions, cataracts, age-related macular degeneration, and increases in intraocular pressure (IOP). Functional alterations of blood flow are particularly relevant to the eye. The primary vascular dysregulation syndrome (PVD), which often includes systemic hypotension, is associated with disturbed autoregulation of ocular blood flow (OBF). Fluctuation of IOP on a high level or blood pressure on a low level leads to instable OBF and oxygen supply and therefore to oxidative stress, which is particularly involved in the pathogenesis of glaucomatous neuropathy. Vascular dysregulation also leads to a barrier dysfunction and thereby to small retinal haemorrhages.

Background: The optic nerve compartment syndrome is a pathological condition in which cerebrospinal fluid of the subarachnoid space surrounding the optic nerve is partly or totally segregated from the cerebrospinal fluid of the intracranial subarachnoid space, leading – inter alia – to an increase in the diameter of the optic nerve sheath. The pathogenesis of this condition remains unclear. We have observed clinically that optic nerve compartment syndrome often occurs in normal tension glaucoma patients with Flammer syndrome. To treat Flammer syndrome, some glaucoma patients received a low dose of a calcium channel blocker and we analysed whether this treatment also had an effect on the optic nerve compartment syndrome. Patients and Methods: We retrospectively analysed the data of 10 eyes of seven patients suffering from a combination of primary open angle glaucoma, optic nerve compartment syndrome, and Flammer syndrome. We included subjects who had eye socket echography before and after a few months of therapy with a calcium channel blocker. Therapy and Results: All patients received a low dose of a calcium channel blocker (nifedipine or amlodipine) to treat Flammer syndrome. As expected, the symptoms of Flammer syndrome were mitigated. To our surprise, the optic nerve compartment syndrome also improved in eight of the 10 eyes (80 %), but remained unchanged in the remainder. Conclusions: To some extent, the optic nerve compartment syndrome is related to the combination of primary open angle glaucoma and Flammer syndrome. On the basis of our results, we hypothesise that treatment of Flammer syndrome may also improve the optic nerve compartment syndrome.

Branch retinal vein occlusion (BRVO) commonly occurs at the arteriovenous crossing in the unilateral eye, and cardiovascular diseases can be risk factors of BRVO. However, the pathomechanism leading to BRVO is not yet clear. In addition to mechanical compression, the vein might locally constrict due to an altered biochemical environment, such as an increase in the concentration of endothelin-1 (ET-1). We evaluated changes in ET-1 following injection of intravitreal bevacizumab (IVB), which is the anti-vascular endothelial growth factor (VEGF) agent with the longest serum half-life, to determine the effect on BRVO-related macular edema. Twenty consecutive patients with BRVO-related macular edema (10 males, 10 females; age range 56–83 years) who visited our hospital were included in this prospective study. Visual acuity (VA); central retinal thickness (CRT), determined by macular optical coherence tomography (OCT); and plasma ET-1 levels were obtained before IVB treatment and 1 month later. Patients had hypertension (80 %), dyslipidemia (50 %), diabetes mellitus (35 %), or collagen disease (5 %). Mean CRT was significantly decreased from 673.0 ± 327.8 to 388.2 ± 155.0 μm (P = 0.0007), and mean VA was significantly improved after IVB (P = 0.0239). Mean plasma ET-1 was significantly decreased from 1.272 ± 0.451 to 1.095 ± 0.316 pg/mL (P = 0.0238); however, the plasma ET-1 level was increased in all five patients who did not show improved VA after IVB. In patients with BRVO-related macular edema, anti-VEGF therapy leads to an expected reduction in ET-1 levels; however, the ET-1 level was found to increase in some patients; this is clearly related to less improvement of VA after anti-VEGF therapy. University hospital Medical Information Network (UMIN) Center UMIN000013236 . Registered 10 October, 2012.

It is generally assumed that skin vascular resistance contributes only to a small extent to total peripheral resistance and hence to blood pressure (BP). However, little is known about the impact of skin blood flow (SBF) changes on the diurnal variations of BP under ambulatory conditions. The main aim of the study was to determine whether diurnal patterns of distal SBF are related to mean arterial BP (MAP). Twenty-four-hour ambulatory measurements of BP, heart rate (HR) and distal (mean of hands and feet) as well as proximal (mean of sternum and infraclavicular region) skin temperatures were carried out in 51 patients (men/women = 18/33) during a 2-d eye hospital investigation. The standardized ambulatory protocol allowed measurements with minimal interference from uncontrolled parameters and, hence, some conclusive interpretations. The distal minus proximal skin temperature gradient (DPG) provided a measure for distal SBF. Individual cross-correlation analyses revealed that the diurnal pattern of MAP was nearly a mirror image of DPG and hence of distal SBF. Scheduled lunch and dinner induced an increase in DPG and a decline in MAP, while HR increased. Low daytime DPG (i.e. low distal SBF) levels significantly predicted sleep-induced BP dipping (r = -.436, p = .0014). Preliminary path analysis suggested that outdoor air temperature and atmospheric pressure may act on MAP via changed distal SBF. Changes in distal SBF may contribute to diurnal variation in MAP, including sleep-induced BP dipping and changes related to food intake. This finding might have an impact on individual cardiovascular risk prediction with respect to diurnal, seasonal and weather variations; however, the underlying mechanisms remain to be discovered.

The retinal venous pressure (RVP) can be measured non-invasively. While RVP is equal to or slightly above intraocular pressure (IOP) in healthy people, it is often markedly increased in patients with eye or systemic diseases. Beside a mechanical obstruction, the main cause of such an elevation is a local dysregulation of a retinal vein, particularly a constriction induced by endothelin-1 (ET-1). A local increase of ET-1 can result from a high plasma level, as ET-1 can diffuse from the fenestrated capillaries of the choroid into the optic nerve head (ONH), bypassing the blood retinal barrier. A local increase can also result from increased local production either by a sick neighboring artery or retinal tissue. Generally, the main factors increasing ET-1 are inflammations and hypoxia, either locally or in a remote organ. RVP is known to be increased in patients with glaucoma, retinal vein occlusion (RVO), diabetic retinopathy, high mountain disease, and primary vascular dysregulation (PVD). PVD is the major vascular component of Flammer syndrome (FS). An increase of RVP decreases perfusion pressure, which heightens the risk for hypoxia. An increase of RVP also elevates transmural pressure, which in turn heightens the risk for retinal edema. In patients with RVO, a high level of RVP may not only be a consequence but also a potential cause of the occlusion; therefore, it risks causing a vicious circle. Narrow retinal arteries and particularly dilated retinal veins are known risk indicators for future cardiovascular events. As the major cause for such a retinal venous dilatation is an increased RVP, RVP may likely turn out to be an even stronger predictor.

Purpose: To assess risk factors for failure in canaloplasty. Methods: Nonrandomized prospective study involving 51 eyes of 51 patients with medically uncontrolled primary open-angle glaucoma undergoing canaloplasty. Visual acuity, intraocular pressure (IOP) and slit-lamp examinations were performed before and after surgery at 1 and 7 days, and at 1 month and every 3 months thereafter. Factors like age, gender, preoperative IOP and microhyphema on day 1 were evaluated. Results: The mean follow-up was 20.6 (SD 8.3) months. The mean preoperative IOP was 26.8 (SD 5.2) mmHg; the mean postoperative IOP was 8.4 (4.2) mmHg at day 1 and 12.7 (1.7) mmHg at month 24. Microhyphema was found in 40 patients (85.1%) on day 1 after surgery. The height of microhyphema was 1.8 mm ± 0.4 (SD) (range 1–2.5), and the time of resorption was 6.6 days ± 2.8 (SD) (range 3–14) on average. No recurrence of hyphema has been observed. IOP

Aim To report on the cerebrospinal fluid (CSF) exchange between the intracranial spaces (ie, basal cisterns) and the subarachnoid space (SAS) of the optic nerve (ON) in subjects with normal-tension glaucoma (NTG) compared with control subjects without NTG or other forms of glaucoma. Methods CT cisternography of the brain and orbits was performed in 18 patients with NTG (7 women, 11 men; mean age 64.9±8.9 years) and in four patients without glaucoma or intracranial disease (4 women; mean age 62.8±18.4 years). The density of contrast-loaded cerebrospinal fluid (CLCSF) in the intracranial spaces and in the SAS surrounding the ONs was measured in Hounsfield units. Study design Unmasked, prospective series. Statistical analysis was performed using an independent two-tailed t test and the non-parametric Spearman correlation test. Results The density of CLCSF in the SAS surrounding the ONs in the NTG group was significantly reduced compared with its density in the intracranial CSF spaces and in the SAS of ONs measured in the control group (p=0.006). There were no significant differences between men and women within the NTG group (p>0.35). Conclusions The finding of a difference in the concentration gradients between the CLCSF within the intracranial spaces and the SAS of the ONs in this group of NTG patients compared with control subjects supports the hypothesis of a disturbed CSF exchange between the CSF in the intracranial spaces and the CSF in the SAS surrounding the ONs. The disturbance of CSF dynamics in this specific CSF pathway can be explained by ON compartmentation. The clinical importance of this finding warrants further investigation.

To analyze pulse wave propagation in the ocular circulation and vessel stiffness in untreated eyes of normal tension primary open-angle glaucoma (NTG) patients.Inferotemporal retinal vessels of 22 NTG eyes and 25 controls were examined with a Retinal Vessel Analyzer. Inferotemporal peripapillary retinal nerve fiber layer thickness was measured by ocular coherence tomography. Phase delay between venous trough and arterial peak was assessed at 3 sites centrifugal from the disc and a choroid-to-retina pulse delay was calculated as an estimation of vessel rigidity.There was choroid-to-retina pulse delay of 0.26±0.08, 0.30±0.11, and 0.33±0.11 seconds, respectively, in NTG eyes at proximal, middle, and distal sites; in control eyes, the corresponding values were 0.28±0.10, 0.35±0.12, and 0.40±0.17 seconds. Average choroid-to-retina pulse delay was shorter in NTG eyes (P=0.028). Retinal nerve fiber layer (inferotemporal) showed an opposite correlation with choroid-to-retina pulse delay in controls (r=-0.48, P=0.019) and in NTG eyes (r=0.47, P=0.032 ).Untreated NTG eyes show stiffer retinal vessels. Vessel rigidity correlates with level of glaucomatous damage.

To report on the optic nerve sheath diameter (ONSD) in patients with normal-tension glaucoma (NTG) compared with controls without known optic nerve (ON) or intracranial disease.In 18 patients with NTG (mean age 64.9 ± 8.9 years; 7 women and 11 men), CT of the orbit was performed. 17 age- and gender-matched patients without ON or intracranial disease, who underwent CT of the orbits for non-ophthalmological reasons, served as controls. The widest intraorbital ONSD in axial sections was measured using a standardised technique.unmasked. Statistical analysis was performed using an independent two-tailed t Test and the non-parametric Spearman correlation test.ONSD was significantly (p0.001) increased in NTG patients (right side: mean 7.9 ± 0.9 mm SD; left: 8.0 ± 1.1 mm) compared with controls (right: 6.3 ± 0.5 mm; left: 6.1 ± 0.6 mm). Neither the NTG nor the control group had a significant difference in ONSD between males and females or between right and left sides.An increased ONSD is generally associated with increased intracranial pressure; however, ONSDs in a group of NTG patients also were significantly increased compared with controls. ON sheath compartmentation and thinning of the ON sheath are two possible explanations for an increase in the ONSD in patients with NTG.

To investigate the vasoactive effect of ET(A)-endothelin receptor antagonists avosentan (SPP-301) and BQ-123 in isolated porcine ciliary arteries with and without endothelium. To investigate the effect of avosentan on the endothelin-1 induced contractions in comparison with BQ-123 and BQ-788 (ET(B)-endothelin receptor antagonist) in isolated porcine ciliary arteries with and without endothelium.Vessels were placed in a myograph system to measure isometric forces. In a first set of experiments, quiescent vessels were exposed, cumulatively, to increasing concentrations of avosentan and BQ-123 (10(-9) M-3 × 10(-6) M). In a second set of experiments, quiescent vessels were first incubated with avosentan (10(-6) M and 10(-8) M), BQ-123 (10(-6) M), and BQ-788 (10(-6) M), respectively. Then the vessels were exposed, cumulatively, to increasing concentrations of endothelin-1 (10(-12) M-3 × 10(-8) M). Each set of experiments was conducted in the vessels with and without endothelium.Cumulative concentrations of avosentan and BQ-123 had no vasoactive effect in quiescent vessels. Avosentan had a strong inhibitory effect on the endothelin-1-induced contractions. The inhibitory effect of 10(-6) M avosentan was significantly stronger than the effect of 10(-8) M avosentan. The effect of avosentan (10(-6) M) tended to be stronger than the effect of BQ-123 (10(-6) M). To a lesser extent, BQ-788 also had an inhibitory effect on the endothelin-1-induced contractions.Avosentan has a strong inhibitory effect on the endothelin-1-induced contractions. Blockade of ET receptors is potentially an attractive target in many eye diseases including glaucoma. Further studies are needed to evaluate the usefulness of endothelin blockers in ophthalmology.

The treatment of normal tension glaucoma can be difficult. Some normal tension glaucoma patients show progression of glaucomatous optic neuropathy despite an intraocular pressure in the normal range, and sometimes even with an intraocular pressure in the low teens. The question therefore arises as to whether there are other therapeutic options besides lowering the intraocular pressure. One treatment modality discussed in the literature is calcium channel blockers. We suspect that calcium channel blockers are particularly useful in glaucoma patients having a primary vascular dysregulation.