bluuebunny/crossref_metadata_2025 huggingface dataset:
Current concepts and future directions in the pathogenesis and treatment of infectious and non‐infectious intraocular inflammation
Authors: DICK A
Published: August 2012

Purpose Moving away from the morbidity of steroid therapy for inflammatory disease or the overburdonsome adverse events of immunosuppressive therapy, the advent of understanding of immune response during non‐infectious uveitis alongside the explosion in biotechnology has facilitated the development of biologic therapy. This has generated a new era for increasing equisitely specific therapy. Improved diagnostics have lead to specific targeting for infectious aetiologies

Methods The review will highlight experimental evidence of targets of inhibiting T cell activation, B cell responses, Trafficking of cells, and cytokine inhibition. However, most importantly is the increasing abibility to predict and therefore target responses.Addiotionally the ability to rapidly identify infectious causes will be discussed

Results We will highlight the strength of predicting response to steroid and highlighting mechanisms of steroid refractiveness has generated avenues of approach for specific therapy. In addition the efficacy of regulating trafficking and inhibiting myeloid cell function shows promise in the future treatments of non‐infectious intraocular inflammatory disease.

Conclusion Biologic therapy has the opportunity to not only specifically and powerfully immunomodulate but also with the increase in understanding of individual immune response adapt to generate a more stratified and personalised approach to therapy.

Commercial interest
Novel therapeutic strategies for the induction of tolerance in corneal transplantation
Authors: RITTER T , TREACY O , O'FLYNN L , WILK M , MORCOS M , RYAN A , NOSOV M
Published: August 2012

Purpose To develop novel treatment protocols for the prolongation of corneal allograft survival.

Methods Genetic manipulation of donor corneas prior to transplantation is an attractive approach to protect the graft from allogeneic rejection. A lentiviral construct which encodes for Programmed Death‐Ligand 1 (PD‐L1) was applied for ex‐vivo genetic modification of corneal grafts before transplantation. Moreover, the generation and application of regulatory cell populations such as mesenchymal stem cells (MSCs) and tolerogenic dendritic cells (tolDCs) to modulate immune‐mediated rejection in transplanted animals and their mechanism of action will be discussed in this presentation.

Results Overexpression of PD‐L1 in ex‐vivo cultured corneas prior to transplantation significantly prevents corneal allograft rejection by modulating both innate and adaptive intra‐graft allo‐immune responses. Moreover, systemic injection of MSCs and tolDCs is able to prolong corneal allograft survival and reduces neovascularisation and graft opacity. A significant reduction of graft‐infiltrating inflammatory cells was also recorded for both applications.

Conclusion Local overexpression of immunomodulatory molecules is a promising approach to prevent corneal graft rejection. In addition treatment of transplanted animals with regulatory cells also modulates corneal allograft survival. These novel therapies may have the potential to be further developed towards a clinical application. [Supported by Science Foundation of Ireland (SFI 07/IN.1/B925). TR is supported by a Travel Grant from Millennium Research Funds, National University of Ireland, Galway]
Counselling the patient with advanced disease
Authors: ANSARI E
Published: August 2012

Purpose To provide an understanding of how to counsel patients about irreversible sight loss.

Methods Understanding : the patient's perspective the grief reaction sharing information the role of the clinician the role of the counsellor

Results Time‐ listen listen and listen to the patient and their concerns. Team‐ you cannot manage this alone! Trust‐ this happens if time, transparency and team approach are employed.

Conclusion Glaucoma is responsible for irreversible loss of vision. It is very important to inform the patient fully about this from the outset and to be transparent and supportive if blindness supervenes. A solid team approach with the help of a counsellor is very important.
Natural compounds as lead therapeutic agents against diabetic eye disease
Authors: PETRASH M
Published: August 2012

Diabetes is a leading cause of new cases of blindness throughout the world. Given the rapid increase in diabetes incidence in recent years, diabetic eye disease will likely become an even bigger problem in the future. There are currently no medical therapies for prevention of early stage ophthalmic complications of diabetes, and treatment for late stage disease is complicated and prohibitively expensive for deployment on a large scale. We have centered our efforts on identifying therapeutic compounds identified as natural products, with a particular focus on plant materials identified over time to be associated with efficacy against diabetes and its complications. The Indian gooseberry (Emblica officinalis), commonly known as Amla, is used in the practice of Indian traditional medicine (Ayurveda) to minimize the effects of diabetes and its complications. We previously showed that treatment of experimentally diabetic rats with crude extracts from Amla fruit delayed the onset and progression of cataracts and prevented the accumulation of sorbitol and diabetes‐induced markers of lipid peroxidation and protein oxidation products in the eye. Because these results were consistent with the effects of aldose reductase (AR) inhibition, we embarked on a bioassay‐guided scheme to search for putative AR inhibitors (ARI), using human AR (AKR1B1) activity as an assay read out. Fractionation of materials in an Amla extract resolved several compounds with ARI activity. Structure elucidation by NMR identified the major inhibitor as 1‐O‐galloyl‐beta‐D‐glucose, also known as beta‐glucogallin (bGG). We and others have shown that AR inhibition by sorbinil and a variety of other validated ARIs suppresses inflammatory markers associated with exposure to lipopolysaccharide (LPS) endotoxins. Our studies show that treatment of LPS‐exposed mice with bGG dose‐dependently suppresses infiltration of inflammatory cells in the anterior and posterior chambers and prevents morphological disruption of retinal layers. Using macrophage cell cultures, we demonstrated that bGG down‐regulates endotoxin‐induced expression of a variety of pro‐inflammatory cytokines including TNFa and IL1b. Similar studies are being carried out with a novel drug lead recently identified in a family of flowering plants commonly cultivated in India and Malaysia (Piperaceae). Overall, our studies suggest that natural products may be a rich source of lead compounds useful for development as therapeutic agents against diabetic complications.
EBO exam: how to succeed?
Authors: ACLIMANDOS W
Published: August 2012

Abstract not provided
Evaluation remains a key point
Authors: MATHYSEN D
Published: August 2012

Purpose European postgraduate medical assessment have developed during the last 25 years. Currently, all European medical specialties examinations use MCQs. The European Board of Ophthalmology Diploma (EBOD) examination uses multiple independent true/false MCQs for the written part of the examination. Since true/false MCQs may be prone to guessing, thorough statistical evaluation has been set‐up over the last five years to monitor the performance of the examination and its MCQs.

Methods In 2010, the European Board of Ophthalmology (EBO) decided to introduce negative marks for the MCQs. To study the influence of negative marks on the performance/reliability of the examination, the following statistical performance parameters of test items have been compared: P‐value, Rit‐value, Cronbach‐alpha and 3‐parameter item‐response analysis.

Results A decrease in average P‐value (P < 0.66) was observed compared to the situation without negative marks (P > 0.75). An increase in average Rit‐value (Rit > 0.15) was observed compared to the situation without negative marks (Rit < 0.15). An increase in Cronbach‐alpha (> 0.85) was observed compared to the situation without negative marks (< 0.80). 3‐parameter item‐response analyses revealed that almost none of the questions was influenced by guessing correctly (average c <<< 0.33), while without negative marks all questions were influenced by guessing correctly (average c ~ 0.33).

Conclusion Introduction of negative marks at the EBO examination, did lead to a decrease in item‐facility (P‐value) due to less "wild" guessing; an increase in Pearson correlation (Rit‐value) between item and total scores and an increase in reliability (Cronbach‐alpha). 3‐parameter analysis showed that the portion of correct answers due to guessing is negligible with the use of negative marks.
I have got a grant
Authors: GRIGORIU D
Published: August 2012

Purpose Ever since the EBO grants have been awarded, the aim was to open communication channels between doctors from all over Europe, particularly linking the East to the West. From my point of view the actual collaboration between the young and the more experienced does just that, enabling the grant recipient to broaden her/his horizon, thus greatly enhancing self‐confidence; and my aim is to prove this.

Methods I am going to share some of my personal experience during my stay in VU Medical Center in Amsterdam and speak about the impact that meeting the renowned team there had on the way I perceive my work and my responsibility towards my patients.

Results During my one month stay in Amsterdam I found excellent support in Prof. Ringens and his team – the vitreo‐retinal surgeons, strabismus specialists and the retinoblastoma team. I thus made important steps in learning how to use an indirect ophthalmoscope, got to talk about complex retinoblastoma cases and saw some uveitis cases which are more frequent in Latin America or Asia and not so common in Eastern Europe.

Conclusion By receiving this grant I had the opportunity to come into contact with some of the best European ophthalmologists, to get new ideas on how to improve my practice and upgrade my skills in examining the patients. And, above all, I felt more than welcome among them and I feel certain I can count on them for further guidance and support.
Complexity of genetics in keratoconus
Authors: GAJECKA M , KAROLAK JA , MOLINARI A , PITARQUE JA , BEJJANI BA , POLAKOWSKI P , SZAFLIK J , SZAFLIK JP , NOWAK DM
Published: August 2012

Purpose Mapping and genome sharing among affected individuals continue to be important for establishing a link between a genomic variant and its phenotypic consequences. In one large Ecuadorian keratoconus (KC) family a mutation and three other sequence variants were recognized, showing 100% segregation with disease phenotype in DOCK9, IPO5 and STK24 at 13q32 locus. Here we present further linkage and sequencing results of candidate KC genes identified in other Ecuadorian families.

Methods Linkage analyses were performed in 3 large KC families. Next, candidate genes at indentified loci were screened by standard techniques using genomic DNA samples from these families and selected individuals from other Ecuadorian families and control Ecuadorian individuals. Coding exons and intron‐exon boundaries of the genes were evaluated.

Results Suggestive keratoconus loci, 2q13‐q14.3, 20p13, and 5q31 were identified. Sequencing of IL1A, IL1B and IL1RN at 2q13‐q14.3, SLC4A11 at 20p13, TGFBI, PITX1 and IL9 at 5q31 have been completed. Numerous SNV were identified in coding and non‐coding regions.

Conclusion Identified keratoconus loci and the sequence variants are specific for the studied families only. Our results indicate high complexity of genetics in familial keratoconus. Support: Polish Ministry of Science and Higher Education, Grant NN402591740 and National Science Center, Grant 2011/03/N/NZ5/01470
OPA1‐related sensorineural hearing loss
Authors: LERUEZ S , BONNEAU D , AMATI‐BONNEAU P , DEFOORT‐DHELLEMMES S , CROCHET M , DROUIN V , BLANCHET C , JUUL G , LARSEN M , LAENERS G , REYNIER P , MILEA D
Published: August 2012

Purpose The OPA1 gene, encoding a dynamin‐like mitochondrial GTPase, is responsible for autosomal dominant optic atrophy (ADOA, OMIM #165500), which can be associated with extra‐ocular abnormalities including sensorineural deafness.The purpose of this study is to determine, in a large series of patients carrying OPA1 mutations, the prevalence of the R445H mutation and of rarer OPA1 mutations in patients with ADOD and to describe the phenotype associated with these rarer mutations.

Methods We retrospectively reviewed the files of all the OPA 1 patients with documented deafness diagnosed in our laboratory between 2003 and 2011.

Results In our series, deafness occurred in 6.4% of OPA1 patients. Hearing loss occurred as the first sign of the disease in one third of the patients, prior to visual loss. In addition to the most common mutation responsible for ADOA and deafness (R445H), we report 6 additional mutations responsible for this association.

Conclusion Deafness can be associated with dominant optic atrophy, due to OPA1 mutations, other than the classical R445H mutation. Unexplained sensorineuronal hearing loss can even be the first event and its association to optic atrophy and should prompt molecular genetic analysis, which can lead to an appropriate diagnosis.
Analysis of lincRNA at 13q32 keratoconus locus
Authors: KAROLAK JA , NOWAK DM , MOLINARI A , PITARQUE JA , BEJJANI BA , GAJECKA M
Published: August 2012

Purpose Keratoconus (KC) is a disease of the eye characterized by thinning and protrusion of the cornea. The causes of KC remain unknown. Our mutation screening of genes from 13q32 KC locus have revealed substitution in STK24 showing 100% segregation with KC phenotype in the Ecuadorian family. To continue the KC causes search, some non‐coding RNA from 13q32 locus were selected for further molecular analysis. Here, we present sequencing results of lincRNA localized ~1kb from 5’ end of STK24.

Methods The lincRNA was screen by sequencing technique using DNA samples from 23 members of KC‐014 family and selected affected and unaffected individuals from Ecuador.

Results Sequencing analysis of lincRNA localized ~1kb from 5’ end of STK24 have revealed g.99230266C>T substitution showing segregation with KC phenotype in the Ecuadorian KC‐014 family.

Conclusion Mutation analysis of lincRNA mapped at the 13q32 locus have revealed sequence alteration segregating with the KC phenotype in Ecuadorian family. Since it is known, that lincRNAs are co‐expressed with neighboring coding genes and may function as a regulator of epigenetic marks and gene expression, we suggest that this lincRNA localized in close proximity to STK24 gene might play a role in development and/or progression of familial KC in patients from Ecuador. To our knowledge, this is the first report presenting lincRNA analysis in KC. Support: Polish Ministry of Science and Higher Education, Grant NN402591740
Retinal oxygen saturation in health and disease
Authors: HARDARSON S
Published: August 2012

Purpose Measurements of retinal vessel oxygen saturation can provide insight into the nature of several eye diseases.

Methods Dual wavelength oximeters are used by our group and others. They measure light absorbance at one oxygen‐sensitive and one oxygen‐insensitive wavelength and use the absorbance values to calculate retinal vessel oxygen saturation.

Results Oxygen saturation in the larger retinal venules is decreased in central retinal vein occlusion but increased in diabetic retinopathy and age‐related macular degeneration. In glaucoma, retinal venous oxygen saturation increases with increased visual field defect.

Conclusion Oxygen saturation in the larger retinal vessels, particularly the venules, reflects the balance between oxygen supply and oxygen consumption in the retina. In glaucoma, for example, a rise in the retinal venous oxygen saturation is most likely due to tissue atrophy and less oxygen consumption. Oxygen saturation in the larger vessels can also be affected by the efficiency of oxygen distribution by the retinal capillaries. Increased retinal venous oxygen saturation in diabetic retinopathy may for example partly be explained by shunting of blood through preferential channels in the capillary network.

Commercial interest
Oxygen metabolism in age related macular degeneration
Authors: STEFANSSON E , GEIRSDOTTIR A , HARDARSON S
Published: August 2012

Purpose To determine whether oxygen saturation in retinal vessels of patients with age‐related macular degeneration (AMD) is different from that of a healthy population.

Methods The non‐invasive retinal oximeter is based on a fundus camera. It simultaneously captures images of the retina at 600 nm and 570 nm and estimates retinal vessel oxygen saturation. Mean oxygen saturation of hemoglobin was measured in retinal arterioles and venules of 28 individuals with AMD, 6 were males. Eight patients had early AMD in at least one eye, 8 patients had untreated exudative AMD in at least one eye, and 12 patients had early AMD in one eye and untreated exudative AMD in the other eye. The age of AMD patients was 78 ± 9 years (mean ± SD) compared to 66 ± 4 years for the healthy controls (n=26).

Results Oxygen saturation of hemoglobin in arterioles, after adjusting for vessel width, was 94.3 ± 3.7% in the healthy population compared to 93.5 ± 3.1% in early AMD (n= ;p=0.42) and 93.7 ± 3.8% in exudative AMD (n= ;p=0.55). The corresponding values in venules were 60.9 ± 5.6% in healthy eyes compared to 64.9 ± 7.0% in exudative AMD (p=0.017). In eleven patients with early AMD in one eye and exudative AMD in the other eye, oxygen saturation in arterioles was 93.5 ± 3.0% and 92.4 ± 2.8% (p=0.52) and in venules 66.3 ± 4.9% and 64.4 ± 5.3% (p=0.080).

Conclusion Oxygen saturation in venules in exudative AMD is higher than in healthy controls and there is a similar trend in early AMD. Arteriovenous difference is smaller in AMD subjects than normals. The study suggests that retinal oxygen metabolism is affected in AMD.

Commercial interest
Oxygen distribution in the retina
Authors: POURNARAS CJ
Published: August 2012

Purpose To evaluate the distibution of the preretinal and transretinal partial pressure of oxygen(PO2) in normal and ischemic retinas.

Methods Evaluation of either the preretinal or intraretinal oxygen partial pressure (PO2) distribution, using oxygen sensitive microelectrodes, in normal or ischemic retinal conditions.

Results The distribution of PO2 close to the vitreoretinal interface is heterogeneous, being higher near the arteriolar wall. Preretinal and transretinal PO2 profiles indicate that O2 diffusion from the arterioles affects the PO2 in the juxta‐arteriolar preretinal region. Both the preretinal and inner retinal PO2 recorded far from the vessels remain constant in all retinal areas. The oxygen tension (PO2) in the inner half of the retina remains largely unaffected by moderate changes in perfusion pressure, systemic PaO2 changes occuring during either hyperoxia or hypoxia. However, an increase in PaCO2 (hypercapnia), as well as an intravenous injection of acetazolamide (carbonic anhydrase inhibitor) both lead to an increase in preretinal PO2 due to dilation of the retinal vessels. In eyes with experimental branch retinal vein occlusion, PO2 values within the inner retinal layers are indicative of hypoxic conditions, whereas adjacent areas appear to remain normal. In diabetic patients undergoing vitrectomy a lowered vitreal PO2 in the affected retinal areas has also reported.Occlusion of the retinal circulation renders most of the inner retina anoxic.

Conclusion Thanks to the autoregulatory ability of the retinal circulation, the oxygen tension (PO2) in the inner half of the retina, remains largely unaffected during physiological stimuli. In both normal and inner retinal ischemic conditions,the oxygen supply from the choroid is sufficient to support only the photoreceptor inner segments.
Neurodegeneration as an early event in the pathogenesis of Diabetic Retinopathy: A multicentric, prospective, phase II‐III, randomised controlled trial to assess the efficacy of neuroprotective drugs administered topically to prevent or arrest Diabetic Retinopathy. EUROCONDOR – EU FP7 Project
Authors: CUNHA‐VAZ J
Published: August 2012

Purpose To assess whether neuroprotective drugs administered topically (somatostatin and brimonidine) are able to prevent or arrest neurodegeneration as well as the development and progression of Diabetic Retinopathy (DR) in its early stages.

Methods Primary: 1) To assess whether somatostatin, administered topically, is able to prevent or arrest the development and progression of neurodegenerative changes. 2) To assess whether, brimonidine, administered topically, is able to prevent or arrest the development and progression of neurodegenerative changes.

Results Primary: Changes in the Implicit Time assessed by mfERG (IT‐mfERG). Secondary: 1) Neurodegenerative variables: Retinal Nerve Fiber Layer (RNFL); Ganglion Cell Layer (GCL) and central retinal thickness assessed by SD‐OCT. 2) Microaneurysm turnover assessed by Colour Fundus Photography; DR severity. 3) Other variables: BCVA; Visual Fields; Visual‐related Quality of Life; Need for rescue treatment.

Conclusion Clinical Trial Population Type II diabetic patients; ETDRS levels <20 (50%) or ≤35 (50%). 450 patients to be enrolled in 11 or more clinical centres in Europe (41 patients per centre).
The interest of imaging for corneal lamellar grafting
Authors: NUBILE M
Published: August 2012

Abstract not provided
New trends in endothelial transplantation: DSAEK vs DMEK
Authors: SCORCIA V
Published: August 2012

Abstract not provided
Is there still room for penetrating keratoplasty in 2012
Authors: GICQUEL JJ
Published: August 2012

Penetrating keratoplasty (PK) is the most commonly performed graft in the western world. Recent advances in the medical management of corneal diseases and the advent of lamellar surgeries have considerably changed patterns in the indications of PK. Hence we will apprehend what indications are left for PK, as well as the enhanced PK techniques.
New therapeutic approaches in uveitis
Authors: FERAOUN N , HESBERT A , MONNET D , BREZIN A , BATTEUX F
Published: August 2012

Purpose Autoimmune uveitis is a severe disease, responsible for approximately 10% of acquired blindness. The side effects induced by systemic steroids or immunosuppressive therapies have prompted us to search for more specific treatments. Recently, tyrosine kinase inhibitors, including imatinib and sunitinib, have shown interesting properties in several autoimmune diseases. Their immunomodulating properties make them potential interest in the treatment of autoimmune uveitis and we analyzed their therapeutic effects in the mouse model of experimental autoimmune uveitis.

Methods We induced uveitis to C57BL6 mice by immunization with IRBP protein, and we performed a randomized blinded controlled trial in 30 mice treated with either sunitinib (50mg/kg/day), imatinib (50mg/kg/day) or placebo. We then compared the efficiency of these treatments by measuring the frequency and the severity of the uveitis induced.

Results An effect of sunitinib in the prevention of experimental autoimmune uveitis was observed, with an average uveitis clinical score of 1.1 in the control group, 0.70 in the imatinib group (p=0.28) and 0.36 in the sunitinib group (p=0.02). This effect was confirmed by retina histological examination, with a histopathological score of 0.95 in the control group versus 0.19 (p=0.003) in the sunitinib group. We furthermore demontrasted that sunitinib efficiency is most likely related to the immunomodulation of the immune response, with a reduction in the Th17 response and an inhibition of T cell proliferation.

Conclusion Thus, we report for the first time that a tyrosine kinase inhibitor can prevent experimental autoimmune uveitis or decrease its intensity. In particular, sunitinib could be considered as a potential treatment for autoimmune uveitis.
Atypical panuveitis parasitic and Herpes virus co‐infection in immunocompetent adults: real co‐infection or false positive?
Authors: NGUYEN AM , DENIS P , GRANGE JD , KODJIKIAN L
Published: August 2012

Purpose Acute panuveitis with retinitis diagnosis may sometimes be difficult. Contribution of microbiological analyzes of intraocular samples currently allows a rapid diagnosis to guide therapeutic management when visual function is severely threatened.

Methods We report three original cases of panuveitis with retinitis for which analyzes showed concomitant infection with Toxoplasma and Herpes viruses.

Results PCR techniques have increased the sensitivity and specificity of diagnostic tests for ocular pathogens, including Toxoplasmosis and Herpes viruses. For Toxoplasmosis, Western blot and Desmonts coefficient remain standards tests in immunocompetent adults. As for central nervous system infections, Herpes viruses PCR is the gold standard test for intraocular samples. The clinical cases described here are atypical and the clinical examination failed to set the diagnosis. The detection of two infectious agents has led to the establishment of a double etiologic treatment, due to the severity of the ocular involvement. However, we may suppose that certain viruses in dormant states can be liberated in an inflammed eye, causing DNA to be detected on PCR testing, making more than one true positive result both possible and clinically relevant.

Conclusion In actual clinical use, false‐positive results are possible from contamination, and false‐negative results are possible from polymorphism, specimen degradation, or failure to sample in the acute stages of disease. It remains difficult to determine the responsibility of both infectious agents revealed. Is it a real co‐infection, or false positive?
Quantitative assessment of the visual pathway by DTI‐MRI in Glaucoma
Authors: MICHELSON G , WAERNTGES S , ENGELHORN T , HORNEGGER J , DöRFLER A
Published: August 2012

Purpose In glaucomatous optic nerve atrophy (glOA) damage of retinal ganglion cells may continue to the linked optic radiations (OR). This study investigated differences between glOA and non‐glOA in relation to impairment of the optic radiations using DTI‐MRI.

Methods We examined 42 patients with healthy optic nerve head and no ophthalmological signs of an affected visual pathway, 134 glOA patients, and 35 non‐glOA patients (mean age 54±15.9 years, 64±12.4 years, and 49±15.2 years, respectively). The participants underwent the diffusion tensor imaging (DTI) to measure the axonal integrity, i.e. fractional anisotropy (FA) and mean diffusivity (MD), and demyelination, i.e. radial diffusivity (RD), in the semi‐automatically outlined optic radiations. The results were correlated with the retinal nerve fiber layer thickness (RNFL) acquired by the Spectralis optical coherence tomography and with the mean defect provided by standard automatic perimetry.

Results Age correlated significantly with the DTI parameters in all groups. If corrected for age only in the glOA patient group the mean defect correlated with FA (r=‐0.31; p=0.004) and RD (r=0.22; p=0.043). In the non‐glOA group the RNFL correlated with MD (r=‐0.57; p=0.027) and RD (r=‐0.59; p=0.019). The control group did not show a correlation of DTI parameters with the mean defect or RNFL.

Conclusion In both types of optic nerve atrophy a correlation was found between visual field and axonal integrity/ demyelination of the optic radiations, and the reduction of the RNFL was associated with an impairment of the axonal integrity/ demyelination of the optic radiation. The damage of the optic nerve was significantly associated with loss of RNFL and ageing.
Neurodegeneration of the visual pathway in glaucoma
Authors: CORDEIRO MF
Published: August 2012

Glaucoma has recently become recognized as a neurodegenerative disorder. This has been predominantly because that neuronal and axonal changes occur throughout the visual pathway from the retina to the brain. Furthermore, as in other neurodegenerative conditions, there are numerous studies investigating neuroprotective agents in glaucoma, using vitro and in vivo models. Historically, there has been a problem translating results however, from the laboratory to the clinic. In fact, there is a real shortage of good clinical trials in this area. In glaucoma, it is recognized that there is a need an alternative therapeutic approach, independent of IOP reduction. Several mechanisms have been implicated in initiating the apoptotic cascade in glaucomatous retinopathy and numerous drugs have been shown to be neuroprotective in animal models of glaucoma, although translating to the clinical arena has been difficult to date. This lecture will summarize neurodegeneration of the visual pathway in glaucoma and review current potential neuroprotective strategies.
Neuroprotective therapy of the visual pathway in glaucoma
Authors: ARAIE M
Published: August 2012

Purpose To review our results of experiments relating to neuroprotective therapy of glaucoma at various levels of the visual pathway.

Methods Using isolated retinal ganglion cell (RGC) culture system, drug effects on hypoxic stress‐induced damage of RGCs were studied. Using monkey unilateral experimental glaucoma model, 1) drug effects on the optic nerve head (ONH) circulation, and 2) neural degeneration secondary to experimental glaucoma in the CNS visual pathway were studied. Drug effects on CNS degeneration secondary to RGC death were also studied in a mice model. A double‐masked placebo‐controlled trial was conducted to investigate the effect of oral nilvadipine, a Ca2+‐blocker, on the visual field in normal tension glaucoma (NTG) patients.

Results Ca2+‐blockers and some of the beta‐blockers were found to be neuroprotective against hypoxia‐induced cultured RGC damage. Both nilvadipine and lomerizine, another Ca2+‐blocker, increased the ONH circulation not only in normal, but also experimental glaucoma eyes in monkeys. In the lateral geniculate nucleus (LGN) of experimental glaucoma monkeys, M‐cells were first damaged, and then both M‐ and P‐cells damaged, where endoplasmic reticulum (ER) stress in apoptotic processes and activation of glial cells were involved. Systemic lomerizine and memantine were found to alleviate CNS damages secondary to NMDA‐induced RGC death in mice. In a clinical trial, a low dose of oral nilvadipine (4mg/day) significantly decreased the rate of mean deviation (MD) deterioration in NTG patients as compared to placebo.

Conclusion A systemic drug administration such as oral nilvadipine which can alleviate damage at various levels of visual pathway may have potential in neuroprotective therapy in glaucoma.
Retinal vessels as biomarkers
Authors: SCHMETTERER L
Published: August 2012

Purpose In the recent years much interest was directed towards the analysis of retinal vessel diameters. This is related to our improved understanding of the systemic, ocular, environmental and genetic factors that control retinal vascular calibers.

Methods Methods to assess retinal vessel diameters are described. In addition, more sophisticated analyses of vessel structure are presented based on fractional analysis. Finally, techniques to study retinal vascular responses during stimulation, such as diffuse flicker light, are presented.

Results Narrower retinal arteriolar caliber is associated with aging, systemic hypertension and obesity. Wider retinal venular caliber is associated with impaired fasting glucose and diabetes, dyslipidemia and cigarette smoking. In addition, wider venular calibers are considered markers of inflammation and endothelial dysfunction. Reduced flicker‐induced vasodilatation is an early process in diabetes.

Conclusion Assessment of retinal vessel diameters is an interesting approach for risk stratification based on ophthalmological findings. Refined technology and longitudinal studies are required to fully explore the potential of these techniques.
Combining vessel analysis with Doppler OCT
Authors: GARHOFER G
Published: August 2012

Purpose It has been recognized that morphological and functional changes of retinal vessels do not only reflect ocular vascular pathologies, but are also associated with systemic disease. Changes of the retinal vascular system may therefore serve as an indicator for systemic vascular related disorders such as diabetes and hypertension. The resolution of classical fundus‐camera based systems is, however, limited, and vessels smaller than 40 ‐60µm cannot be adequately imaged.

Methods As such, much emphasis has been put into the development of new and sophisticated methods to assess retinal blood flow in vivo. One approach is based on Doppler optical coherence tomography (OCT), yielding in principle information on both, velocity and diameter. We investigated the validity of this approach by comparing vessel diameters with values as obtained using the Dynamic Vessel Analyzer (DVA) and blood velocities as obtained with laser Doppler velocimetry (LDV).

Results Comparison of velocity data as obtained with bi‐directional Fourier Domain Doppler OCT showed good correlation with LDV data during both normoxic and hyperopic conditions (p < 0.01 each). Diameter data as obtained from OCT images were, however, significantly lower as those measured with DVA (p < 0.01). This was the case when data were extracted from both the amplitude and the phase images. In some cases the OCT technique underestimates the vessel diameter by as much as 20 µm.

Conclusion Whereas velocity data are adequately measured using Doppler OCT velocity data are significantly underestimated. As such adequate data on retinal blood flow can only be extracted using a combination of fundus camera‐based vessel analysis and OCT‐based velocity extraction. This technique may have considerable potential for risk stratification of cardiovascular patients.
Biology of metastatic disease
Authors: COUPLAND SE , KALIRAI H , DODSON A , DAMATO B
Published: August 2012

Purpose Despite successful treatment of the primary tumour, uveal melanoma (UM) disseminates haematogeneously in approx. 50% of patients, usually to the liver. In a few patients, metastases can be treated surgically; however, in the majority, there is no effective chemotherapy, as the “magic bullet” for metastatic UM has yet to be found.

Methods Literature review to provide an overview of the morphological, immunohistochemical and molecular genetic features of metastatic UM. In addition, immunohistochemical studies for various proteins, including BRCA1 associated protein 1 (BAP‐1), were performed on tissue microarrays of matched primary and metastatic UM. The percentage of tumor cell positivity was scored blind by independent assessors, and correlations were measured with statistical tests.

Results Literature review revealed only a few studies of human UM metastases, including some on fine needle aspiration biopsies, liver resections, or on autopsy material. Occasional studies examined matched primary and metastatic tumour samples. The majority of investigations had performed immunohistochemistry, with only a few examining the genetic changes of these tumours. The results of our analyses of a cohort comprising >100 metastatic UM will be presented. We confirm that absence of BAP1 correlates with metastasis of UM; however, metastasis can occur despite BAP1 expression.

Conclusion In order to understand the dissemination process of UM, including the mechanisms involved in successful tumour cell colonisation, the tumour microenvironment‐, the immunophenotype‐, genotype and possible susceptible signalling pathways of the melanoma cells, it is essential that greater efforts are made to access and investigate these samples. Only in this way can treatment of the systemic phase of UM be successful.
Difficult counselling issues
Authors: HALL G
Published: August 2012

Purpose Families present to the genetic ophthalmic clinic in a wide variety of challenging situations. Unexpected, complex diagnoses have an impact on individuals and their families that require multidisciplinary genetic counselling and support. While there is limited research into the impact or service needs of families with inherited eye disease, we can learn a great deal from the cases presenting in clinic.

Results In this presentation, we describe clinical situations that have presented challenges for the genetic eye team in order to highlight counselling issues and improvements in care. Examples will include the diagnosis of multisystemic disease, approaching sudden and unexpected vision loss in children and the impact and ethical challenges in cascade screening in families.

Conclusion Genetic counselling as part of a multidisciplinary approach for inherited eye disease is required to support families around diagnosis, impact of vision loss and testing in the wider family.
Mitochondrial optic neuropathies
Authors: VOTRUBA M
Published: August 2012

Purpose This update will focus on recent and exciting new developments in mitochondrial optic neuropathies after reviewing the background, including clinical and molecular features.

Methods Mitochondrial optic neuropathies are a group of conditions which are currently untreatable and which comprise non‐syndromic conditions such as Leber's Hereditary optic neuropathy, dominant optic atrophy, recessive optic atropby, as well as syndromic optic neuropathies. A number of key developments in genetic testing, counselling and potential therapies will be reviewed together with difficult or challenging cases as examples.

Results Understanding the pathophysiology of the mitochondrial optic neuropathies will aid in our quest for new diagnostic, management and therapeutic interventions. The focus of the update will be to highlight some key developments and encourage discussion and participation from the floor.

Conclusion This is a rapidly advancing field with a potential for future therapies emerging on the horizon.
Inherited retinal disease
Authors: LEROY BP
Published: August 2012

Purpose To illustrate several inherited retinal dystrophies and dysfunctions and their management in the ophthalmic genetic clinic.

Methods A case presentation format will be used to illustrate different genetically determined retinal dystrophies and dysfunctions. Case descriptions will include clinical and electrophysiological phenotypes as well as genotypes.

Results Phenotypes and genotypes of genetically determined retinal diseases are very different. An important distinction to be made is the one between stationary and progressive diseases, as the visual outcome differs considerably between different conditions.

Conclusion Inherited retinal diseases are very diverse. Taking a thorough history in combination with an extensive clinical examination and psychophysical and electrophysiological tests most often allows a to make a specific diagnosis. It is important to distinguish between progressive and stationary conditions.
CSCR/ DRPE : a same disease?
Authors: GAUDRIC A
Published: August 2012

Abstract not provided
Perspectives for new treatments at Alcon ‐ part 2
Authors: RICH C
Published: August 2012

In an effort to continue to meet unmet medical needs for ophthalmology conditions Alcon continues to have a well developed pipeline of products in the Ophthalmology space. This presentation will give the audience an overview of how we identify a wide variety of potential products to develop and how we condense this list down to the final candidates that will establish our pipeline strategy. This process is conducted across the 3 main franchises of Alcon: Pharmaceuticals, Surgical and Vision Care. This presentation will review products in development in the area of Retina and this is an exciting area for Alcon with several projects in development for the treatment of a number of conditions. Alcon is conducting multiple projects in the area of vitreo‐retinal diseases including products for vitreolysis, dry and wet AMD, retinal vein occlusion and diabetic retinopathy. In the area of rare diseases Alcon currently has a program to evaluate the treatment of multifocal choroiditis. During this presentation we will discuss these programs on a high level and also discuss our approach to retina, which we see as a growing area within ophthalmology. The treatment of retinal conditions is still early in its evolution and Alcon looks forward to developing products that treat significant unmet medical needs in the area of Retina.
Stargardt macular dystrophy
Authors: HOLZ F , SCHMITZ‐VALCKENBERG S , CHARBEL ISSA P
Published: August 2012

Initiation of a number of upcoming clinical trials for patients with Stargardt disease emphasizes the urge of determining objective outcome measures derived from retinal imaging. Especially novel techniques such as fundus autofluorescence (AF) and quantitative AF imaging as well as spectral domain optical coherence tomography (SD‐OCT) now allow assessing the characteristic pathology of Stargardt disease at different disease stages. Fundus AF highlights lipofuscin accumulation in the retinal pigment epithelium (RPE), the phenotypic finding that defines Stargardt disease. Also, fundus AF delineates areas of RPE atrophy with high contrast, allowing to longitudinally monitoring respective changes with high accuracy. SD‐OCT, on the other hand, is a clinically meaningful outcome measures since is allows to delineate the photoreceptor layer of the retina. Structural alterations within this layer have been shown to correlate directly with retinal function. Relevant functional parameters include visual acuity and microperimetry. Disease phenotyping (including comparison of various imaging modalities) as well as analysis of longitudinal imaging data, structure‐function‐correlations and genotype‐phenotype correlations will be prudent. In a prospective, multicenter, non‐interventional, non‐randomized, unmasked, observational study the natural history of patients with Stargardt’s disease will be characterized, prognostic markers identified and microstructural alterations and functional variations determined. Allö probands will be ABCA4‐genotyped.
Autophagy: a new way to retinal neuroprotection
Authors: RUSSO R , BAGETTA G , CORASANITI MT
Published: August 2012

Purpose Autophagy is a highly conserved catabolic pathway in which proteins and organelles are engulfed by autophagic vacuoles (AVs) that are then targeted to lysosomes for degradation. Basal autophagy serves homeostatic function and it is induced during periods of cell stress. Defects in the autophagic machinery have been described in several neurodegenerative diseases. In this study we investigated the role of autophagy in the retinal neurodegeneration associated to ischemic conditions.

Methods Retinal ischemia was induced in adult rats by acute elevation of intraocular pressure. Expression of autophagy related proteins, beclin‐1 and LC3, was studied by western blotting and immunofluorescence. NMDA antagonists, calpain inhibitors or siRNA were intravitreally administered. Effects of autophagy modulation on retinal ganglion cell (RGC) survival was evaluated in serum‐starved RGC‐5 treated with autophagy inhibitors or transfected with beclin‐1 siRNA.

Results Beclin‐1 is part of the complex involved in the induction of autophagy, while LC3 plays an essential role in the expansion of AVs. Retinal ischemia produced a reduction of the autophagosome‐associated form of LC3 (LC3II) and induced a significant decrease of beclin‐1 expression. The latter event was dependent on NMDA receptors and calpain activation as shown by the prevention afforded by MK801, calpain inhibitors or calpain siRNA. Inhibition of autophagy or beclin‐1 silencing in RGC‐5 significantly reduced cell viability under serum starvation conditions.

Conclusion Our results, while provide the first in vivo evidence of a calpain‐mediated cleavage of beclin‐I, show that retinal ischemia alters the dynamic of the autophagic process and suggest a neuroprotective role of autophagy in RGCs exposed to detrimental stimuli.
Neuroprotective factors against retinal injury in response to hypoxia: new perspectives
Authors: BAGNOLI P , DAL MONTE M
Published: August 2012

Purpose In the retina, hypoxia is considered one of the key factors to trigger angiogenesis and to promote apoptosis by reducing photoreceptors and other retinal neurons, each of them contributing to vision loss. We recently demonstrated that the beta‐adrenergic system interferes with angiogenesis‐dependent diseases in the retina by regulating endogenous VEGF. Aim of the present study was to investigate the role of distinct beta‐adrenergic receptors (BARs)in neurodegenerative processes in response to hypoxia.

Methods Ex vivo mouse retinal explants and in vivo models were used. BARs were blocked with antagonists or silenced with siRNAs. VEGFR2 was blocked with SU1498, whereas iNOs and eNOS with AG, L‐NIO or L‐NAME. mRNA levels were evaluated with quantitative RT‐PCR. BARs, iNOS, eNOS and apoptotic signals were determined with Western blot. Immunohistochemistry was used to localize BARs and to assess neovascularization. VEGF release and NO production were measured with colorimetric assays. Hoechst and TUNEL were used to evaluate cell loss.

Results Among the BARs, BAR3 is localized to blood vessels, is upregulated by hypoxia and acts through iNOS/NO to control VEGF levels and degenerative responses to the hypoxic insult. In particular, BAR3 blockade is accompanied by increased levels of apoptotic signals and cell loss. Pharmacological interaction with the VEGF signalling demonstrates that BAR3 exerts a protective action on retinal cells through a modulation of endogenous VEGF.

Conclusion Our findings demonstrate that modulation of BAR3 activity during ischemia may be a powerful means to achieve neuroprotection. VEGF's role in retinal cell survival has important implications for treatments with VEGF blockade within the context of ocular vascular diseases.
Retinal neuronal death caused by ocular hypertension
Authors: VIDAL‐SANZ M , SALINAS‐NAVARRO M , VALIENTE‐SORIANO FJ , ORTíN‐MARTíNEZ A , NADAL‐NICOLáS FM , ALARCóN‐MARTíNEZ L , AVILéS‐TRIGUEROS M , AGUDO‐BARRIUSO M , VILLEGAS‐PéREZ MP
Published: August 2012

Purpose To characterize the anatomical and functional changes that follow ocular hypertension (OHT).

Methods In adult albino rats or mice, the episcleral and perilimbar veins were photocauterized with laser diode. This resulted in OHT that reaches basal levels by one week in mice and by three weeks in rats.

Results OHT induces anatomical and functional degenerative retinal changes. One week after lasering there is impairment of the retrograde axonal transport which is first functional and then mechanic. By two weeks there is loss of approximately 80% of the RGC population without further progression. RGCs loss occurs mainly in pie‐shaped sectors but is also diffuse throughout the retina. The intraretinal RGC axons and somas show signs compatible with a slow retrograde axonal degeneration resembling an optic nerve crush. OHT induces loss of RGCs but not of other non RGC neurons present in the ganglion cell layer, namely the displaced amacrine cells, for periods of up to six months after OHT. There is a protracted and progressive affectation of the outer retina which results in a major loss of LM‐ and S‐cones. This anatomical data are supported by functional analyses. Electroretinogram recordings show maintained and significant diminutions of the scotopic threshold responses as well as of the a‐ and b‐waves indicating permanent alterations of the inner and outer retinal layers, respectively.

Conclusion OHT results both in RGC axonal crush‐like injury and in an ischemic damage to the outer retinal layers. Thus, this model may be used to study axotomy‐ or ischemia‐induced neuronal death in the innermost retina or in the outer retina, respectively.