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Purpose: Over the past two decades, lamellar keratoplasty procedures, such as Descemet's Stripping Automated Endothelial Keratoplasty (DSAEK) and Descemet's Membrane Endothelial Keratoplasty (DMEK) as well as Deep Anterior Lamellar Keratoplasty (DALK), have become an integral part of clinical practice. With advances in contact lens fitting for keratoconus management and the implementation of UVA-Riboflavin Crosslinking (CXL), the landscape of keratoplasty indications is undergoing changes. Procedures and indications in a single tertiary care center over the past two decades are reviewed in this retrospective analysis., Methods: Retrospective analysis utilized anonymized electronic data from the LIONS cornea bank Baden-Württemberg, Eye Center Freiburg, spanning from beginning of 2004 to end of 2023. The primary focus was on surgical procedures and indications for keratoplasty., Results: The study encompassed a comprehensive analysis of 7130 corneal transplants. Penetrating keratoplasty (PK) exhibited a significant decline from 95% (n = 206, 2004) to 11% (n = 46, 2023), while DMEK increased from 48% (n = 157, 2012) to 82% (n = 347, 2023). Fuchs endothelial dystrophy (FED) emerged as the dominant indication, witnessing a significant increase from 24% (2004, n = 39) to 72% (2023, n = 288). Conversely, keratoconus (KC) showed a reciprocal change from 25% (2004, n = 40) to 4% (2023, n = 17). PK demonstrated a noteworthy indication shift in descending order from Bullous Keratopathy (BK), FED, and KC in 2004 to KC, graft failure, corneal scars, and ulcers in 2023. Repeat keratoplasty following DMEK remained rare, but a discernible upward trend was observed for PK., Conclusion: This retrospective analysis highlights significant changes in both keratoplasty indications and techniques over the past two decades. DMEK has emerged as a successful intervention for treating endothelial diseases, while PK retains its qualitative indispensability for a wide range of indications. Modern corneal banks are urged to maintain a robust supply of grafts for all surgical techniques in anticipation of potential increased demand in the future, particularly for repeat keratoplasties., Key Messages: What is known • Over the past two decades, lamellar keratoplasty procedures such as DSAEK and DMEK have increasingly replaced penetrating keratoplasty (PK) in clinical practice due to their improved outcomes and reduced complications for certain indications. New Findings • Our study reveals a significant shift in keratoplasty indications, with Fuchs endothelial dystrophy (FED) emerging as the predominant indication, increasing from 24% in 2004 to 72% in 2023, while keratoconus (KC) declined from 25 to 4% during the same period. • Penetrating keratoplasty (PK) has shown a marked decline in use, dropping from 95% of keratoplasties in 2004 to 11% in 2023, whereas DMEK has grown to represent 82% of procedures in 2023. • Despite the rise of DMEK, PK remains vital for a broad spectrum of indications, highlighting the necessity for corneal banks to maintain a versatile supply of grafts to meet diverse clinical needs, particularly in cases of repeat keratoplasties., (© 2024. The Author(s).)

Endothelial cell density (ECD) is a crucial parameter for the release of corneal grafts for transplantation. The Lions Eye Bank of Baden-Württemberg uses the "Rhine-Tec Endothelial Analysis System" for ECD quantification, which is based on a fixed counting frame method considering only a small sample of 15 to 40 endothelial cells. The measurement result therefore depends on the frame placement and manual correction of the cells counted within the frame. To increase the sample size and create higher objectivity, we developed a new method based on "deep learning" that automatically detects all visible endothelial cells in the image. This study aims to compare this new method with the conventional Rhine-Tec system. 9375 archived phase-contrast microscopic images of consecutive grafts from the Lions Eye Bank were evaluated with the deep learning method and compared with the corresponding archived analyses of the Rhine-Tec system. Means, Bland-Altman and correlation analyses were compared. Comparable results were obtained for both methods. The mean difference between the Rhine-Tec system and the deep learning method was only - 23 cells/mm 2 (95% confidence interval - 29 to - 17). There was a statistically significant positive correlation between the two methods, with a correlation coefficient of 0.748. What was striking in the Bland-Altman analysis were clustered deviations in the cell density range between 2000 and 2500 cells/mm 2 - with higher values in the Rhine-Tec system. The comparable results for cell density measurement values underline the validity of the deep learning-based method. The deviations around the formal threshold for graft release of 2000 cells/mm 2 are most likely explained by the higher objectivity of the deep learning method and the fact that measurement frames and manual corrections were specifically selected to reach the formal threshold of 2000 cells/mm 2 when the full area endothelial quality was good. This full area assessment of the graft endothelium cannot currently be replaced by deep learning methods and remains the most important basis for graft release for keratoplasty., Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht./The authors declare that there is no conflict of interest., (Thieme. All rights reserved.)

The microbiome of the ocular surface has been characterised, but only limited information is available on a possible silent intraocular microbial colonisation in normal eyes. Therefore, we performed next-generation sequencing (NGS) of 16S rDNA genes in the aqueous humour. The aqueous humour was sampled from three patients during cataract surgery. Air swabs, conjunctival swabs from patients as well as from healthy donors served as controls. Following DNA extraction, the V3 and V4 hypervariable regions of the 16S rDNA gene were amplified and sequenced followed by denoising. The resulting Amplicon Sequence Variants were matched to a subset of the Ribosomal Database Project 16S database. The deduced bacterial community was then statistically analysed. The DNA content in all samples was low (0-1.49 ng/µL) but sufficient for analysis. The main phyla in the samples were Acinetobacteria (48%), Proteobacteria (26%), Firmicutes (14%), Acidobacteria (8%), and Bacteroidetes (2%). Patients' conjunctival control samples and anterior chamber fluid showed similar patterns of bacterial species containing many waterborne species. Non-disinfected samples showed a different bacterial spectrum than the air swab samples. The data confirm the existence of an ocular surface microbiome. Meanwhile, a distinct intraocular microbiome was not discernible from the background, suggesting the absence of an intraocular microbiome in normal eyes.

Purpose: Tectonic keratoplasties (TK) are used to treat corneal and scleral perforations and to prevent the loss of the eye. In this study, we retrospectively analyzed indications, surgical procedures, and outcomes of eccentric mini and corneo-scleral tectonic keratoplasties with respect to anatomical survival and clear graft survival rates to identify risk factors for graft failure., Methods: This retrospective study includes 33 eccentric mini (graft diameter <6 mm) and/or corneo-scleral TK of 32 consecutive patients of a total of 41 TK carried out between 2005 and 2020 in the Eye Center, University of Freiburg, Germany, making up 0.7% of all keratoplasties performed during this period (n = 5557). Patient and graft specific data were extracted from medical files. Anatomical survival-defined as achieving integrity of the globe without further surgical interventions-and clear graft survival-defined as persisting graft clarity-were estimated using the Kaplan-Meier method. We also fitted Cox proportional hazard models to account for factors influencing anatomical and clear graft survival., Results: Median duration of anatomical success was 72.5 months (95% confidence interval (CI) 18.1-infinite (inf.)) and median duration of clear graft survival was 29.6 months (95% CI 12.5-Inf.). The 1-year survival rate for anatomical survival was 67.6% (95% CI 52.2% - 87.6%) and for clear graft survival 66.4% (95% CI 50.5%- 87.1%). No enucleation was necessary during this time-period. Non-inflammatory primary causes (n = 14) presented a trend towards better anatomical survival rates (median remained above 0.75 during follow-up) compared to inflammatory primary causes (n = 19, median 18.1 months (95% CI 2.8 - inf.)) and longer clear graft survival (median 29.6 months (95% CI 12.5 - inf.) versus 13.1 months (95% CI 3.2 - inf.)). Corneo-scleral grafts (n = 18) compared to corneal grafts (n = 15) showed a trend towards better anatomical survival (more than 50% of eyes did not fail during follow-up period (95% CI 21.9-Inf. months) versus 18.1 months (95% CI 2.4-Inf.)) and clear graft survival (median 29.6 months (95% CI 12.6-Inf.) versus 6.2 months (95% CI 2.8-Inf.)). Old age (n = 11, 75.2 - 90.1 years) compared to young age (n = 11, 6.2 - 60.2 years) was the only hazard ratio (hazard ratio 0.04 (95% CI 0.002-0.8)) that reached the level of significance (p = 0.03)., Conclusion: Eccentric TK is helpful in the successful treatment of a variety of severe eye diseases. Patients at young age, with pre-existing inflammatory conditions or corneal TK are at higher risk for anatomical failure as well as clear graft failure and therefore need to be monitored closely., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Wiedenmann et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

In recent years, various forms of caloric restriction (CR) and amino acid or protein restriction (AAR or PR) have shown not only success in preventing age-associated diseases, such as type II diabetes and cardiovascular diseases, but also potential for cancer therapy. These strategies not only reprogram metabolism to low-energy metabolism (LEM), which is disadvantageous for neoplastic cells, but also significantly inhibit proliferation. Head and neck squamous cell carcinoma (HNSCC) is one of the most common tumour types, with over 600,000 new cases diagnosed annually worldwide. With a 5-year survival rate of approximately 55%, the poor prognosis has not improved despite extensive research and new adjuvant therapies. Therefore, for the first time, we analysed the potential of methionine restriction (MetR) in selected HNSCC cell lines. We investigated the influence of MetR on cell proliferation and vitality, the compensation for MetR by homocysteine, the gene regulation of different amino acid transporters, and the influence of cisplatin on cell proliferation in different HNSCC cell lines.

Background: Immune-mediated corneal graft rejection (IR) is a leading cause of corneal graft failure. The endothelium, stroma, epithelium, or a combination can be affected. Little is known about the long-term outcomes of different types of IR., Methods: We reviewed the medical records of all keratoplasties that had been performed at our eye centre between 2003 and 2016 (n = 3934) for any kind of IR that occurred between the surgery and 2019. All patients with a definite diagnosis of IR and sufficient clinical data were included in the analysis. IRs were grouped according to the affected part of the graft (endothelial, stromal, epithelial, and mixed). We analysed the dynamics of recovery and the clinical outcomes., Results: We identified a total of 319 patients with IR. Twenty-seven of those were lost to follow-up and were excluded from further analysis. Of the IRs, 89% affected the endothelium. Endothelial IR resulted more frequently in a considerable loss of endothelial cell density than other forms of IR. Stromal IR showed a lower relapse rate and a better visual recovery than other types of IR and resulted less often in a failure of the graft., Conclusions: We herein report comprehensive data about the prognosis regarding functional recovery after different types of IR following keratoplasty. Our data underline that timely recognition and correct classification of IR are important because they determine the clinical course and prognosis., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Abstract: We illustrate the algorithmic advantages of the recently introduced single-boson exchange (SBE) formulation for the one-loop functional renormalization group (fRG), by applying it to the two-dimensional Hubbard model on a square lattice. We present a detailed analysis of the fermion-boson Yukawa couplings and of the corresponding physical susceptibilities by studying their evolution with temperature and interaction strength, both at half filling and finite doping. The comparison with the conventional fermionic fRG decomposition shows that the rest functions of the SBE algorithm, which describe correlation effects beyond the SBE processes, play a negligible role in the weak-coupling regime above the pseudo-critical temperature, in contrast to the rest functions of the conventional fRG. Remarkably, they remain finite also at the pseudo-critical transition, whereas the corresponding rest functions of the conventional fRG implementation diverge. As a result, the SBE formulation of the fRG flow allows for a substantial reduction of the numerical effort in the treatment of the two-particle vertex function, paving a promising route for future multiboson and multiloop extensions., (© The Author(s) 2022.)

Background: Penetrating keratoplasty (PK) gets more and more reserved to cases of increasing complexity. In such cases, ocular comorbidities may limit graft survival following PK. A major cause for graft failure is endothelial graft rejection. Suture removal is a known risk factor for graft rejection. Nevertheless, there is no evidence-based regimen for rejection prophylaxis following suture removal. Therefore, a survey of rejection prophylaxis was conducted at 7 German keratoplasty centres., Objective: The aim of the study was documentation of the variability of medicinal aftercare following suture removal in Germany., Methods: Seven German keratoplasty centres with the highest numbers for PK were selected. The centres were sent a survey consisting of half-open questions. The centres performed a mean of 140 PK in 2018. The return rate was 100%. The findings were tabulated., Results: All centres perform a double-running cross-stitch suture for standard PK, as well as a treatment for rejection prophylaxis with topical steroids after suture removal. There are differences in intensity (1 - 5 times daily) and tapering (2 - 20 weeks) of the topical steroids following suture removal. Two centres additionally use systemic steroids for a few days., Discussion: Rejection prophylaxis following PK is currently poorly standardised and not evidence-based. All included centres perform medical aftercare following suture removal. It is assumed that different treatment strategies show different cost-benefit ratios. In the face of the diversity, a systematic analysis is required to develop an optimised regimen for all patients., Competing Interests: The authors declare that they have no conflict of interest./Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht., (Thieme. All rights reserved.)

Purpose: Recently, intraoperative optical coherence tomography (iOCT) has evolved in the field of ophthalmic surgery. So far, the use of iOCT was mainly focused to lamellar keratoplasty, especially deep anterior lamellar keratoplasty (DALK) and Descemet membrane endothelial keratoplasty (DMEK). The aim of this study was to report our experiences with iOCT to introduce new possibilities of this application., Methods: We used iOCT in 18 patients who underwent the following surgeries: DALK, DMEK, penetrating keratoplasty, autologous limbal transplantation, transscleral suture fixation of a posterior chamber lens, pannus removal on corneal surface and newborn investigation in Peters' anomaly. We obtained qualitative video data for all procedures., Results: With the iOCT, the cannula placement during DALK preparation of the recipient cornea and bubble formation could be visualized to improve the success rate of the big bubble injection. In DMEK, the iOCT enables the visualization of Descemet's membrane removal in the recipient and graft orientation as well as better control of graft attachment. The iOCT enables intraoperative visualization of the graft-host interface during penetrating keratoplasty. During autologous limbal transplantation, transscleral suture fixation of a posterior chamber lens and removal of corneal surface pannus the iOCT is capable of showing the thickness of lamellar preparations to avoid penetrations and to save healthy recipient's tissue., Conclusion: The iOCT is a helpful device for intraoperative anterior segment imaging not only for DALK and DMEK. It is also beneficial in penetrating keratoplasty and every other form of lamellar preparation during corneoscleral surgery.

Background: Human corneal grafts from organ culture need to have more than 2000 endothelial cells/mm 2 to be suitable for transplantation. Measurement of the endothelial cell density is complicated by invisible cell borders in phase contrast microscopy, as well as by limited areas for counting due to folds in the Descemet membrane of the swollen corneal grafts. To date, no automated counting method for measuring the endothelial cell density exists. The neuronal network U-Net has already proven itself in automated segmentation of specular microscopy images of human corneal endothelium. The aim of this study was the application of the U-Net in the quality control of human corneal grafts., Material and Methods: Training of the U-Net was performed using 100 manually tagged endothelial cell images of corneal grafts from the Lions eye bank in Baden-Württemberg. Another 100 images were obtained for testing the precision of measurements of the U-Net. These were adjudged manually by a) an experienced investigator and b) a less experienced ophthalmologist. The endothelial cells in identical images were then counted automatically by the trained U-Net. Comparison with the manually counted results was drawn by Pearson correlation., Results: The correlation coefficient between the U-Net and the experienced investigator as gold standard was 0.9. The correlation coefficient between the less experienced ophthalmologist and the gold standard was only 0.81. Both correlations were statistically highly significant (p < 0.0001)., Discussion: The strong correlation between the U-Net and the gold standard points out that, given medical approval, effective assistance for eye banks is possible in quality control by automated counting. This could improve objectivity and efficiency of work flow., Competing Interests: Die Autoren geben an, dass kein Interessenkonflikt besteht., (Georg Thieme Verlag KG Stuttgart · New York.)

A 53-year-old patient consulted our practice clinic complaining of progressive visual loss, increased glare sensitivity and color sense disorder. Extensive diagnostic investigation, including multifocal ERG (mfERG) and macular thickness map with the help of optical coherence tomography (OCT), supported the suspected diagnosis of a cone dystrophy. There are, however, no established therapeutic options. A diagnostic confirmation by means of molecular genetics was not successful.

Purpose: Descemet membrane endothelial keratoplasty (DMEK) seems to be the most promising technique for treating endothelium-related disorders of the cornea. However, graft detachment is a frequent complication. It often can be treated by rebubbling procedures. Unfortunately, this increases the risk of subsequent graft failure. It is therefore essential to define risk factors for graft detachment in DMEK. In this study, postoperative intraocular pressure (IOP) is investigated in this regard., Methods: In total, 1047 DMEK procedures in patients with Fuchs endothelial dystrophy or bullous keratopathy were reviewed. All rebubbling procedures were recorded as well as postoperative IOP values (first measure 2 hours postoperatively and highest and lowest value within 3 days after surgery), donor factors (donor age, organ culture time, and endothelial cell count), and whether DMEK surgery had been combined with cataract surgery (triple-DMEK). Incidence rates were estimated with the Kaplan-Meier method. Cox regression was used to assess statistical significance., Results: The overall rebubbling rate was 24% after 8 weeks. Relative dips in IOP may be associated with a higher risk for graft detachment (hazards ratio = 0.41; P < 0.001). Graft detachment was neither significantly influenced by donor factors, first or maximum IOP, nor by simultaneous cataract surgery (triple-DMEK)., Conclusions: Avoiding dips in IOP may reduce the risk for graft detachment after DMEK. To prevent lowering of IOP values in the early postsurgical period, it may be advisable to achieve tight surgical wounds at the end of DMEK surgery and optimal filling of the anterior chamber with air and optionally with gas.

Purpose: The prevalence of pseudophakia increases with age and affects more than 30% of people older than 80 years. Because grafts from older donors seem to be more suitable for Descemet membrane endothelial keratoplasty (DMEK) surgery rather than grafts from younger donors, eye bank technicians and corneal surgeons have to deal with corneas from pseudophakic donors for DMEK graft preparation. However, graft preparation from corneas of pseudophakic donors can be more complicated., Methods: We retrospectively analyzed our donor registry for the prevalence of pseudophakia. We compared grafts from phakic and pseudophakic donors concerning graft survival, rebubbling rates, and endothelial cell loss after DMEK surgery., Results: More than 20% of our donors were pseudophakic, of which 35% were primarily suitable for transplantation. Regarding the comparison of grafts from phakic and pseudophakic donors used for DMEK, we observed comparable survival rates (90% after 3 years) and similar endothelial cell loss (30% with an endothelial cell density above 1000 cell/mm after 3 years) but significantly lower rebubbling rates for grafts from pseudophakic donors (18% vs. 28%)., Conclusions: Our data strongly suggest that pseudophakic persons should not be excluded from corneal donation because success rates after DMEK with grafts from pseudophakic eyes are comparable to those with grafts from phakic eyes. However, in the eye bank, grafts from pseudophakic donors have a higher primary discard rate because of low endothelial cell counts.

UVA crosslinking is used for treatment of corneal diseases such as keratoconus in order to stabilize the corneal tissue by crosslinking of the collagen fibers. It has been shown that the crosslinking treatment leads to a stiffening of the central corneal tissue. However, knowledge of lateral extent of the corneal stiffening as well as a systematic study of the mechanical response of human cornea is still missing. In our study we measured the stiffness (elastic modulus) of the anterior surface of healthy and crosslinked human corneas by instrumented indentation using a spherical indenter. The results show that the stiffness of the central and paracentral cornea increased almost two times after the crosslinking but the stiffening effect rapidly decreased towards the periphery of the radiation field. These new insights into the understanding of the biomechanical response of corneal crosslinking shall contribute to a better understanding and an optimization of this perspective medical treatment. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 1413-1420, 2018., (© 2018 Wiley Periodicals, Inc.)

Purpose: Descemet membrane endothelial keratoplasty (DMEK) is superior to penetrating keratoplasty (PK) in terms of visual rehabilitation, intraoperative safety and risk of rejection. Therefore, it seems reasonable to perform DMEK in eyes with endothelial failure following PK. We herein report our first clinical results., Methods: Nineteen eyes with endothelial graft failure following PK were treated with DMEK. The majority of these eyes (12) had limited visual potential. The major indication for DMEK was pain relief in patients with bullous keratopathy. Visual acuity (VA), central corneal thickness (CCT), rate of graft dislocations, graft survival, graft rejections and other complications were extracted from the medical records., Results: Although comorbidities limiting VA were present in 12 of the 19 eyes, VA increased from 0.05 to 0.1 (median) in 16 eyes. CCT decreased substantially (range 63-363 μm). Rebubbling was necessary in five eyes with incomplete graft adherence. There were two immunologic graft reactions and three graft failures. No major complications like endophthalmitis or expulsive bleeding occurred., Conclusions: DMEK is feasible to treat endothelial graft failure following PK. This is even true for eyes with limited visual potential.

Background: Patients with intermediate uveitis (IU) represent a heterogenous group characterized by a wide spectrum of etiologies and regional differences. Aim of the study was to analyze the characteristics of patients with IU examined in an academic center in Germany., Methods: We conducted a retrospective analysis of the clinical records of all patients with intermediate uveitis referred to the Eye Center, University of Freiburg from 2007 to 2014. Diagnosis followed the Standardization in Uveitis Nomenclature (SUN) criteria. Data analysis included: etiology of IU, demographics, complications, treatment and visual acuity., Results: We identified 159 patients with intermediate uveitis during that period. Mean age at diagnosis was 35 years. Most are female (64%), and the mean duration of IU was 6.1 years (range 1 month - 35 years). Etiology of IU was idiopathic in 59%. Multiple sclerosis (MS) (20%) and sarcoidosis (10%) were frequent systemic causes of IU. Other etiologies including infectious diseases (tuberculosis, borreliosis) or immune-mediated conditions (eg, after vaccination) were present in 11%. The pattern of complications included macular edema (CME) (36%), cataract (24%), secondary glaucoma (7%), and epiretinal membrane formation (19%). Periphlebitis and optic neuritis were more frequent in conjunction with MS. Treatment comprised local and systemic steroids, immunosuppressive agents, biologics, and surgery. Best corrected visual acuity was better than 20/25 in 60% of the eyes after more than 10 years of follow-up., Conclusions: In our German academic center, most IU cases were idiopathic or associated with MS or sarcoidosis. In contrast to other countries, infectious cases were rare. Patients' overall visual prognosis is favorable even when the duration of IU has been long and and despite numerous complications.

Purpose: Although the functional results following DMEK are better than after DSAEK, DSAEK still seems to be the standard procedure, as surgeons fear losing grafts during DMEK graft preparation. Therefore, eye banks offer precut DMEK grafts for direct use by the surgeon. Here, we analysed the functional results and complication rates for a precut technique compared to fresh preparations., Methods: We retrospectively compared 453 standard to 11 precut (1-2 days before surgery) DMEK cases. Precut preparations did not differ from the standard preparation, except that the preparation was stopped after trephination with the graft still attached in a small central area. The preparation had to be completed before surgery by peeling off the centrally attached part of the graft. This technique was first tested in an experimental series of 14 grafts, which were unsuitable for transplantation. All surgeries were performed in the same standardized way., Results: There was no significant endothelial cell loss during the storage period following precut preparation. We found a statistically significantly higher endothelial cell loss and graft failure rate for the precut grafts., Conclusion: Because of the statistically significant higher graft failure rate in the precut group, we stopped using this technique, so the numbers in this retrospective case series are small. The higher graft failure rate may be explained by (ultra)structural changes in the DMEK graft (e.g. accumulation of dextran) during the second storage period. Therefore, careful evaluation is recommended before using precut DMEK grafts stored in dextran containing media in order to avoid early primary graft failures.

Presentation of 3 cases of intraocular inflammation: 1. 47-year old female patient with severe necrotising scleritis and uveitis with underlying granulomatous polyangiitis (formerly known as Wegener granulomatosis, in honour of the German pathologist Friedrich Wegener), known for 10 years. 2. 48-year old male patient with longstanding bilateral uveitis and granulomatous polyangiitis for 2 years. In the histopathological examination of the enucleation specimen, a retrolental tumour turned out to be a granuloma. 3. 57-year old male patient in status post renal transplantation with intraocular cellular infiltration suspicious for lymphoma, which surprisingly proved to be Toxoplasma gondii-associated uveitis. The clinical course and characteristic histological signs and therapeutic options are discussed., (Georg Thieme Verlag KG Stuttgart · New York.)

Purpose: To study the impact of soluble IL2 receptor (sIL2R), chest x-ray (CxR), and angiotensin-converting enzyme (ACE) as markers for sarcoidosis in uveitis patients., Design: Retrospective study., Methods: Serum concentrations of sIL2R and ACE were measured in patients with active uveitis. Those with elevated sIL2R and /or ACE values were examined for suspected systemic sarcoidosis., Main Outcome Measure: Our main outcome parameters were the specificity and sensitivity of sIL2R, CxR and ACE in screening for ocular sarcoidosis., Results: We measured 261 patients with uveitis for sarcoidosis using sIL2R and ACE between January 2008 and November 2011; sarcoidosis was been diagnosed using other tests (e.g. computer tomography, brochoalveolar lavage, biopsy) in 41 of 53 patients with elevated sIL2R values (>639 U/ml) and in one patient with normal sIL2R (582 U/ml). Their mean sIL2R value was 1310 U/ml, extending from 582 to 8659 U/ml. Only 9 patients, however, presented elevated ACE (>82 U/l). Their mean ACE value was 116.4 U/l, ranging from 84.1 to 175.5 U/l. IL2R specificity was 94% with 98% sensitivity. In contrast, ACE had a specificity of 99.5%, but a sensitivity of only 22%; the chest x-ray had a specificity of 100% with 50% sensitivity in detecting sarcoidosis. We observed the entire spectrum of uveitis: sixteen patients suffered from anterior, 8 from intermediate, 16 from posterior, and 2 from panuveitis., Conclusions: An elevated level of soluble IL2R suggests sarcoidosis with uveitis more convincingly than ACE, making sIL2R a more effective marker parameter for sarcoidosis than ACE or chest x-ray in uveitis patients.

Oncogenic transformation is dependent on activated membrane-associated NADPH oxidase (NOX). However, the resultant extracellular superoxide anions are also driving the NO/peroxynitrite and the HOCl pathway, which eliminates NOX-expressing transformed cells through selective apoptosis induction. Tumor progression is dependent on dominant interference with intercellular apoptosis-inducing ROS signaling through membrane-associated catalase, which decomposes H2O2 and peroxynitrite and oxidizes NO. Particularly, the decomposition of extracellular peroxynitrite strictly requires membrane-associated catalase. We utilized small interfering RNA (siRNA)-mediated knockdown of catalase and neutralizing antibodies directed against the enzyme in combination with challenging H2O2 or peroxynitrite to determine activity and localization of catalase in cells from three distinct steps of multistage oncogenesis. Nontransformed cells did not generate extracellular superoxide anions and only showed intracellular catalase activity. Transformed cells showed superoxide anion-dependent intercellular apoptosis-inducing ROS signaling in the presence of suboptimal catalase activity in their membrane. Tumor cells exhibited tight control of intercellular apoptosis-inducing ROS signaling through a high local concentration of membrane-associated catalase. These data demonstrate that translocation of catalase to the outside of the cell membrane is already associated with the transformation step. A strong local increase in the concentration of membrane-associated catalase is achieved during tumor progression and is controlled by tumor cell-derived H2O2 and by transglutaminase.

Intercellular apoptosis-inducing HOCl signaling is known as an interplay between superoxide anions/H₂O₂ of transformed target cells and dual oxidase 1 (DUOX1)-related peroxidase that is released from neighboring non-transformed or transformed effector cells. Effector cells are dispensable when the release of the peroxidase domain of DUOX1 from target cells is prevented through inhibition of matrix metalloproteinase (MMP) activity. Membrane-associated peroxidase is then co-localized to NADPH oxidase 1 (NOX1) and establishes HOCl signaling specifically in transformed cells, using the same biochemical pathways as classical intercellular HOCl signaling. Membrane-associated peroxidase protects against exogenous HOCl through reversal of the peroxidase reaction. In addition, membrane-associated peroxidase protects against NO/peroxynitrite signaling as it oxidates NO and decomposes peroxynitrite. The protective function of membrane-associated peroxidase (in the absence of MMP) is analogous to that of catalase, whereas the destructive effect of the enzyme, i.e. the synthesis of HOCl, is independent of its localization and of MMP activity., (Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Intercellular apoptosis-inducing HOCl signaling is discussed as a control step during oncogenesis. It is defined as a sophisticated interplay between transformed target cells and non-transformed or transformed effector cells. In this study, transformed target cells were seeded as clumps of high local cell density, but low total cell number. They were surrounded by large numbers of effector cells, seeded at low local density. This spatially defined experimental arrangement allowed study of the impact of siRNA-mediated knockdown of NADPH oxidase 1 (NOX1) or dual oxidase 1 (DUOX1) on intercellular HOCl signaling. Our data show that the target function of transformed cells is defined as expression of NOX1 and subsequent extracellular superoxide anion generation. The NOX domain of DUOX1 does not contribute to the target function. The peroxidase domain of DUOX1 is released from transforming growth factor β1-treated non-transformed and transformed cells and acts in trans as HOCl-synthesizing peroxidase. These findings clarify the biochemical source of HOCl during HOCl-mediated signaling., (Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Purpose: Treatment of secondary glaucoma in uveitis patients is challenging. Owing to the young age of these patients, sufficient lowering of the intraocular pressure (IOP) is essential to prevent progression of visual field loss. However, because of the chronic inflammatory stimulus, filtration surgery has an increased risk of failure, especially in patients who have previously undergone surgery. Therefore, minimally invasive glaucoma surgery is a valuable alternative., Methods: The clinical records of 24 consecutive patients with uveitic secondary glaucoma who underwent trabeculectomy ab interno with the Trabectome® at the Eye Center of the Albert-Ludwigs University of Freiburg between June 2009 and June 2014 (registered in the Freiburg trabectome database) were retrospectively analyzed. The general baseline information for each patient included age, gender, glaucoma type, ocular medication and current IOP. The postoperative IOP and number of antiglaucomatous medications were recorded at each visit. Statistical analyses were performed using the Kaplan-Meier estimator and Dunnett's t-test., Results: The mean IOP before surgery was 31 ± 6.7 mmHg (median 32 mmHg). Both the IOP and the number of medications significantly decreased over the various follow-up intervals after trabeculectomy ab interno with the Trabectome®. Patients with follow-ups continuing past one year showed an IOP-reduction of approximately 40 % and a medication number reduction from 2 to 0.67. The failure rate (necessitating further glaucoma surgery) was N = 3 (12.5 %) patients., Conclusions: Trabeculectomy ab interno with the Trabectome® is a minimally invasive and effective method for controlling IOP in uveitic secondary glaucoma.

Background: The opacification of an artificial intraocular lens is a rare but serious complication following cataract surgery as an exchange of the intraocular lens can become necessary. At our eye center we observed single cases of IOL opacifications following complicated posterior lamellar keratoplasty (Descemet stripping automated endothelial keratoplasty = DSAEK or Descemet membrane endothelial keratoplasty = DMEK). Therefore, we performed a retrospective analysis of all our digital charts regarding the incidence of this serious complication with respect to posterior lamellar keratoplasty, penetrating keratoplasty or sole cataract extraction., Methods: We searched our digital patient database from 2003 to 2015 using the following headings: intraocular lens, artificial lens or IOL and opacification or calcification and selected only those patients who had undergone either DSAEK, DMEK, penetrating keratoplasty or sole cataract surgery (n = 19,565)., Results: In total we found five IOL opacifications out of 153 DSAEK and two out of 450 DMEK cases, respectively. Five of these seven cases had a complicated clinical course with repeated rebubbling or additional intraocular surgery (i.e., repeat DSAEK or DMEK or secondary penetrating keratoplasty). There were no documented IOL opacifications following penetrating keratoplasty or sole cataract extraction. In two cases intraocular lens exchange became necessary. All opacifications showed similar clinical appearance in form of small granular deposits on the surface of the intraocular lens. Almost all implanted lenses were made from hydrophilic acrylate., Discussion: In total we found seven cases of intraocular lens opacification that have only been observed following DSAEK or DMEK. According to reports from the literature these opacifications are superficial calicifications of the hydrophilic lenses. As five of the seven cases had a complicated clinical course, the repeated air contact of the lens could be one major factor in inducing the calcification. Besides the air contact a breakdown of the blood-aqueous barrier could also play a role in the induction of calcium phosphate crystallisation on the intraocular lens. The risk of this serious complication in mainly hydrophilic intraocular lenses with respect to posterior lamellar keratoplasty should be kept in mind for the selection of the type of intraocular lens in patients with endothelial diseases or in patients undergoing combined cataract extraction and DSAEK/DMEK., (Georg Thieme Verlag KG Stuttgart · New York.)

Background: To determine the incidence and potential risk factors of cystoid macular oedema (CMO) following Descemet membrane endothelial keratoplasty (DMEK) with or without simultaneous cataract surgery., Methods: In this study, 155 eyes of 88 patients suffering from Fuchs endothelial dystrophy (81%), bullous keratopathy (17.6%) or other corneal diseases (1.4%) underwent DMEK. 52% were pseudophacic (DMEK) and 48% received simultaneous cataract surgery (DMEK combined with cataract surgery (Triple-DMEK)) at the Eye Center at Albert Ludwigs University of Freiburg between May 2011 and June 2013. Spectral-domain optical coherence tomography (SD-OCT) was performed 6 weeks, 3 months and 6 months following (Triple-)DMEK and in unscheduled visits due to limited or decreased visual acuity. The medical records were reviewed for pre-existing comorbidities limiting visual acuity. Patients with a history of macular oedema were excluded. We estimated the incidence of CMO using the Kaplan-Meier method. Potential risk factors for CMO were analysed with a Cox regression analysis and Pearson's correlation. The Cox model included the following variables: patient age and axial length, simultaneous cataract surgery, rate of rebubbling, donor age and donor endothelial cell density., Results: 13% of all eyes developed a single episode of CMO at the end of the follow-up. After 6 months, 13.3% of eyes following Triple-DMEK and 12.5% of eyes following DMEK showed CMO. There was a statistically significant correlation between CMO development and best spectacle corrected visual acuity. Long axial length had a protective effect on CMO development (HR=0.3; p=0.03). Under medical therapy, central foveal thickness decreased in all patients. CMO did not have a relevant effect on long-term visual acuity., Conclusions: CMO is a frequent complication following DMEK in phacic and pseudophacic eyes. The prognosis is excellent given medical treatment. We recommend regular SD-OCT monitoring during the first 6 months following DMEK., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Purpose: To assess the diagnostic accuracy of contrast material-enhanced magnetic resonance (MR) imaging of superficial cranial arteries in the initial diagnosis of giant cell arteritis ( GCA giant cell arteritis )., Materials and Methods: Following institutional review board approval and informed consent, 185 patients suspected of having GCA giant cell arteritis were included in a prospective three-university medical center trial. GCA giant cell arteritis was diagnosed or excluded clinically in all patients (reference standard [final clinical diagnosis]). In 53.0% of patients (98 of 185), temporal artery biopsy ( TAB temporal artery biopsy ) was performed (diagnostic standard [ TAB temporal artery biopsy ]). Two observers independently evaluated contrast-enhanced T1-weighted MR images of superficial cranial arteries by using a four-point scale. Diagnostic accuracy, involvement pattern, and systemic corticosteroid ( sCS systemic corticosteroid ) therapy effects were assessed in comparison with the reference standard (total study cohort) and separately in comparison with the diagnostic standard TAB temporal artery biopsy ( TAB temporal artery biopsy subcohort). Statistical analysis included diagnostic accuracy parameters, interobserver agreement, and receiver operating characteristic analysis., Results: Sensitivity of MR imaging was 78.4% and specificity was 90.4% for the total study cohort, and sensitivity was 88.7% and specificity was 75.0% for the TAB temporal artery biopsy subcohort (first observer). Diagnostic accuracy was comparable for both observers, with good interobserver agreement ( TAB temporal artery biopsy subcohort, κ = 0.718; total study cohort, κ = 0.676). MR imaging scores were significantly higher in patients with GCA giant cell arteritis -positive results than in patients with GCA giant cell arteritis -negative results ( TAB temporal artery biopsy subcohort and total study cohort, P < .001). Diagnostic accuracy of MR imaging was high in patients without and with sCS systemic corticosteroid therapy for 5 days or fewer (area under the curve, ≥0.9) and was decreased in patients receiving sCS systemic corticosteroid therapy for 6-14 days. In 56.5% of patients with TAB temporal artery biopsy -positive results (35 of 62), MR imaging displayed symmetrical and simultaneous inflammation of arterial segments., Conclusion: MR imaging of superficial cranial arteries is accurate in the initial diagnosis of GCA giant cell arteritis . Sensitivity probably decreases after more than 5 days of sCS systemic corticosteroid therapy; thus, imaging should not be delayed. Clinical trial registration no. DRKS00000594 ., (© RSNA, 2014.)

The aim of this study was to evaluate the diagnostic value of a 32-channel head coil for the characterization of mural inflammation patterns in the superficial cranial arteries in patients with giant cell arteritis (GCA) compared to a standard 12-channel coil at 3T MRI. 55 patients with suspected GCA underwent high resolution T1-weighted post-contrast MRI at 3T to detect inflammation related vessel wall enhancement using both coils. To account for different time delays between contrast agent injection and sequence acquisition, the patients were divided into two cohorts: 27 patients were examined with the 32-channel coil first and 28 patients with the 12-channel coil first. Images were evaluated by two blinded readers with regard to image quality, artifact level and arteries' inflammation according to a standardized ranking scale; furthermore signal-to-noise ratio (SNR) measurements were performed at three locations. Identification of arteries' inflammation was achieved with both coils with excellent inter-observer agreement (κ=0.89 for 12-channel and κ=0.96 for 32-channel coil). Regarding image grading, the inter-observer variability was moderate for the 12-channel (κ=0.5) and substantial for the 32-channel coil (κ=0.63). Significantly higher SNR and improved image quality (p<0.01) were obtained with the 32-channel coil in either coil order. Image quality for depiction of the superficial cranial arteries was superior for the 32-channel coil. For standardized GCA diagnosis, the 12-channel coil was sufficient., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Purpose: Penetrating keratoplasty is being replaced by posterior lamellar techniques like Descemet stripping automated endothelial keratoplasty or Descemet membrane endothelial keratoplasty (DMEK) for the surgical treatment of patients with endothelial insufficiency. Although DMEK leads to the best visual results, Descemet stripping automated endothelial keratoplasty is still the standard procedure for many surgeons because it is technically more standardized. Here, we investigated how donor characteristics may influence DMEK surgery., Methods: After in vitro preparation of DMEK grafts (n = 28), we measured the width of the graft roll, which we correlated to various donor characteristics. In 31 DMEK cases, we measured the intraoperative time from implantation to attachment of the graft, which we correlated to the respective donor characteristics and endothelial cell loss. We used Pearson's method and a multifactorial linear model for the statistical assessments., Results: We found a statistically significant correlation between donor age (P < 0.001) and endothelial cell density (P < 0.05), and the width of the DMEK rolls. That is, older donors and grafts with higher endothelial cell densities formed broader graft rolls. Donor age also showed a trend to directly influence the unfolding time that took longer using younger grafts. Furthermore, the relative endothelial cell loss increased with longer unfolding times., Conclusions: We found that donor age and endothelial cell density influence the properties of DMEK grafts, and thereby the duration of the surgical procedure. Increased unfolding times result in higher endothelial cell loss. Therefore, it seems reasonable to accept preferably older donors with high endothelial cell densities for DMEK, which may be particularly true for inexperienced surgeons or complex clinical situations.

Purpose: Descemet-stripping automated endothelial keratoplasty (DSAEK) is an advanced method of lamellar endothelial keratoplasty. In comparison with penetrating keratoplasty, visual rehabilitation seems to be faster. Final visual outcome of DSAEK, however, seems to be limited, especially in comparison with Descemet membrane endothelial keratoplasty (DMEK). DSAEK cases without graft failure often do not show any definite correlate for the reduced optical performance. In this study, we tried to correlate visual acuity following DSAEK with interface reflectivity as measured by a rotating Scheimpflug system., Methods: We examined 14 eyes of 13 patients with the pentacam for 2-11 months following DSAEK. Reflectivity of the interface region in the centre of the optical axis as well as central corneal thickness was determined. Statistical correlation between interface reflectivity and best spectacle-corrected visual acuity, central corneal thickness and follow-up time was drawn (multifactorial linear regression analysis)., Results: Statistically significant correlation between interface reflectivity and BSCVA as well as follow-up time was found. Reflectivity was highest in regions of interface (metal) particles. There was no statistically significant correlation between interface reflectivity and central corneal thickness., Conclusion: We present a measurable correlate for reduced visual outcome following DSAEK despite a clear graft. Inverse correlation between interface reflectivity and best spectacle-corrected visual acuity (BSCVA) indicates that irregularities or scarring in the interface region may influence the optical quality following DSAEK., (© 2013 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Purpose: In cataract and refractive surgery, implantation of a light-adjustable lens (LAL) represents a promising method to noninvasively correct deviation from target refraction. In this method, UVA irradiation is used to induce controlled changes in the form and refraction of the lens. UVA irradiation is known to have a damaging effect on corneal tissue. So far, no studies about the toxicity of LAL treatment on the human corneal endothelium exist. We tested the effect of LAL treatment on human donor endothelium under organ culture conditions., Methods: Two pairs of human donor corneas not suitable for transplantation but with good endothelial quality were exposed either to LAL treatment with a target refraction of the maximum adjustable profile for hyperopia with astigmatism (right corneas) or to the white light of the same slit lamp for identical time frames (left corneas). Development of endothelial cell number, morphology and percentage of necrosis was observed. After 6 weeks, histologic analysis was performed., Results: Comparing morphology, cell count, percentage of necrosis, and histologic examination in vitro, no significant differences between right and left corneas could be detected., Conclusions: The maximum dose of UVA irradiation used in LAL treatment was not detrimental for human corneal endothelium in vitro. Further in vivo studies and longer observation periods should be performed for ensuring the safety of LAL treatment as a routine procedure.

Tumor cells are protected against intercellular reactive oxygen species (ROS)-mediated apoptosis signaling mediated by the HOCl and/or the nitric oxide (NO)/peroxynitrite signaling pathway. We have recently shown that tumor cell resistance against HOCl signaling can be abrogated through inhibition of catalase. The protection of tumor cells against the NO/peroxynitrite signaling pathway has remained enigmatic so far. Here, we show that suboptimal inhibition of catalase by 3-aminotriazole or a monoclonal antibody against catalase, as well as partial knockdown of catalase by specific siRNA allows selective reactivation of the NO/peroxynitrite pathway in MKN 45 gastric carcinoma cells, followed by the HOCl pathway at higher inhibitor or siRNA concentrations. In SKN-MC Ewing sarcoma cells, catalase inhibition causes apoptosis induction solely based on the NO/peroxynitrite pathway. Protection against NO/peroxynitrite signaling is shown to be due to the potential of catalase to decompose peroxynitrite. The direct interaction of catalase with peroxynitrite is verified through the detection of compound I (CAT Fe(IV)=O(+)*) after the interaction of peroxynitrite with catalase. In a complementary experiment, addition of catalase protects sensitive transformed cells against ROS-mediated apoptosis induction. Thus, the expression of membrane-associated catalase is sufficient to protect tumor cells against multiple intercellular ROS-mediated signaling pathways.