Konstanz, Germany
Konstanz, Germany

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Karabag R.Y.,Dokuz Eylül University | Parlak M.,Klinikum Konstanz | Cetin G.,Dokuz Eylül University | Yaman A.,Dokuz Eylül University | Osman Saatci A.,Dokuz Eylül University
Digital journal of ophthalmology : DJO | Year: 2015

PURPOSE: To report the prevalence of postoperative retinal tear or rhegmatogenous retinal detachment secondary to intravitreal injections.METHODS: Surgical and medical records of patients who received intravitreal injections at the practice of a single retina specialist from January 2004 to May 2013 and who were followed for at least 6 months were investigated retrospectively.RESULTS: During the study period, a total of 3,907 intravitreal injections were performed in 1,049 eyes of 784 patients (416 males [47%]). The mean number of injections per eye was 3.72 ± 3.43 (range, 1-22). The mean age of the participants was 67.03 ± 13.56 (range, 5-94 years). The mean follow-up time was 31.98 ± 22.86 months (range, 6-144 months). Retinal break or rhegmatogenous retinal detachment occurred in 3 injections of 3 eyes, yielding an overall prevalence of 0.077% per injection and 0.29% per eye.CONCLUSIONS: Retinal tear and rhegmatogenous detachment are rare complications of intravitreal injection. Precautions should be taken especially in patients having predisposing conditions, such as high myopia, or any other vitreoretinal disorders.


Trew G.,Hammersmith and Queen Charlottes Hospital | Trew G.,University of London | Pistofidis G.,Lefkos Stavros Hospital | Pados G.,Center for Endoscopic Surgery | And 22 more authors.
Human Reproduction | Year: 2011

Background: Gynaecological laparoscopic surgery outcomes can be compromised by the formation of de novo adhesions. This randomized, double-blind study was designed to assess the efficacy and safety of 4 icodextrin solution (Adept ®) in the reduction of de novo adhesion incidence compared to lactated Ringers solution (LRS). Methods: Patients undergoing laparoscopic surgery for removal of myomas or endometriotic cysts were treated with randomized solution as an intra-operative irrigant and 1l post-operative instillate. De novo adhesion incidence (number of sites with adhesions), severity and extent were independently scored at a second-look procedure and the efficacy of the two solutions compared. The effect of surgical covariates on adhesion formation was also investigated. Initial exploratory analysis of individual anatomical sites of clinical importance was progressed. Results: Of 498 patients randomized, 330 were evaluable (160 LRS 75 myomectomy/25 endometriotic cysts; 170 Adept 79 myomectomy/21 endometriotic cysts). At study completion, 76.2 LRS and 77.6 Adept had <1 de novo adhesion. The mean (SD) number of de novo adhesions was 2.58 (2.11) for Adept and 2.58 (2.38) for LRS. The treatment effect difference was not significant (P=0.909). Assessment of surgical covariates identified significant influences on the mean number of de novo adhesions regardless of treatment, including surgery duration (P 0.048), blood loss in myomectomy patients (P=0.019), length of uterine incision in myomectomy patients (P < 0.001) and number of suture knots (P < 0.001). There were 15 adverse events considered treatment-related in the LRS patients (7.2) and 18 in the Adept group (8.3). Of 17 reported serious adverse events (9 LRS; 8 Adept) none were considered treatment-related. Conclusions: The study confirmed the safety of Adept in laparoscopic surgery. The proportion of patients with de novo adhesion formation was considerably higher than previous literature suggested. Overall there was no evidence of a clinical effect but various surgical covariates including surgery duration, blood loss, number and size of incisions, suturing and number of knots were found to influence de novo adhesion formation. The study provides direction for future research into adhesion reduction strategies in site specific surgery. © 2011 The Author Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved.


Czekelius P.,Klinikum Konstanz | Wenzel H.,Independent Health Economic Consultant
Zeitschrift fur Geburtshilfe und Neonatologie | Year: 2016

Introduction: Crowther et al. 3 analysed the effectivity of magnesium tocolysis in preventing preterm birth. They conclude that there is no evidence for protection. In its latest guidelines, based on this Cochrane analysis, the German Association of Gynaecology and Obstetrics (DGGG) does not recommend any more the use of magnesium for tocolysis. Magnesium tocolysis is said neither to delay nor to prevent preterm birth. Moreover, magnesium could be responsible for increased mortality in infants. These conclusions are mostly based on the research of Mittendorf et al. 4. In a Cochrane study from 2014, which in principal was identical to the study mentioned above 3, Crowther et al. 6 confirm the previous findings and conclusions. Method: Having successfully applied magnesium tocolysis for many years, these surprising conclusions led us to review the soundness of the publications mentioned above. Combining the practical experience of many years with the results of a comprehensive literature retrieval, we finally contrasted this knowledge with the findings of the aforementioned publications that caused the DGGG to withdraw the recommendation for magnesium. Results: To draw binding consequences from a meta-analysis is possible only when stringent quality guidelines are observed. The studies that were included in the Cochrane review of Crowther et al. 3 are very heterogeneous and are not suitable for concluding on poor or even lacking effectiveness of magnesium tocolysis. Furthermore, the cases of infant deaths, as stated by Mittendorf et al. 4, are very unlikely caused by magnesium. Conclusion: When including studies in a meta-analysis special attention has to be given to the relevance and unbiased selection of studies. To prevent any misjudgment, a thorough knowledge of the included studies seems essentiell. There is not sufficient evidence to withdraw the recommendation for applying magnesium tocolysis as a preventive measure to prevent preterm birth. In the sense of evidence-based medicine, long-standing, scientifically proven therapeutic success should be incorporated into the meta-analysis as well. © Georg Thieme Verlag KG.


Hauser M.A.,University of Konstanz | Schaeuble K.,University of Konstanz | Schaeuble K.,University of Lausanne | Kindinger I.,University of Konstanz | And 5 more authors.
Immunity | Year: 2016

Host defense depends on orchestrated cell migration guided by chemokines that elicit selective but biased signaling pathways to control chemotaxis. Here, we showed that different inflammatory stimuli provoked oligomerization of the chemokine receptor CCR7, enabling human dendritic cells and T cell subpopulations to process guidance cues not only through classical G protein-dependent signaling but also by integrating an oligomer-dependent Src kinase signaling pathway. Efficient CCR7-driven migration depends on a hydrophobic oligomerization interface near the conserved NPXXY motif of G protein-coupled receptors as shown by mutagenesis screen and a CCR7-SNP demonstrating super-oligomer characteristics leading to enhanced Src activity and superior chemotaxis. Furthermore, Src phosphorylates oligomeric CCR7, thereby creating a docking site for SH2-domain-bearing signaling molecules. Finally, we identified CCL21-biased signaling that involved the phosphatase SHP2 to control efficient cell migration. Collectively, our data showed that CCR7 oligomers serve as molecular hubs regulating distinct signaling pathways. © 2016 Elsevier Inc.


PubMed | University of Zürich, University of Konstanz and Klinikum Konstanz
Type: Journal Article | Journal: Immunity | Year: 2016

Host defense depends on orchestrated cell migration guided by chemokines that elicit selective but biased signaling pathways to control chemotaxis. Here, we showed that different inflammatory stimuli provoked oligomerization of the chemokine receptor CCR7, enabling human dendritic cells and Tcell subpopulations to process guidance cues not only through classical G protein-dependent signaling but also by integrating an oligomer-dependent Src kinase signaling pathway. Efficient CCR7-driven migration depends on a hydrophobic oligomerization interface near the conserved NPXXY motif of G protein-coupled receptors as shown by mutagenesis screen and a CCR7-SNP demonstrating super-oligomer characteristics leading to enhanced Src activity and superior chemotaxis. Furthermore, Src phosphorylates oligomeric CCR7, thereby creating a docking site for SH2-domain-bearing signaling molecules. Finally, we identified CCL21-biased signaling that involved the phosphatase SHP2 to control efficient cell migration. Collectively, our data showed that CCR7 oligomers serve as molecular hubs regulating distinct signaling pathways.


Hauser M.A.,University of Konstanz | Kindinger I.,University of Konstanz | Laufer J.M.,University of Konstanz | Spate A.-K.,University of Konstanz | And 5 more authors.
Journal of Leukocyte Biology | Year: 2016

The homeostatic chemokines CCL19 and CCL21 and their common cognate chemokine receptor CCR7 orchestrate immune cell trafficking by eliciting distinct signaling pathways. Here, we demonstrate that human CCR7 is N-glycosylated on 2 specific residues in the N terminus and the third extracellular loop. Conceptually, CCR7 glycosylation adds steric hindrance to the receptor N terminus and extracellular loop 3, acting as a "swinging door" to regulate receptor sensitivity and cell migration. We found that freshly isolated human B cells, as well as expanded T cells, but not naïve T cells, express highly sialylated CCR7. Moreover, we identified that human dendritic cells imprint T cell migration toward CCR7 ligands by secreting enzymes that deglycosylate CCR7, thereby boosting CCR7 signaling on T cells, permitting enhanced T cell locomotion, while simultaneously decreasing receptor endocytosis. In addition, dendritic cells proteolytically convert immobilized CCL21 to a soluble form that is more potent in triggering chemotactic movement and does not desensitize the receptor. Furthermore, we demonstrate that soluble CCL21 functionally resembles neither the CCL19 nor the CCL21 phenotype but acts as a chemokine with unique features. Thus, we advance the concept of dendritic celldependent generation of micromilieus and lymph node conditioning by demonstrating a novel layer of CCR7 regulation through CCR7 sialylation. In summary, we demonstrate that leukocyte subsets express distinct patterns of CCR7 sialylation that contribute to receptor signaling and fine-tuning chemotactic responses. © Society for Leukocyte Biology.


Bruckner M.,University of Konstanz | Dickel D.,University of Konstanz | Singer E.,Klinikum Konstanz | Legler D.F.,University of Konstanz
European Journal of Immunology | Year: 2012

Migration and homing of DCs to lymphoid organs is pivotal for inducing adaptive immunity and tolerance. DC homing depends on the chemokine receptor CCR7. However, expression of CCR7 alone is not sufficient for effective DC migration. A second signal, mediated by prostaglandin E2 (PGE2), is critical for the development of a migratory DC phenotype. PGE2 is important for inducing efficient immune responses, but, if deregulated, contributes to chronic inflammation, autoimmune diseases through Th17-cell development and tumorigenesis. In contrast, activation of liver X receptor (LXR)α has recently been shown to interfere with CCR7 expression and migration of DCs resulting in a reduced immune response. Here, we demonstrate that PGE2 downregulates LXRα expression in human monocyte derived as well as ex vivo DCs. Moreover, PGE2 stimulation dampens LXR activation, auto-regulation and LXR-mediated gene transcription. Consequently, we show that PGE2 enhances CCR7 expression and migration of LXR-activated DCs. Furthermore, we provide evidence that PGE2 signaling and LXR activation specifically elicit converse effects on CCR7 expression and DC migration. In contrast, production of MMP9, CCL4, COX-2, and IL-23 is solely regulated by PGE2, but not by LXR activation, offering new perspectives for therapeutic interventions. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


PubMed | University of Konstanz and Klinikum Konstanz
Type: Journal Article | Journal: Journal of leukocyte biology | Year: 2016

The homeostatic chemokines CCL19 and CCL21 and their common cognate chemokine receptor CCR7 orchestrate immune cell trafficking by eliciting distinct signaling pathways. Here, we demonstrate that human CCR7 is N-glycosylated on 2 specific residues in the N terminus and the third extracellular loop. Conceptually, CCR7 glycosylation adds steric hindrance to the receptor N terminus and extracellular loop 3, acting as a swinging door to regulate receptor sensitivity and cell migration. We found that freshly isolated human B cells, as well as expanded T cells, but not nave T cells, express highly sialylated CCR7. Moreover, we identified that human dendritic cells imprint T cell migration toward CCR7 ligands by secreting enzymes that deglycosylate CCR7, thereby boosting CCR7 signaling on T cells, permitting enhanced T cell locomotion, while simultaneously decreasing receptor endocytosis. In addition, dendritic cells proteolytically convert immobilized CCL21 to a soluble form that is more potent in triggering chemotactic movement and does not desensitize the receptor. Furthermore, we demonstrate that soluble CCL21 functionally resembles neither the CCL19 nor the CCL21 phenotype but acts as a chemokine with unique features. Thus, we advance the concept of dendritic cell-dependent generation of micromilieus and lymph node conditioning by demonstrating a novel layer of CCR7 regulation through CCR7 sialylation. In summary, we demonstrate that leukocyte subsets express distinct patterns of CCR7 sialylation that contribute to receptor signaling and fine-tuning chemotactic responses.


PubMed | Dokuz Eylül University and Klinikum Konstanz
Type: Journal Article | Journal: Digital journal of ophthalmology : DJO | Year: 2016

To report the prevalence of postoperative retinal tear or rhegmatogenous retinal detachment secondary to intravitreal injections.Surgical and medical records of patients who received intravitreal injections at the practice of a single retina specialist from January 2004 to May 2013 and who were followed for at least 6 months were investigated retrospectively.During the study period, a total of 3,907 intravitreal injections were performed in 1,049 eyes of 784 patients (416 males [47%]). The mean number of injections per eye was 3.72 3.43 (range, 1-22). The mean age of the participants was 67.03 13.56 (range, 5-94 years). The mean follow-up time was 31.98 22.86 months (range, 6-144 months). Retinal break or rhegmatogenous retinal detachment occurred in 3 injections of 3 eyes, yielding an overall prevalence of 0.077% per injection and 0.29% per eye.Retinal tear and rhegmatogenous detachment are rare complications of intravitreal injection. Precautions should be taken especially in patients having predisposing conditions, such as high myopia, or any other vitreoretinal disorders.

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