Roselie M.H. Diederen

Balance of vascular endothelial growth factor and pigment epithelial growth factor prior to development of proliferative vitreoretinopathy.

Background: Pigment epithelium-derived factor (PEDF) and vascular endothelial growth factor (VEGF) are imbalanced in eyes with proliferative diabetic retinopathy or proliferative vitreoretinopathy (PVR). It is not known whether such an imbalance is already present in early PVR stages. We therefore analyzed VEGF and PEDF concentrations in subretinal fluids prior to PVR development. Methods: A large number (n = 137) of subretinal fluid samples were obtained at the time of scleral buckling surgery for rhegmatogenous retinal detachment (RRD). Thirty patients developed PVR within 6 months after surgery. One hundred and seven patients undergoing the same surgery but without complications served as controls. Furthermore, vitreous from 16 patients with macular hole or pucker (MHP) served as reference for baseline intraocular concentrations. PEDF and VEGF concentrations were measured by commercial ELISAs. Results: PEDF levels were substantially higher (9.6 µg/ml) compared to MHP vitreous (0.3 µg/ml, p < 0.001). VEGF levels were also higher (RRD: 0.07 ng/ml; MHP: 0.01 ng/ml, p < 0.05). Subretinal concentrations were not significantly different between PVR and control RRD patients. Conclusions: Although both VEGF and PEDF are increased at first surgery for RRD, they do not predict PVR development later on. The high PEDF concentrations and its known antiangiogenic activity suggest a protective role against neovascularization.

Incidence of redetachment 6 months after scleral buckling surgery

Purpose:u2002 The preoperative and intraoperative clinical variables associated with redetachment and/or a poor visual outcome following scleral buckling (SB) surgery for rhegmatogenous retinal detachment (RRD) have mainly been studied after a short follow‐up. This study aimed to analyse long‐term effects by following patients for at least 6u2003months.

Selective blockade of phosphodiesterase types 2, 5 and 9 results in cyclic 3′5′ guanosine monophosphate accumulation in retinal pigment epithelium cells

Aim: To investigate which phosphodiesterase (PDE) is involved in regulating cyclic 3′5′ guanosine monophosphate breakdown in retinal pigment epithelium (RPE) cells. Methods: cGMP content in the cultured RPE cells (D407 cell line) was evaluated by immunocytochemistry in the presence of non-selective or isoform-selective PDE inhibitors in combination with the particulate guanylyl cyclase stimulator atrial natriuretic peptide (ANP) or the soluble guanylyl cyclase stimulator sodium nitroprusside (SNP). mRNA expression of PDE2, PDE5 and PDE9 was studied in cultured human RPE cells and rat RPE cell layers using non-radioactive in situ hybridisation. Results: In the absence of PDE inhibitors, cGMP levels in cultured RPE cells are very low. cGMP accumulation was readily detected in cultured human RPE cells after incubation with Bay60–7550 as a selective PDE2 inhibitor, sildenafil as a selective PDE5 inhibitor or Sch51866 as a selective PDE9 inhibitor. In the presence of PDE inhibition, cGMP content increased markedly after stimulation of the particulate guanylyl cyclase. mRNA of PDE2,PDE5 and PDE9 was detected in all cultured human RPE cells and also in rat RPE cell layers. Conclusions: PDE2, PDE5 and PDE9 have a role in cGMP metabolism in RPE cells.

Expression of the diabetes risk gene wolframin (WFS1) in the human retina.

Wolfram syndrome 1 (WFS1, OMIM 222300), a rare genetic disorder characterized by optic nerve atrophy, deafness, diabetes insipidus and diabetes mellitus, is caused by mutations of WFS1, encoding WFS1/wolframin. Non-syndromic WFS1 variants are associated with the risk of diabetes mellitus due to altered function of wolframin in pancreatic islet cells, expanding the importance of wolframin. This study extends a previous report for the monkey retina, using immunohistochemistry to localize wolframin on cryostat and paraffin sections of human retina. In addition, the human retinal pigment epithelial (RPE) cell line termed ARPE-19 and retinas from both pigmented and albino mice were studied to assess wolframin localization. In the human retina, wolframin was expressed in retinal ganglion cells, optic axons and the proximal optic nerve. Wolframin expression in the human retinal pigment epithelium (RPE) was confirmed with intense cytoplasmic labeling in ARPE-19 cells. Strong labeling of the RPE was also found in the albino mouse retina. Cryostat sections of the mouse retina showed a more extended pattern of wolframin labeling, including the inner nuclear layer (INL) and photoreceptor inner segments, confirming the recent report of Kawano et al. [Kawano, J., Tanizawa, Y., Shinoda, K., 2008. Wolfram syndrome 1 (Wfs1) gene expression in the normal mouse visual system. J. Comp. Neurol. 510, 1-23]. Absence of these cells in the human specimens despite the use of human-specific antibodies to wolframin may be related to delayed fixation. Loss of wolframin function in RGCs and the unmyelinated portion of retinal axons could explain optic nerve atrophy in Wolfram Syndrome 1.

Increased nitric oxide (NO) pathway metabolites in the vitreous fluid of patients with rhegmatogenous retinal detachment or diabetic traction retinal detachment

BackgroundNitric oxide (NO) plays a significant role in physiological and pathological processes in the retina. In the L-arginine-NO pathway, NO synthase (NOS) converts L-arginine to NO and L-citrulline. Increased NO production, mediated by inducible NOS has been implicated in the pathogenesis of various vitreoretinal diseases. In the present study it is hypothesized that in rhegmatogenous retinal detachment (RRD), the production of NO pathway metabolites might be upregulated.MethodsUsing high-pressure liquid chromatography citrulline, arginine and nitrite were measured in vitreous fluid of 93 eyes with RRD, nine eyes with a traction retinal detachment due to proliferative diabetic retinopathy (PDR), and in 49 control samples of vitreous fluid from eyes without retinal detachment.ResultsThe mean vitreous concentrations of citrulline and arginine were significantly increased in eyes with RRD (9.6±4.3 and 97.3±29.2; respectively) or in eyes with a traction retinal detachment (25.8±10.3 and 130.7±23.7; respectively) as compared to control eyes (7.1±3.2 and 75.9±18.1; respectively). The mean level of nitrite was also higher in vitreous fluid of patients with RRD (2.24±1.4) or patients with a traction retinal detachment (2.21±0.72) than in the controls (2.01±0.72), although not significantly so.ConclusionsWe found increased levels of NO pathway metabolites in the vitreous fluid of eyes with retinal detachment, which may reflect a possible role of NO in the pathogenesis of this disease.

Cyclic GMP Synthesis by Human Retinal Pigment Epithelial Cells Is Mainly Mediated via the Particulate Guanylyl Cyclase Pathway

Background/Aims: Cyclic 3′,5′-guanosine monophosphate (cGMP), a central molecule in the phototransduction cascade, is also involved in a number of other physiological processes in the retina, like stimulating the absorption of subretinal fluid by activating the retinal pigment epithelium (RPE) cell pump. The aim of this study was to quantify cGMP synthesis by RPE cells and to investigate the role of two separate enzymatic pathways (soluble versus particulate guanylyl cyclase) in its production. Methods: cGMP expression was evaluated by immunochemistry and radioimmunoassay following culture of the D407 RPE cell line in the presence of a nonselective phosphodiesterase inhibitor (IBMX), in combination with the particulate guanylyl cyclase stimulator atrial natriuretic peptide (ANP) or the soluble guanylyl cyclase stimulator sodium nitroprusside (SNP). Results: Stimulation of the particulate guanylyl cyclase in RPE cells with ANP resulted in high intra- and extracellular cGMP levels. Stimulation of the soluble guanylyl cyclase by SNP resulted in a slight elevation of cGMP levels compared to controls. Conclusions: These results show that cultured human RPE cells are capable of producing cGMP and that most cGMP is generated following stimulation of the particulate guanylyl cyclase pathway.

Two autocrine pathways to regulate cyclic GMP synthesis in cultured human retinal pigment epithelial cells.

Aim: To investigate the role of two separate enzymatic pathways [soluble (sGC) vs. particulate (pGC) guanylyl cyclase] in the synthesis of cyclic GMP (cGMP) in cultured human retinal pigment epithelial (RPE) cells. Methods: cGMP accumulation was evaluated by quantitative analysis of cGMP immunoreactivity. RPE cells were also stained for inducible nitric oxide synthase (iNOS), ANP and β1- and α2-subunits of sGC. Results: We showed nicotinamide adenine dinucleotide phosphate (NADPH) diaphorase activity and iNOS immunoreactivity in RPE cells. Incubation of the cells in the presence of 1 mM IBMX to inhibit phosphodiesterase activity, and the simultaneous inhibition of NOS activity with L-NAME suggested the involvement of sGC in maintaining a low level of cGMP in the RPE cells. The involvement of sGC was further supported by detection of the β1- and α2-subunits of sGC. Incubation of the cells in the presence of atrial natriuretic peptide (ANP) to stimulate pGC strongly increased cGMP immunoreactivity. We also demonstrated the presence of ANP in all RPE cells. Conclusion: Cultured human RPE cells are capable of producing cGMP after stimulation of sGC or pGC. The presence of iNOS and ANP in all cells suggests two different autocrine pathways of stimulating cGMP production in these cells. The possible role of cGMP in the regulation iNOS gene expression and in the regulation of ANP is discussed.

Appointment of New Section Editors

Pinar Aydin O’Dwyer, Professor of Ophthalmology and neuroophthalmologist, is a member of the Advisory Committee and Assessment Committee and Head of the Ethics Subcommittee of the International Council of Ophthalmology. She serves as Executive Board Member and Treasurer of the Turkish Board of Ophthalmology and General Secretary of the Postgraduate and Continuing Education Committee. Since 2000 she has been Program Secretary of the Scientific Section for Neuroophthalmology of the European Association for Vision and Eye Research (EVER); since 2002 she has been a Regional Representative on the EVER Board and is currently the treasurer of EVER. She has held conferences, and organized and given courses in America, Europe, Asia and Africa. She has authored approximately 150 scientific publications in peer-reviewed ophthalmology journals and edited seven books in ophthalmology. Since 2004 she has served on the Editorial Board of Ophthalmic Research . Ophthalmic Research is pleased to announce the appointment of new section editors for the field of Neuroophthalmology and Glaucoma. In addition, a new section – Clinical Retina – is introduced to manage the growing number of submissions in this field. Section editors have important duties and are responsible for guiding a submission through the peer review process. They are assigned to a particular article and are responsible for selecting reviewers for that submission, communicating with the authors and reviewers throughout the process, making a decision in favor of acceptance or rejection, and finally managing the successful papers through the editing process. Drs. Aydin (Neuroophthalmology) and Wiedemann (Clinical Retina) have already served as board members of Ophthalmic Research . Dr. Orgül (Glaucoma) begins his tenure on the board this year. We hope to continue the success of the journal and to provide useful information to the medical and scientific communities. At the same time, I personally would also like to thank Drs. Tsukahara and van den Berg for their time and commitment as section editors for many years. Uwe Pleyer, Editor-in-Chief Published online: December 11, 2006