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Corneal wound, associated with pain, impaired vision, and even blindness, is the most common ocular injury. In this study, we investigated the effect of a novel ferroptosis inhibitor, UAMC-3203 (10 nM–50 µM), in corneal epithelial wound healing in vitro in human corneal epithelial (HCE) cells and ex vivo using alkali-induced corneal wounded mice eye model. We evaluated in vivo acute tolerability of the compound by visual inspection, optical coherence tomography (OCT), and stereomicroscope imaging in rats after its application (100 µM drug solution in phosphate buffer pH 7.4) twice a day for 5 days. In addition, we studied the partitioning of UAMC-3203 in corneal epithelium and corneal stroma using excised porcine cornea. Our study demonstrated that UAMC-3203 had a positive corneal epithelial wound healing effect at the optimal concentration of 10 nM (IC50 value for ferroptosis) in vitro and at 10 µM in the ex vivo study. UAMC-3203 solution (100 µM) was well tolerated after topical administration with no signs of toxicity and inflammation in rats. Ex-vivo distribution study revealed significantly higher concentration (~12–38-fold) and partition coefficient (Kp) (~52 times) in corneal epithelium than corneal stroma. The UAMC-3203 solution (100 µM) was stable for up to 30 days at 4 °C, 37 °C, and room temperature. Overall, UAMC-3203 provides a new prospect for safe and effective therapy for corneal wounds.

Aim To compare differences in clinical dry eye features and meibomian gland health status between dry eye patients from rural and urban populations in Ghana. Methods We examined 211 (rural=109, urban=102) participants with subjective dry eye symptoms. Tear film break -up time (TBUT), Schirmer's test and ocular surface staining (OSS) were assessed. Symptoms were evaluated using the SPEED II questionnaire. Meibomian glands (MG) in the right eye upper (UL) and lower lids (LL) were imaged using a custom meibographer. MG area was determined by intensity threshold segmentation using Image J software. MG loss (MGL) was also graded based on Pult's grading scheme. Mann-Whitney, Spearman correlation, chi-square and odds analyses were performed; p

Purpose Chronic graft versus host disease is a major consequence after allogeneic stem cell transplantation (allo-SCT) and has great impact on patients’ morbidity and mortality. Besides the skin, liver, and intestines, the eyes are most commonly affected, manifesting as severe ocular surface disease. Treatment protocols include topical steroids, cyclosporine, tacrolimus, and ASED. Since these patients often receive systemic immunosuppressant therapy from their oncologists, a topical re-administration of these drugs via ASED with potentially beneficial or harmful effects is possible. The purpose of the study was to determine whether and to which extent systemic immunosuppressants are detectable in ASED. Methods A total of 34 samples of ASED from 16 patients with hemato-oncological malignancies after allo-SCT were collected during the manufacturing process and screened for levels of cyclosporine, mycophenolic acid, everolimus, and tacrolimus via liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). The study followed the tenets of the Declaration of Helsinki and informed consent was obtained from the subjects after explanation of the nature and possible consequences of the study. Results Cyclosporine was found in 18 ASED samples in concentrations ranging from 6.5–105.0 ng/ml (32.0 ± 22.8 ng/ml, mean ± SD). The concentration range of mycophenolic acid in 19 samples was 0.04–25.0 mg/l (4.0 ± 5.4 mg/l, mean ± SD). Everolimus and tacrolimus concentrations were well below the respective limits of quantification ( Conclusions Our study suggests that orally administered cyclosporine and mycophenolic acid for the treatment of systemic GvHD, but not everolimus and tacrolimus, are distinctly detectable in ASED in relevant concentrations. It is highly likely that these agents affect topical therapy of ocular GvHD. However, the extent of this effect needs to be evaluated in further studies.

Objectives Determining the changes in symptomatology suffered by dry eye disease (DED) patients after an intervention is difficult because there is only one validated questionnaire specifically designed to measure these changes and it is somewhat complex. This work uses a simplified questionnaire to evaluate the changes in DED-related symptoms. Methods A new questionnaire based on a global rating of change scale was designed. The Change in Dry Eye Symptoms Questionnaire (CDES-Q) consists of 2 questions: CDES-Q1 asks for the change in symptoms ("better," "same," or "worse") relative to a determined previous time and CDES-Q2 quantifies this change (range: 0 to +100). To evaluate the CDES-Q, a prospective observational study was performed. At baseline (V1; day-0), DED-related symptoms were evaluated using the ocular surface disease index (OSDI). In the post-treatment visit (V2; day-90), OSDI, Symptoms Assessment Questionnaire in Dry Eye (SANDE) II, and CDES-Q were used. Also, clinical evaluations were performed in each visit. Results Thirty-six patients were included. At V2, OSDI, SANDE II, and CDES-Q showed a significant reduction in symptoms (-7.17±12.73, P=0.0021; -11.29±20.95, P=0.0035; -25.28±42.28, P=0.0011, respectively). Patients who answered "better" in CDES-Q1 showed a significantly lower SANDE II than those who answered "same" or "worse," while SANDE II did not discriminate between these groups. Conclusions CDES-Q can be a useful tool for the evaluation of changes in DED-related symptoms. It is simple and better discriminates patients without changes from those who suffered a worsening than SANDE II.

Producción Científica, Dry eye (DED) is a prevalent disease with immune-mediated inflammation as the principal pathophysiological etiology. Olive pomace, the major by-product of the olive oil industry, is rich in high-value polyphenols. Their anti-inflammatory and immunomodulatory activities were determined on human CD4+ T cells (hTCD4+) and in a DED animal model. The viability of hTCD4+ cells isolated from peripheral blood and activated with phytohemagglutinin-M was evaluated after treatment for 48 h with an olive pomace extract (OPT3, 0.10–0.40 mg/mL) and its major compound, hydroxytyrosol (25–100 μM). Regarding the DED animal model, 100 μM hydroxytyrosol, 0.20 mg/mL OPT3, or vehicle (borate buffer) were topically administered to 14 days-desiccating stress-exposed (constant airflow/scopolamine administration) C57BL/6 mice. Tear volume, corneal fluorescein staining (CFS), CD4+, and CD8+ T cell count in lymph nodes (flow cytometry), and IP-10 and TNF-α gene expression (qRT-PCR) in the cornea, conjunctiva, and lacrimal glands were evaluated. OPT3 (0.2–0.4 mg/mL) and hydroxytyrosol (100 μM) significantly reduced hTCD4+ proliferation. In mice, both treatments reduced lacrimal gland IP-10 gene expression. OPT3 also decreased CFS, and conjunctival IP-10 and corneal TNF-α gene expression. In lymph nodes, hydroxytyrosol reduced CD3+, OPT3, and CD8+ count. Thus, a high-value application as a promising DED protection was proposed for olive pomace., European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie Initial Training Network (ITN) “IT-DED3” (H2020-MSCA-ITN-2017) grant agreement No. 765608, Ministerio de Ciencia e Innovación y Fondo Europeo de Desarrollo Regional (FEDER) (RTI2018-094071-B-C21)

Desiccating stress (DS) is known to induce dry eye disease but has not been studied in the context of ocular graft-versus-host disease (oGVHD). Patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) are exposed to DS on transplantation wards, which are highly climate-regulated for hygienic purposes. Because oGVHD demonstrates features of dry eye disease, this retrospective study aimed to analyze DS as a risk factor for chronic oGVHD. A total of 444 patients undergoing allo-HSCT were investigated with a maximum follow-up of 5.8 years post-transplantation. Relative humidity (%rH) on the transplantation ward was monitored, and data were correlated with the occurrence, severity, and onset of chronic oGVHD, as well as the occurrence of acute skin GVHD. A logistic regression model was used to predict the development of oGVHD. One hundred three of 213 surviving patients developed oGVHD. oGVHD was significantly correlated with a lower %rH (r = .2; P = .03), and more patients (73%) developed oGVHD after transplantation under DS compared with patients after transplantation under high-humidity conditions (30%; P = .02). Reduced humidity increased the relative risk for oGVHD by 4% for each %rH, but it did not affect the severity or time of first diagnosis of oGVHD. In this study, we demonstrate that DS is an independent risk factor for oGVHD. Adjusting air humidity during allo-HSCT has the potential to serve as a preventive measure with clinical relevance.

Purpose To evaluate the outcome of phacoemulsification in patients with chronic ocular Graft-versus-host disease (oGVHD) after allogeneic hematopoietic stem cell transplantation (aHSCT). Methods Retrospective, observational multicenter study from 1507 oGVHD patients. From the patient files, data were collected including best-corrected visual acuity (BCVA), intraocular pressure (IOP), Schirmer’s test I, tear film break-up time (TFBUT), corneal fluorescein staining score, postoperative complications, and pre- and post-operative topical therapy. Results Seventy-three patients underwent cataract surgery in 104 eyes. In n = 84 eyes, the oGVHD NIH grade was documented; 12% (n = 12) of analyzed eyes were staged oGVHD NIH grade 1, 31% (n = 32) NIH 2 and 39% (n = 41) NIH 3. The mean BCVA improved in 82% of the eyes (n = 86 eyes). BCVA significantly increased from 0.7 ± 0.5 to 0.4 ± 0.4 LogMAR after surgery independent from oGVHD severity. The mean IOP decreased from 14 ± 4 to 13 ± 4 mmHg after surgery. Visual acuity was moderately correlated to the pre-operative degree of corneal staining (Pearson p = 0.26, p = 0.002, Cohen’s effect size f = 0.29). The visual acuity decreased by 0.078 LogMar units (95% CI = 0.027–0.141) with each increase of corneal staining by one grade (p = 0.05). After surgery, corneal epitheliopathy increased significantly in 42% (n = 44) of the eyes. Postoperative complications included corneal perforation (n = 6, 6%), cystoid macular edema (n = 4, 4%), and endophthalmitis (n = 1, 1%). Conclusion Phacoemulsification in patients with chronic oGVHD significantly improves visual acuity, but is associated with an increased risk of complications in particular corneal epitheliopathy and corneal perforations.

Dry eye disease (DED) is a multifactorial disease, with limitations regarding efficacy and tolerability of applied substances. Among several candidates, the endocannabinoid system with its receptors (CB1R and CB2R) were reported to modulate inflammation, wound healing and pain, which are also core DED pathomechanisms. This study is to investigate the therapeutic responses of Δ-9 tetrahydrocannabinol (a non-selective agonist) and two selective antagonists, SR141716A (CB1R antagonist) and SR144528 (CB2R antagonist), as a topical application using a DED mouse model.Experimental DED was induced in naïve C57BL/6 mice. Expression of CBR at the ocular surface of naïve and DED mice was determined by qPCR and in-situ hybridization. Either THC or CBR antagonists were compounded in an aqueous solution and dosed during the induction of DED. Tear production, cornea sensitivity, and cornea fluorescence staining were tested. At the end of each experiment, corneas were stained with β3-tubulin for analysis of corneal nerve morphology. Conjunctiva was analyzed for CD4CB1R and CB2R are present at the ocular surface, and desiccating stress increased CBR expressions (p 0.05). After 10 days of DED induction, treated groups demonstrated a reduced CBR expression in the cornea, which was concurrent with improvements in the DED phenotype including fluorescence staininginflammation. Applying THC protected corneal nerve morphology, thus maintained corneal sensitivity and reduced CD4Endocannabinoid receptor modulation presents a potential multi-functional therapeutic approach for DED.

Chronic graft-versus-host disease (GVHD) can be associated with significant morbidity, in part because of nonreversible fibrosis, which impacts physical functioning (eye, skin, lung manifestations) and mortality (lung, gastrointestinal manifestations). Progress in preventing severe morbidity and mortality associated with chronic GVHD is limited by a complex and incompletely understood disease biology and a lack of prognostic biomarkers. Likewise, treatment advances for highly morbid manifestations remain hindered by the absence of effective organ-specific approaches targeting “irreversible” fibrotic sequelae and difficulties in conducting clinical trials in a heterogeneous disease with small patient numbers. The purpose of this document is to identify current gaps, to outline a roadmap of research goals for highly morbid forms of chronic GVHD including advanced skin sclerosis, fasciitis, lung, ocular and gastrointestinal involvement, and to propose strategies for effective trial design. The working group made the following recommendations: (1) Phenotype chronic GVHD clinically and biologically in future cohorts, to describe the incidence, prognostic factors, mechanisms of organ damage, and clinical evolution of highly morbid conditions including long-term effects in children ; (2) Conduct longitudinal multicenter studies with common definitions and research sample collections ; (3) Develop new approaches for early identification and treatment of highly morbid forms of chronic GVHD, especially biologically targeted treatments, with a special focus on fibrotic changes ; and (4) Establish primary endpoints for clinical trials addressing each highly morbid manifestation in relationship to the time point of intervention (early versus late). Alternative endpoints, such as lack of progression and improvement in physical functioning or quality of life, may be suitable for clinical trials in patients with highly morbid manifestations. Finally, new approaches for objective response assessment and exploration of novel trial designs for small populations are required.

Ocular graft-versus-host disease (oGVHD) is a fast progressing, autoimmunological disease following hematopoietic stem cell transplantation, leading to severe inflammation of the eye and destruction of the lacrimal functional unit with consecutive sight-threatening consequences. The therapeutic “window of opportunity” is narrow, and current treatment options are limited and often insufficient. To achieve new insights into the pathogenesis and to develop new therapeutic approaches, clinically relevant models of oGVHD are desirable. In this study, the ocular phenotype was described in a murine, chemotherapy-based, minor-mismatch GVHD model mimicking early-onset chronic oGVHD, with corneal epitheliopathy, inflammation of the lacrimal glands, and blepharitis. Additionally, corneal lymphangiogenesis was observed as part of oGVHD pathogenesis for the first time, thus opening up the investigation of lymphangiogenesis as a potential therapeutic and diagnostic tool.

Zusammenfassung Hintergrund Bei der Graft-versus-Host Disease (GvHD) kommt es zu einer Abstoßung des Empfängerkörpers nach allogener Blutstammzelltransplantation (aBSZT). Hierbei werden akute von chronischen Formen unterschieden. Circa 40 – 80% der Patienten, bei denen eine chronische GvHD diagnostiziert wurde, entwickeln eine okuläre GvHD. Für diese ist es wichtig, einen einfachen Zugang zu multidisziplinärer Versorgung zu erhalten. Um Entwicklungen in den Versorgungsstrukturen zu erfragen, führten wir eine Umfrage durch. Methoden Von der Arbeitsgruppe okuläre GvHD der Sektion Kornea wurde die „Umfrage zur okulären GvHD 2016“ erstellt und an alle Universitäts- und Schwerpunktkliniken in Deutschland versendet. Ausgewertet wurden die Antworten sowie Veränderungen zu einer Umfrage 2014, um so Rückschlüsse auf die Entwicklung der Versorgungsstrukturen zuzulassen. Neben den Fragen aus dem Jahr 2014 zur Anzahl von BSZT und Untersuchungshäufigkeit und -setting wurden Fragen zur Verordnung von Ciclosporin- und autologen Serumaugentropfen aufgenommen. Zudem wurde die Frage nach der Untersuchungshäufigkeit unterteilt, um diese auch bei Kindern zu erfassen. Ergebnisse Von 30 antwortenden Kliniken hatten 22 auch an der 1. Umfrage teilgenommen. Den Angaben nach wurden im Jahr 2016 ca. 1860 aBSZT in den assoziierten Zentren der befragten Kliniken durchgeführt. Dies entspricht etwas mehr als der Hälfte der 2016 insgesamt transplantierten Patienten. Jährlich wurden zwischen 2 und 250 Patienten augenärztlich pro Klinik untersucht. Acht Kliniken bieten hierfür eine gesonderte Sprechstunde an. In fast allen der teilnehmenden Kliniken werden Ciclosporin-Augentropfen verordnet. Circa ⅔ der Krankenhäuser stellen autologe Serumaugentropfen her, 7 beziehen diese aus externen Quellen. Insgesamt wurden 2016 ca. 125 – 140 Kinder untersucht. Schlussfolgerungen Aufgrund der schweren Verläufe der okulären GvHD mit gravierenden Beeinträchtigungen der Patienten und drohenden Erblindungen wäre der Ausbau von Spezialsprechstunden mit Bindung von Expertise in örtlicher Nähe zu jedem Transplantationszentrum zu empfehlen. Hier sind vor allem Augenärztinnen und Augenärzte gefragt, sich an der Versorgung zu beteiligen, um die Lebensqualität nach aBSZT zu verbessern. Zusammenfassend gehen wir weiterhin von einer Unterversorgung der okulären GvHD in Deutschland aus, wobei jedoch Anzeichen für eine Verbesserung der Situation bestehen.

Purpose: To compare the efficacy, safety, and tolerability of waterfree cyclosporine formulation (CyclASol) at 2 concentrations (0.1% and 0.05% of cyclosporine [CsA]) to vehicle when applied twice daily for 16 weeks in patients with dry eye disease (DED). An open-label Restasis (Allergan, Irvine, CA) arm was included to allow a direct comparison with an approved therapy. Design: An exploratory phase II, multicenter, randomized, vehicle-controlled clinical trial, double-masked between CyclASol and vehicle with an open-label comparator. Participants: Two hundred and seven eligible patients with a history of dry eye disease were randomized 1:1:1:1 to 1 of 4 treatment arms (CyclASol 0.05%, n = 51; CyclASol 0.1%, n = 51; vehicle, n = 52, and Restasis, n = 53). Methods: After a 2-week run-in period with twice-daily dosing of Systane Balance (Alcon, Fort Worth, TX), patients were randomized to the respective treatment arm and dosed twice daily for 16 weeks. Main Outcome Measures: The study was set up to explore efficacy on a number of sign and symptom end points including total and subregion corneal fluorescein staining, conjunctival staining, visual analog scale (VAS) for dry eye symptoms VAS severity, and Ocular Surface Disease Index (OSDI) questionnaire. Results: CyclASol showed a consistent reduction in corneal and conjunctival staining compared with both vehicle and Restasis over the 16-week treatment period, with an early onset of effect (at day 14). A mixed-effects model–based approach demonstrated that the CyclASol drug effect was statistically significant over vehicle (total corneal staining P < 0.1, central corneal staining P < 0.001, conjunctival staining P < 0.01). This model-based analysis suggests a significant CyclASol effect for OSDI as symptom parameter (P < 0.01). The numbers of ocular adverse events were low in all treatment groups. Conclusions: CyclASol showed efficacy, safety, and tolerability at 2 concentrations in moderate-to-severe DED. In a direct head-to-head against open-label Restasis, CyclASol was found to have an earlier onset of action, as early as after 2 weeks of treatment, in relieving the signs of DED, as measured by corneal and conjunctival staining. The central region of the cornea, an important area for visual function in dry eye sufferers, was shown to have the most benefit from treatment. Excellent safety, tolerability, and comfort profile supports this new CsA formulation as having a positive benefit-to-risk ratio.

Segmentation and evaluation of in vivo confocal microscopy (IVCM) images requires manual intervention, which is time consuming, laborious, and non-reproducible. The aim of this research was to develop and validate deep learning-based methods that could automatically segment and evaluate corneal nerve fibers (CNFs) and dendritic cells (DCs) in IVCM images, thereby reducing processing time to analyze larger volumes of clinical images.CNF and DC segmentation models were developed based on U-Net and Mask R-CNN architectures, respectively; 10-fold cross-validation was used to evaluate both models. The CNF model was trained and tested using 1097 and 122 images, and the DC model was trained and tested using 679 and 75 images, respectively, at each fold. The CNF morphology, number of nerves, number of branching points, nerve length, and tortuosity were analyzed; for DCs, number, size, and immature-mature cells were analyzed. Python-based software was written for model training, testing, and automatic morphometric parameters evaluation.The CNF model achieved on average 86.1% sensitivity and 90.1% specificity, and the DC model achieved on average 89.37% precision, 94.43% recall, and 91.83% F1 score. The interclass correlation coefficient (ICC) between manual annotation and automatic segmentation were 0.85, 0.87, 0.95, and 0.88 for CNF number, length, branching points, and tortuosity, respectively, and the ICC for DC number and size were 0.95 and 0.92, respectively.Our proposed methods demonstrated reliable consistency between manual annotation and automatic segmentation of CNF and DC with rapid speed. The results showed that these approaches have the potential to be implemented into clinical practice in IVCM images.The deep learning-based automatic segmentation and quantification algorithm significantly increases the efficiency of evaluating IVCM images, thereby supporting and potentially improving the diagnosis and treatment of ocular surface disease associated with corneal nerves and dendritic cells.

Microscopic optical coherence tomography (mOCT) has an imaging resolution of 1 µm in all voxel dimensions, but individual epithelial cells are difficult to resolve due to lack of scattering contrast. Adding dynamic contrast processing to mOCT (dmOCT) results in color images that enable visualization of individual cells and possibly give information on cellular function via the calculation of a motility coefficient. We propose this technique as a novel method of evaluating the ocular surface after exposure to a toxic chemical, benzalkonium chloride (BAK).Ex vivo cross-section images were acquired with a custom-built, frequency-domain mOCT system. Eyes were explanted from healthy adult C57BL/6 mice and imaged every 30 minutes with five sets of dmOCT scans at each imaging time. Total epithelium and stroma thicknesses were measured from a single mOCT B-scan, and measures of color changes (hue) and the motility coefficient were acquired from dmOCT scans.After 30-minute exposures to 0.005% BAK, local motility decreased and total epithelium thickness increased compared to controls. For basal epithelium cells, local motility decreased after 60-minute exposures, and the hue shifted red after 90-minute exposures. Stroma thickness did not significantly swell until 150-minute exposures to BAK.dmOCT allows us to view the behavior of the cornea epithelium under toxic stress due to BAK, revealing parallel swelling of the extracellular matrix and changes in local subcellular motion.The evaluation of the cornea epithelium using dmOCT is helpful to our understanding of the toxic effects of BAK.

Meibomian glands (MG) are large sebaceous glands located below the tarsal conjunctiva and the abnormalities of these glands cause Meibomian gland dysfunction (MGD) which is responsible for evaporative dry eye disease (DED). Accurate MG segmentation is a key prerequisite for automated imaging based MGD related DED diagnosis. However, Automatic MG segmentation in infrared meibography is a challenging task due to image artifacts. A deep learning-based MG segmentation has been proposed which directly learns MG features from the training image dataset without any image pre-processing. The model is trained and evaluated using 728 anonymized clinical meibography images. Additionally, automatic MG morphometric parameters, gland number, length, width, and tortuosity assessment were proposed. The average precision, recall, and F1 score were achieved 83%, 81%, and 84% respectively on the testing dataset with AUC value of 0.96 based on ROC curve and dice coefficient of 84%. Single image segmentation and morphometric parameter evaluation took on average 1.33 s. To the best of our knowledge, this is the first time that a validated deep learning-based approach is applied in MG segmentation and evaluation for both upper and lower eyelids.

Purpose: Meibomian gland disease is generally accepted as the leading cause for evaporative dry eye disease (DED). In a previous study, perfluorohexyloctane, a semifluorinated alkane, has been demonstrated to significantly increase tear film breakup time and to reduce corneal fluorescein staining in patients with evaporative DED, thereby vastly reducing dry eye-related symptoms. This study was set up to evaluate perfluorohexyloctane in a larger population of patients with Meibomian gland dysfunction. Methods: Seventy-two patients with Meibomian gland disease and associated dry eye received 1 drop of perfluorohexyloctane 4 times daily during an observational, prospective, multicenter, 6–8-week study. Clinical assessment included best-corrected visual acuity, intraocular pressure, Schirmer test I, tear film breakup time, anterior and posterior blepharitis assessment, number of expressible Meibomian glands, meibum quality and quantity, ocular surface fluorescein staining, lid margin and symptom assessment, and Ocular Surface Disease Index (OSDI©). Results: From the 72 patients recruited, 61 completed the trial per protocol. Nine patients did not apply the medication as recommended and 2 patients were lost to follow-up. Tear film breakup time, corneal and conjunctival fluorescein staining, number of expressible Meibomian glands, and severity of anterior and posterior blepharitis significantly improved after 6–8 weeks of perfluorohexyloctane application. In addition, symptoms improved as demonstrated by a significant decrease of OSDI-values from 37 (±13) to 26 (±16). Conclusions: In concordance with previous findings, 6–8 weeks of topical application of perfluorohexyloctane significantly improves clinical signs of Meibomian gland disease and associated mild to moderate DED.

Lymphangiogenesis is essential for fluid homeostasis in vascularized tissues. In the normally avascular cornea, however, pathological lymphangiogenesis mediates diseases like corneal transplant rejection, dry eye disease, and allergy. So far, a physiological role for lymphangiogenesis in a primarily avascular site such as the cornea has not been described. Using a mouse model of perforating corneal injury that causes acute and severe fluid accumulation in the cornea, we show that lymphatics transiently and selectively invade the cornea and regulate the resolution of corneal edema. Pharmacological blockade of lymphangiogenesis via VEGFR-3 inhibition results in increased corneal thickness due to delayed drainage of corneal edema and a trend towards prolonged corneal opacification. Notably, lymphatics are also detectable in the cornea of a patient with acute edema due to spontaneous Descemet´s (basement) membrane rupture in keratoconus, mimicking this animal model and highlighting the clinical relevance of lymphangiogenesis in corneal fluid homeostasis. Together, our findings provide evidence that lymphangiogenesis plays an unexpectedly beneficial role in the regulation of corneal edema and transparency. This might open new treatment options in blinding diseases associated with corneal edema and transparency loss. Furthermore, we demonstrate for the first time that physiological lymphangiogenesis also occurs in primarily avascular sites.

Hintergrund Alterung ist ein wichtiger, bislang in Bezug auf therapeutische Masnahmen jedoch nur unzureichend berucksichtigter Faktor beim Trockenen Auge. Altersabhangige Anderungen in der Funktion des Immunsystems lassen uns davon ausgehen, dass antientzundliche Therapiemasnahmen Schwankungen in Bezug auf Wirkstoff, Wirkeintritt und Wirkstarke nach sich ziehen. Ziel der Studie war es, am Modell des experimentellen Trockenen Auges altersbezogene Unterschiede der antientzundlichen Therapie zu analysieren. Methoden Ein experimentelles Trockenes Auge (sog. Desiccating Stress Model) wurde an 12 Wochen („jung“) und 12 Monate („alt“) alten weiblichen BALB/c-Mausen induziert. Das Trockene Auge wurde anschliesend mit 0,05% Ciclosporin/F4H5 (Novaliq), F4H5 allein, 0,05% Ciclosporin (Restasis®, Allergan) und Dexamethason (Monodex®, Thea Pharma) uber 3 Wochen behandelt. Eine Kontrollgruppe erhielt keine Therapie. Es wurden Tranensekretion, Fluoresceinanfarbbarkeit der Hornhaut an insgesamt 5 Zeitpunkten sowie die Becherzellzahl der Konjunktiva histologisch am Ende des Versuchs analysiert. Ergebnisse Im Vergleich zu nicht behandelten Tieren zeigen alte Mause ein signifikant starkeres Trockenes Auge als junge Tiere. In der Therapie sprechen alte Tiere signifikant spater an als junge Tiere. Im Vergleich der verwendeten Substanzen zeigt Ciclosporin/F4H5 in Bezug auf die Fluoresceinanfarbbarkeit ein schnelleres Ansprechen schon nach 1 Woche Therapie gegenuber den anderen Gruppen. Ebenso war diese Substanz bei der Tranensekretion und der Zahl der Becherzellen den anderen Gruppen und auch gegenuber jungen Tieren uberlegen. Schlussfolgerungen Diese experimentellen Daten implizieren, dass Alterung in der klinischen Beurteilung von Patienten mit Trockenem Auge berucksichtigt werden sollten. Weiterhin bestehen experimentelle Unterschiede zwischen Substanzklassen wie Calcineurinantagonisten und Steroiden, aber auch Unterschiede zwischen unterschiedlichen Substanzformulierungen, die in praklinischen und klinischen Studien berucksichtigt werden sollten.

Hintergrund Die Augenheilkunde ist ein sehr erfolgreicher Teilbereich der Medizin. Dennoch gibt es Erkrankungen mit fehlendem Krankheitsverstandnis und unzureichender Therapie. Hier kann translationale Forschung helfen. Methoden Die Fordermoglichkeiten fur translationale Forschung unter anderem durch die Deutsche Forschungsgemeinschaft (DFG) werden am Beispiel der Forschergruppe 2240 an der Universitatsaugenklinik in Koln dargestellt. Ergebnisse Das Forderinstrument der Forschergruppe erlaubt es mehreren Arbeitsgruppen an verschiedenen Standorten an einer Kernthematik zusammenzuarbeiten. Des Weiteren kann der wissenschaftliche Nachwuchs durch Rotationsstellen und Anschubfinanzierung erheblich unterstutzt werden. Eine Forschergruppe kann ebenfalls zur Strukturbildung an einer medizinischen Fakultat mit besonderer Starkung z. B. der Augenheilkunde beitragen. Schlussfolgerung Das Instrument einer DFG-Forschergruppe ist in hervorragendem Mase geeignet, translationale Forschung z. B. in der Augenheilkunde voranzutreiben, den wissenschaftlichen Nachwuchs nachhaltig zu fordern und den Stellenwert einer medizinischen Teildisziplin, wie z. B. der Augenheilkunde, im arztlichen Facherkanon zu unterstutzen.

Introduction: Anti-inflammatory, topical therapy of severe keratitis in dry eye disease (DED) and ocular graft-versus-host disease (oGvHD) includes steroids, cyclosporine (Cs), and others. In Germany, a commercial product containing 0.1% Cs in a cationic formulation is available since 2015. Objective: The aim of this study was to present real-life data using cationic 0.1% Cs in oGvHD patients. Methods: This was a retrospective study of 26 oGvHD and 41 DED patients with corneal staining of at least Oxford grade III. Parameters analyzed were Ocular Surface Disease Index, corneal staining, intraocular pressure, tear film break-up time, Schirmer, and visual acuity. In addition, it was evaluated how different Cs formulations were tolerated. Results: Corneal staining improved significantly in 1 eye in DED but not in oGvHD. In DED, cationic 0.1% Cs was not tolerated by 32% of the patients, in contrast to 0.05% Cs in castor oil not tolerated by 47% and liposomal 0.05% Cs by 63%. In oGvHD patients, cationic 0.1% Cs was not tolerated by 62%, 0.05% Cs in castor oil by 33%, and liposomal 0.05% Cs by 39% of the patients. Conclusions: This study demonstrates differences between the tolerance of different Cs formulations depending on the underlying cause of severe keratitis. Cationic 0.1% Cs is considerably less tolerated in oGvHD, and its use should be considered with care.

graft-versus-host disease (GvHD) is a common complication after allogeneic haematopoietic stem cell transplantation (allo-SCT) and causes immunological rejection of host tissues, which can occur both acute or chronically. Approximately 40 - 80% of patients with the diagnosis of chronic GvHD (cGvHD) also develop ocular GvHD. For these patients, immediate and uncomplicated access to interdisciplinary patient-centred care is important. We performed this survey to improve understanding of the structure of patient-centred care in Germany.The GvHD working party of the Cornea Section of the German Society of Ophthalmology sent the "Survey of ocular GvHD 2016" to all university and specialised hospitals in Germany. We evaluated the data and compared the information with survey results from 2014, in order to draw conclusions about the structure and process of patient-centred care in ocular GvHD. Besides the questions from 2014 on the numbers of allo-SCT, frequency of examinations, etc. there were additional questions on the prescription of ciclosporin and autologous serum eye drops. The question on frequency examination was further expanded to include examinations of paediatric patients.Of 30 participating hospitals, 22 had already taken part in the first survey. According to the information they provided, approx. 1860 allo-SCTs were performed in the transplantation units of the participating eye hospitals in 2016. This was more than half of the transplantations performed in Germany. Ophthalmologists examined between 2 and 250 Patients per year per centre. Eight clinics provide a specialised outpatient clinic for ocular GvHD. Nearly all the participating clinics prescribe ciclosporin eye drops. About ⅔ provide autologous serum eye drops, seven obtain them from external sources. Overall approx. 125 - 140 children were examined in 2016.Due to the potential severity of ocular GvHD with immobilisation of the patients and the imminent loss of sight, further improvements in eye care are required. For example, offers such as special consultations, with expertise located close to any transplantation unit are recommended. This requires in particular ophthalmologists to participate in the patient care to enhance quality of life after allo-SCT. In summary, we conclude that the present structures are not sufficient to treat all patients suffering from ocular GvHD in Germany, but the situation has evidently improved.Bei der Graft-versus-Host Disease (GvHD) kommt es zu einer Abstoßung des Empfängerkörpers nach allogener Blutstammzelltransplantation (aBSZT). Hierbei werden akute von chronischen Formen unterschieden. Circa 40 – 80% der Patienten, bei denen eine chronische GvHD diagnostiziert wurde, entwickeln eine okuläre GvHD. Für diese ist es wichtig, einen einfachen Zugang zu multidisziplinärer Versorgung zu erhalten. Um Entwicklungen in den Versorgungsstrukturen zu erfragen, führten wir eine Umfrage durch.Von der Arbeitsgruppe okuläre GvHD der Sektion Kornea wurde die „Umfrage zur okulären GvHD 2016“ erstellt und an alle Universitäts- und Schwerpunktkliniken in Deutschland versendet. Ausgewertet wurden die Antworten sowie Veränderungen zu einer Umfrage 2014, um so Rückschlüsse auf die Entwicklung der Versorgungsstrukturen zuzulassen. Neben den Fragen aus dem Jahr 2014 zur Anzahl von BSZT und Untersuchungshäufigkeit und -setting wurden Fragen zur Verordnung von Ciclosporin- und autologen Serumaugentropfen aufgenommen. Zudem wurde die Frage nach der Untersuchungshäufigkeit unterteilt, um diese auch bei Kindern zu erfassen.Von 30 antwortenden Kliniken hatten 22 auch an der 1. Umfrage teilgenommen. Den Angaben nach wurden im Jahr 2016 ca. 1860 aBSZT in den assoziierten Zentren der befragten Kliniken durchgeführt. Dies entspricht etwas mehr als der Hälfte der 2016 insgesamt transplantierten Patienten. Jährlich wurden zwischen 2 und 250 Patienten augenärztlich pro Klinik untersucht. Acht Kliniken bieten hierfür eine gesonderte Sprechstunde an. In fast allen der teilnehmenden Kliniken werden Ciclosporin-Augentropfen verordnet. Circa ⅔ der Krankenhäuser stellen autologe Serumaugentropfen her, 7 beziehen diese aus externen Quellen. Insgesamt wurden 2016 ca. 125 – 140 Kinder untersucht.Aufgrund der schweren Verläufe der okulären GvHD mit gravierenden Beeinträchtigungen der Patienten und drohenden Erblindungen wäre der Ausbau von Spezialsprechstunden mit Bindung von Expertise in örtlicher Nähe zu jedem Transplantationszentrum zu empfehlen. Hier sind vor allem Augenärztinnen und Augenärzte gefragt, sich an der Versorgung zu beteiligen, um die Lebensqualität nach aBSZT zu verbessern. Zusammenfassend gehen wir weiterhin von einer Unterversorgung der okulären GvHD in Deutschland aus, wobei jedoch Anzeichen für eine Verbesserung der Situation bestehen.

Background: Dyslipidemia may be linked to meibomian gland dysfunction (MGD) and altered meibum lipid composition. The purpose was to determine if plasma and meibum cholesteryl esters (CE), triglycerides (TG), ceramides (Cer) and sphingomyelins (SM) change in a mouse model of diet-induced obesity where mice develop dyslipidemia. Methods: Male C57/BL6 mice (8/group, age = 6 wks) were fed a normal (ND, 15% kcal fat) or an obesogenic high-fat diet (HFD, 42% kcal fat) for 10 wks. Tear production was measured and meibography was performed. Body and epididymal adipose tissue (eAT) weights were determined. Nano-ESI-MS/MS and LC-ESI-MS/MS were used to detect CE, TG, Cer and SM species. Data were analyzed by principal component analysis, Pearson&rsquo, s correlation and unpaired t-tests adjusted for multiple comparisons, significance set at p &le, 0.05. Results: Compared to ND mice, HFD mice gained more weight and showed heavier eAT and dyslipidemia with higher levels of plasma CE, TG, Cer and SM. HFD mice had hypertrophic meibomian glands, increased levels of lipid species acylated by saturated fatty acids in plasma and meibum and excessive tear production. Conclusions: The majority of meibum lipid species with saturated fatty acids increased with HFD feeding with evidence of meibomian gland hypertrophy and excessive tearing. The dyslipidemia is associated with altered meibum composition, a key feature of MGD.