bluuebunny/crossref_metadata_2025 huggingface dataset:
Functional brain organization for number processing in pre‐verbal infants
Authors: Edwards Laura A. , Wagner Jennifer B. , Simon Charline E. , Hyde Daniel C.
Published: September 2015

Humans are born with the ability to mentally represent the approximate numerosity of a set of objects, but little is known about the brain systems that sub‐serve this ability early in life and their relation to the brain systems underlying symbolic number and mathematics later in development. Here we investigate processing of numerical magnitudes before the acquisition of a symbolic numerical system or even spoken language, by measuring the brain response to numerosity changes in pre‐verbal infants using functional near‐infrared spectroscopy (fNIRS). To do this, we presented infants with two types of numerical stimulus blocks: number change blocks that presented dot arrays alternating in numerosity and no change blocks that presented dot arrays all with the same number. Images were carefully constructed to rule out the possibility that responses to number changes could be due to non‐numerical stimulus properties that tend to co‐vary with number. Interleaved with the two types of numerical blocks were audio‐visual animations designed to increase attention. We observed that number change blocks evoked an increase in oxygenated hemoglobin over a focal right parietal region that was greater than that observed during no change blocks and during audio‐visual attention blocks. The location of this effect was consistent with intra‐parietal activity seen in older children and adults for both symbolic and non‐symbolic numerical tasks. A distinct set of bilateral occipital and middle parietal channels responded more to the attention‐grabbing animations than to either of the types of numerical stimuli, further dissociating the specific right parietal response to number from a more general bilateral visual or attentional response. These results provide the strongest evidence to date that the right parietal cortex is specialized for numerical processing in infancy, as the response to number is dissociated from visual change processing and general attentional processing.
Atrial Function Assessed by Speckle Tracking Echocardiography Is a Good Predictor of Postoperative Atrial Fibrillation in Elderly Patients
Authors: Verdejo Hugo E. , Becerra Elia , Zalaquet Ricardo , del Campo Andrea , Garcia Lorena , Troncoso Rodrigo , Chiong Mario , Marin Arnaldo , Castro Pablo F. , Lavandero Sergio , Gabrielli Luigi , Corbalán Ramón
Published: September 2015

Objective

Advanced age is an independent predictor of postoperative atrial fibrillation (POAF) in patients undergoing coronary artery bypass surgery. We evaluated whether left atrial (LA) dysfunction assessed by strain contributes to identifying elderly patients prone to POAF.

Methods

Case–control study of 70 subjects undergoing coronary artery bypass surgery. Clinical and laboratory characteristics were recorded at baseline and 72 hours after surgery. Echocardiography was performed during the preoperative period; LA dimensions and deformation by strain (systolic wave [LASs]) as well as strain rate (systolic wave [LASRs] and atrial contraction wave [LASRa]) were assessed.

Results

Postoperative atrial fibrillation occurred in 38.5% of patients within the first 72 hours after surgery (28.5% of the younger vs. 48.6% of the older group). Baseline and postoperative inflammatory markers as well as total surgical and aortic clamp time were similar between groups. LA function was markedly impaired in subjects with POAF. Age correlated with LASs, LASRs, and LASRa. These associations remained consistent when subjects 75 years or older were considered separately. Both LASs and LASRa for patients with or without POAF, respectively, were significantly impaired in elderly subjects with POAF. Multivariate analysis provided further evidence that both LASs and age are independent predictors for POAF.

Conclusion

Age‐related changes in atrial function preceding atrial dilation are evident only upon LA strain analysis. LA strain impairment is an independent predictor of POAF irrespective of age and may serve as a surrogate marker for biological processes involved in establishing the substrate for POAF.
Bilateral ovarian leiomyoma treated by standing laparoscopic ovariectomy
Authors: Daniel A. , McCue P. , Ferris R. , Miller C. , Leise B.
Published: September 2015

An 11‐year‐old Warmblood mare presented to a referral facility due to behavioural problems. A hormonal profile performed prior to referral included increased systemic concentrations of testosterone and progesterone but a low concentration of inhibin. Transrectal ultrasound revealed ovaries consistent with a normal cycling mare. At the request of the owner, standing bilateral laparoscopic ovariectomy was performed without complication. Both ovaries were submitted for histopathological examination which revealed bilateral ovarian leiomyoma.
Mode I fracture toughness of the thermally pretreated red Verona marble by means of the two‐parameter model
Authors: Carpinteri A. , Ferretti D. , Fortese G. , Ronchei C. , Scorza D. , Vantadori S.
Published: September 2015

The paper aims to analyse the effects of pretreatment thermal cycles on both mechanical and fracture parameters of the red Verona marble, which is a natural stone of sedimentary formation. The effects of the thermal pretreatment, consisting of freeze/thaw cycles and simulating the atmospheric ageing on the material, are evaluated in terms of changes of the aforementioned parameters. Note that a wide variety of both specimen types and methods to determine mode I plain strain fracture toughness of rocks are available in the literature. The two‐parameter model originally proposed for plain concrete is herein adopted. Such a method, based on the experimental data obtained from three‐point bending tests on single edge‐notched specimens, is able to take into account the slow nonlinear crack growth occurring before the peak load, typical of quasibrittle materials, and presents the advantages of easy specimens preparation and simple test configuration.
Sulfasalazine augments a pro‐inflammatory response in interleukin‐1β‐stimulated amniocytes and myocytes
Authors: Sykes Lynne , Thomson Kacie R. , Boyce Emily J. , Lee Yun S. , Rasheed Zahirrah B. M. , MacIntyre David A. , Teoh Tiong Ghee , Bennett Phillip R.
Published: September 2015

Preterm birth occurs in 10% of pregnancies and is a major cause of neonatal morbidity and mortality. The majority of cases of early preterm labour are associated with infection/inflammation, which places the fetal central nervous system at risk. Targeting immune activation is therefore an appealing therapeutic strategy for the prevention of preterm labour and neonatal brain injury. The expression of many labour‐associated and inflammatory‐response genes is controlled by the transcription factors nuclear factor‐κB (NF‐κB) and activator protein‐1 (AP‐1), which makes them therapeutic targets of interest. Sulfasalazine (SASP) has been shown to inhibit NF‐κB and reduce lipopolysaccharide‐induced cytokine concentrations in fetal membrane explants and reduce the rate of Escherichia coli‐induced preterm labour in mice. Its effects upon AP‐1 in the context of pregnancy are unknown. In this study the effect of SASP on interleukin‐1β (IL‐1β) ‐induced NF‐κB and AP‐1 activity, cytokine production and cyclo‐oxygenase‐2 (COX‐2) expression was examined in amniocytes and myocytes. A supra‐therapeutic concentration (5 mm) was required to inhibit IL‐1β‐induced NF‐κB (P < 0·0001) in amniocytes and IL‐1β‐induced NF‐κB (P < 0·01), AP‐1 (P < 0·01) and COX‐2 (P < 0·05) in myocytes. Despite inhibiting IL‐1β‐induced cytokines, a basal increase in IL‐6 (P < 0·01), IL‐8 (P < 0·0001) and tumour necrosis factor‐α (TNF‐α) (P < 0·001) was seen with 5 mm SASP in amniocytes, and significant cytotoxic effects were seen in myocytes. The therapeutic concentration of 0·015 mm had no inhibitory effects on pro‐inflammatory mediators, but led to an augmented response to IL‐1β‐induced IL‐6 (P < 0·01), IL‐8 (P < 0·05) and TNF‐α (P < 0·05) in amniocytes and IL‐8 (P < 0·05) in myocytes. SASP is therefore an unlikely therapeutic candidate for the prevention of inflammation‐induced preterm labour.
OCT angiography of the choriocapillaris and choroid
Authors: Coscas G. , Lupidi M. , Coscas F.
Published: September 2015

Age‐related macular degeneration (AMD) is a degenerative disease of the retina, in which the macula is most affected. In dry AMD, loss of vision occurs gradually and progresses to Geographic Atrophy (GA), a degeneration of the RPE and death of photoreceptor cells, leading to irreversible vision loss. Although the introduction of OCT allowed an additional step forward in understanding the major diseases of the macular region, the origin of the GA is almost unclear.

The OCT Angiography (OCT‐A) enables distinct, depth resolved, three‐dimensional visualization of the retinal and choroidal microvasculature. The concept underlying OCT‐A is that in a static eye, the only moving structure in the fundus is blood, flowing in the vessels. The utilization of motion contrast differentiates OCT‐A from fluorescence angiography, which requires administration of intravenous markers such as fluorescein or indocyanine‐green.

All this, is taking a leading role in the identification of perfusion abnormalities, of ischemic areas and retinal or choroidal neovascular lesions. Moreover it might also provide useful information on morphological and functional aspects of choroidal perfusion in GA, that could be partially responsible of such a severe disease.
LHON and extraocular features
Authors: Yu‐Wai‐Man P.
Published: September 2015

LHON is typically a monosymptomatic disease but additional features such as cardiac conduction defects, peripheral neuropathy, dystonia, and myopathy have been reported as occurring more frequently among LHON carriers. There is also a well‐reported association between the three primary mitochondrial DNA LHON mutations and a multiple sclerosis‐like illness, especially among female carriers (so‐called Harding's disease). This presentation will critically appraise the extraocular features that have been associated with LHON and how these atypical phenotypes are potentially informing us about important disease mechanisms.
Retinal detachment
Authors: Berrod J.P. , Conart J.B.
Published: September 2015

High myopia, defined as a refractive error of greater than −6.00 D or an axial length of >26 mm [2], is a growing condition in developed countries. These eyes candevelop myopic foveoschisis andretinal detachment (RD) secondary to macular hole (MH), posterior paravascular breaks that need the use of an internal tamponade. Other complications, such as rhegmatogenous RD due to peripheral retinal or giant tear, can also appear. The use of endotamponade agents such as gas or silicon oil plays a major role in the management of retinal detachment in high myopia. Anatomical and functional results inversely correlate with axial length.
Evaluation of T‐cell related cytokines in the vitreous of proliferative diabetic retinopathy
Authors: Takeuchi M.
Published: September 2015

Macrophages are involved in low‐grade inflammation in diabetes, and play pathogenic roles in proliferative diabetic retinopathy (PDR) by producing proinflammatory cytokines. T cells as well as other cells are activated by proinflammatory cytokines, and the infiltration into the vitreous of patients with PDR has been shown. We have recently found that both positive rates and levels of IL4, IL‐6, IL‐10, IL‐17A, IL‐21, IL‐22, and TNFα in the vitreous of PDR patients were significantly higher than those in the serum, and that vitreous levels of these cytokines and IL‐31 were significantly higher in PDR patients than in epiretinal membrane or macular hole patients. In addition, although vitreous of IFN‐g and sCD40L in the vitreous of endogenous uveitis (EU) patients were significantly higher than those of PDR patients, vitreous levels of IL‐4, IL‐17A, IL‐22, IL‐31, and TNFa were conversely higher in the vitreous of PDR patients than those of EU patients. Although it is unclear whether these cytokines synergistically play facilitative roles or inhibitory roles for the progression of PDR, our study suggested that Th2‐ and Th17‐related immune responses are involved in the pathogenesis of PDR.
Syndromic manifestations in aniridia patients with PAX6 point mutations
Authors: Calvas P. , Chassaing N. , Kaplan J. , Rozet J.M.
Published: September 2015

The PAX6 gene is associated with various congenital ocular defects.Aniridia is typically associated with mutations introducing a premature STOP codon, whereas missense mutations, of which the majority are located in the paired domain, lead to variant phenotypes. The study provides a survey of PAX6 mutations in patients presenting with extraocular features. We performed sequencing of PAX6 exons and boundaries, search for intragenic rearrangements (QMPSF/qPCR) and CNV analysis (aCGH) in 127 index cases. Genotype‐phenotype correlations were searched.We identified mutations in 90% of patients. Yet, a high inter‐ and intra‐familial clinical variability, we noted that heterozygous missense mutations (Asn64, Gly65, Cys66) in Paired‐Domain medial 3rd helix were associated with severe phenotypes (e.g. anophthalmia, and CNS malformations). Cases bearing compound heterozygous mutations were affected with severe malformations. Consistent with previous studies, mutations introducing a premature stop codon and gene rearrangements made up the majority. Some genotype‐phenotype correlations could be drawn. It is necessary to better delineate the expression of PAX6 mutations to provide patients with a prognosis and to set up a tailor‐made follow‐up.
The epithelial‐stromal TGFBI corneal dystrophies
Authors: Lisch W.
Published: September 2015

Purpose

To correct the IC3D classification system from 2008.

Methods

To examine the corneal specimens of 54 patients with lattice, granular 1 and 2, Reis‐Bücklers, and Thiel‐Behnke who underwent unilateral penetrating keratoplasty.

Results

All specimens showed epithelial and stromal pathological deposits by staining with HE and Congo red, and distinct alterations of Bowman's layer.

Discussion

The 5 TGFBI dystrophies are to classify from the clinical, genetic, but also from the histopathological aspect as “Epithelial‐stromal TGFBI corneal dystrophies.”
Venous occlusions
Authors: Paques M.
Published: September 2015

The retinovitreal interface may be altered during retinal vein occlusions, either through vitreal traction participating to macular edema or the development of an epiretinal membrane. Surgical treatment of these may reduce macular thickness, although the severity of the underlying retinal damage may impair visual results. Epiretinal membrane peeling may also be useful to prevent multirecidivant macular edema. An emerging concern is surgical damage to the nerve fiber layer. Beside these well‐known entities, the role of a normal inner limiting membrane in the maintenance of macular edema is debated.
Mutual enhancement between high‐mobility group box‐1 and NADPH oxidase‐derived reactive oxygen species mediates diabetes‐induced upregulation of retinal apoptotic markers
Authors: Ghulam M. , Abu El Asrar A.
Published: September 2015

We hypothesized that a novel mechanism exists where HMGB1and NADPH oxidase (NOX)‐derived ROS are mutually enhanced in the diabetic retina, which may be a novel mechanism for promoting upregulation of retinal apoptotic markers induced by diabetes. To test this hypothesis we analyzed the vitreous samples from PDR and nondiabetic patients, retinas from rats and human retinal microvascular endothelial cells. We found that HMGB1 and the oxidative stress marker protein carbonyl content levels in the vitreous fluid from PDR patients were significantly higher than in controls. There was a significant positive correlation between vitreous fluid levels of HMGB1 and the levels of protein carbonyl content. HMGB1 enhanced interleukin‐1β, ROS, NOX2, and PARP‐1 and cleaved caspase‐3 expression by HRMEC. Diabetes and intravitreal injection of HMGB1 in normal rats induced significant upregulation of ROS, NOX2, PARP‐1 and cleaved caspase‐3 in the retina. Constant glycyrrhizin and apocynin intake from onset of diabetes did not affect the metabolic status of the diabetic rats, but restored these increased mediators to control values. Our results suggest that there is a mutual enhancement between HMGB1 and NOX‐derived ROS in the diabetic retina.
Inflammatory mediators of diabetic retinopathy: lessons from proteomic analysis
Authors: Simo R. , Simó‐Servat O. , Hernández C.
Published: September 2015

Vitreous fluid obtained from diabetic patients undergoing vitreoretinal surgery is currently used to explore the events that are taking place in the retina for clinical research. However, several confounding factors such as vitreous haemorrhage and concentration of vitreous proteins should be considered in the analysis of the results. In addition, the volume of vitreous fluid obtained after vitrectomy is approximately 1 mL and, therefore, only few peptides can be analysed simultaneously. The recent development of proteome analysis has made it feasible to analyse protein profiles with only a small sample. We have used this approach for exploring pathogenic candidates in both proliferative DR (PDR) and DME. Regarding mediators of inflammation involved in PDR, it is worthy of mentioning that several factors of the complement system have been found increased in the vitreous fluid from PDR patients in comparison with control subjects. There is scarse information on this issue in DME. However, an overview will be given and our results showing that hemopexin is a candidate in the pathogenesis of DME will be presented.
Autophagy in neurodegeneration and inflammation and novel modulators of macroautophagy
Authors: Behl C.
Published: September 2015

Deregulated autophagy leads to protein accumulation and has been linked to aging, inflammation and neurodegenerative disease. While studying cell aging we found an expression switch between co‐chaperones BAG1 and BAG3 during aging and acute stress triggering BAG3‐mediated autophagic degradation of aggregated proteins (e.g. mtSOD1) in vitro and in vivo. BAG3‐mediated selective macroautophagy is an important adaptation of the PQC to pro‐oxidant and aggregation‐prone conditions. Recently, we performed a RNAi screen in C.elegans and identified rbg‐1 as modifier of protein aggregation and autophagy. The mammalian ortholog RAB3GAP1/2, components of the TBC domain‐free RAB3GAP complex, affect autophagy at basal and rapamycin‐induced conditions also in human fibroblasts. RAB GTPase activating proteins (RABGAPs) are important factors for vesicle transport. Correlating the activity of RAB3GAP1/2 with ATG3 and ATG16L1 and analyzing ATG5 punctate structures, we found that the RAB3GAPs actually modulate autophagosomal biogenesis: RAB3GAP1/2 colocalizes with lipid droplets, and their autophagy modulatory activity depends on GTPase activating activity of RAB3GAP1.
Bilateral acute iris transillumination
Authors: Tugal‐Tutkun I.
Published: September 2015

Atrophy and/or depigmentation of the iris is seen in a number of inflammatory and noninflammatory conditions, including viral iridocyclitis, Fuchs uveitis syndrome, Vogt–Koyanagi–Harada disease, pigment dispersion syndrome, acute angle closure glaucoma, and trauma. An acute onset of severe photophobia associated with bilateral acute iris transillumination with variable sphincter paralysis and pigment dispersion has been recently reported as an adverse effect of oral moxifloxacin. In our experience, only 23% of patients presenting with these findings report moxifloxacin use while more than 60% report a preceding viral illness. Pigment dispersion may persist for several months, refractory glaucoma may develop, and diffuse iris transillumination and syphincter paralysis are irreversible in this entity.
Extraocular phenotyping of mitochondrial optic neuropathy
Authors: Martinuzzi A. , Vavla M. , Papayannis A. , Petacchi E. , Carraro E. , Paparella G. , Privato F. , Prosdocimo G.
Published: September 2015

The presence of clinical neurophtalmologic manifestations in neurodegenerative disease of early onset such as the hereditary spastic paraplegias (HSP), spino cerebellar ataxias (SCA) or hereditary sensory motor neuropathies (HSMN) has been an inconstant element often reported in case descriptions. A more widespread and subclinical involvement of the retina and the optic nerve however is suspected in most of these conditions. Mitochondrial dysfunction is frequently recognized in the pathophysiology underlining the above mentioned neurodegenerative genetically determined conditions. Retina and the optic nerve are privileged target tissues where mitochondrial pathology is expressed. We systematically explored in a cohort of patients with early onset molecularly defined HSP, SCA or HSMN the occurrence of subclinical involvement of the visual system, with the aim of establishing its real prevalence and its correlation with functional and neuroimaging data. The definition of a typical pattern of alteration may contribute to the inclusion of neuro‐ophtamological measures as sensible objective biomarkers of disease and indicators for disease severity and progression.
Retinal glial cells
Authors: Reichenbach A.
Published: September 2015

Müller cells, the principal glial cells of the retina of all vertebrates, were discovered already in 1851 but it was only in the past decades that it became evident that these cells are essential players in vision. Müller cells constitute the ‘core’ of columnar units of clonally and functionally related groups of neurons. Their primary function is to support neuronal functioning (by increasing the signal‐to‐noise ratio of information processing) and survival (by maintaining a metabolic ‘symbiosis’ with the neurons). It has been shown that Müller cells increase the signal‐to‐noise ratio of retinal information processing by, for instance, (i) guiding the light towards the photoreceptor cells, (ii) removing excess neurotransmitter molecules from extracellular space, and (iii) performing an efficient clearance of excess extracellular potassium ions after neuronal excitation. The latter two functions are also crucial for neuronal survival – to prevent excitotoxic effects of glutamate – and are coupled to water clearance which is equally important for neuronal survival. As another case of glial homeostasis, the maintenance of appropriate microenvironmental biomechanics has recently been described. Normal glial cells are softer than the neurons, and thus provide a suitable substrate for neurite growth during development, and for functional plasticity. Finally it should be pointed out that Müller cells are capable of ‘sensing’ neuronal activity. They respond to physiological light stimulation of their adjacent photoreceptors with two distinct types of intracellular calcium rises. These calcium rises then may trigger the release of signal substances, incl. so‐called ‘gliotransmitters’, from Müller cells which thus even may modify neuronal signal processing in the retina (e.g., in cases of adaptation to bright light, as another mechanism to increase the signal‐to‐noise ratio of information processing in retina). In cases of reactive Müller cell gliosis, the dominant potassium conductance of the membrane is down‐regulated and an increased expression of intermediate filaments is associated with increasing stiffness of the glial cell processes, such that all above‐mentioned glial functions are impaired.
En face OCT
Authors: Scemama Timsit C. , Mauget‐Faÿsse M. , Wolff B.
Published: September 2015

“En face” OCT (Spectral Domain and Swept Source) realizes frontal section of the retina or C‐scans. “En face” OCT software informs immediately the layer of the cuts; it joins viewing images “en face” and B‐scan with the graphical representation of their different scans.

Normal retinal layers have their specific reflectivity.

Atrophy can occur at different stages of many retinal diseases, and at different retinal layers. On “en face” OCT, there are 2 main areas to consider in case of atrophy in retinal diseases:

‐ the inner nuclear layer which may presents pseudocystic lesions that reflect a damage inducing optic nerve atrophy,

‐ the outer retinal layers in degenerative retinal diseases such as age related macular degeneration (AMD), genetic diseases such as Stargardt's macular dystrophy, retinitis pigmentosa, MacTel type 2 and in inflammatory diseases such as Serpiginous and Birdshot retino choroidopathies.

The pseudocystic lesions might represent a mitochondrial dysfunction inducing degeneration of Muller cells.

The outer retinal damage can be related to material resorption (drusen, pseudodrusen, PED), disappearance of choriocapillaris, ellipsoid disruptions .”En face” has increased the understanding of atrophy in retinal disease.
Optic disc tumors
Authors: Boschi A.
Published: September 2015

The optic disc can be involved by a variety of primary and secondary tumors. Primary tumors include capillary and cavernous hemangiomas, astrocytomas, and melanocytomas. Secondary optic disc tumors like leukemia, metastatic carcinoma, and from adjacent structures (choroidal melanoma, retinoblastoma, meningioma) may also invade the nerve head. Clinical features are varied, differential diagnosis and actualised management will be discussed.
Acquired forms of nystagmus not to be missed
Authors: Borruat F.X.
Published: September 2015

The purpose of this section will be to present and discuss some of the most recognizable forms of acquired nystagmus. The followings will be discussed: vestibular nystagmus, downbeat nystagmus, upbeat nystagmus, and dissociated nystagmus. At the end of the session, participants should be able to identify these specific forms of nystagmus and organize proper investigations accordingly.
The EURALOC Project
Authors: Struelens L.
Published: September 2015

For radiation protection purposes, it has generally been assumed that there is a threshold of dose below which no non‐cancer effects arise. Early dose threshold estimates for detectable lens opacities were defined at 0.5–2 Gy after acute or 5–6 Gy after protracted exposures. Due to the heterogeneity of ophthalmological data and too short observation periods, the thresholds were reconsidered in the ICRP report 118 (2012) and reduced to 0.5 Gy. An overview will be given of epidemiological studies that prompted the change in ICRP recommendations. These studies reported excess risks of lens opacities, but could not provide statistical significant evidence of a dose threshold. The results from all these studies are difficult to compare or combine. Moreover, another point of concern is the dosimetry which was often poor. These issues limit the possibility of a quantitative synthesis of evidence for a dose‐response analysis in the low dose region to confirm this new dose threshold and urged the need of a harmonised European initiative. The EURALOC project, initiated in December 2014, aims at quantifying this dose‐response relationship between ionising radiation and cataract among a cohort of European interventional cardiologists.
Corneal neovasculariation: a translational perspective
Authors: Ferrari G.
Published: September 2015

Development of corneal neovascularization (CNV) is a common finding in a number of disorders affecting the ocular surface. The role of infiltrating inflammatory cells, and specifically macrophages, is well described and associated with the development of CNV. Although CNV is commonly regarded as an ominous clinical sign due to its common association with vision reduction, the growth of neovessels can also beneficial in some instances. For example, CNV helps recruiting cellular immunity and provides protection against ocular perforation in corneal infections. Hence, avascularity of the cornea, constantly exposed to the outer environment, is the result of an evolutionary compromise between a prompt and effective reaction to aggression from the outside and the avoidance of corneal opacification. Specifically, the absence of vessels in the normal cornea is generally considered the result of the predominance of anti‐angiogenic over pro‐angiogenic factors. In this paper, we suggest a novel mechanism regulating corneal avascularity and its switch to corneal neovascularization. Potential translational implications are also discussed.
Induced to cure: Engineering iPS cell derived RPE scaffolds to treat degenerative eye diseases
Authors: Bharti K.
Published: September 2015

The recent success with embryonic stem (ES) cell derived retinal pigment epithelium (RPE) has provided hope for a cure for degenerative eye diseases. Induced pluripotent stem (iPS) cells are an autologous source of stem cells potentially with fewer immune‐challenges as compared to ES cells. Using a developmentally guided differentiation protocol we have developed fully polarized RPE tissue from iPS cells. The RPE monolayer along with its secreted ECM and a degradable scaffold form a tissue that mimics the native tissue in structural and functional properties. This RPE tissue performs several key RPE functions like phagocytosis of photoreceptor outer segments, ability to transport water from apical to basal side, and the ability to secrete cytokines in a polarized fashion. Currently, we are testing the safety and the efficacy of this tissue in animal models. We have begun Phase I Investigational New Drug (IND) enabling studies with the goal to transplant autologous iPS cell derived RPE in patients in advanced Geographic Atrophy stage of age‐related macular degeneration (AMD), one of the leading blinding diseases in the US. Our work will provide a potential personalized cell therapy for AMD patients.
Relation of oxygen saturation to stage of diabetic retinopathy
Authors: Sin M. , Chrapek O. , Sinova I. , Stanakova L. , Rehak J.
Published: September 2015

Aim

To assess whether oxygen saturation of the retinal vessels is related to degree of diabetic retinopathy.

Methods

A prospective study included 114 eyes of 76 patients with diagnosed diabetes and 57 eyes of 29 non diabetic patiens. The diabetic patients were divided into groups according to severity of the retinopathy.

Results

In healthy controls mean arterial saturation was 96.5 ± 2.6%, mean vein saturation was 62.3 ± 7.4% and A‐V difference was 34.3 ± 7.2%. In diabetic patients with no retinopathy mean arterial saturation was 96.5 ± 3.2%, mean vein saturation was 66.3 ± 6.3% and A‐V difference was 30.2 ± 4.9%. In patients with mild diabetic retinopathy mean arterial saturation was 96.7 ± 4.6%, mean vein saturation was 67.9 ± 7.2% and and A‐V difference was 28.8 ± 8.2%. In patients with moderate nonproliferative retinopathy mean arterial saturation was 97.8 ± 4.6%. mean vein saturation was 69.9 ± 6.7% and A‐V difference 27.9% ± 5.8%. In patients with severe non‐proliferative and proliferative retinopathy mean arterial saturation was 100.5 ± 5.6%, mean vein saturation was 74 ± 7.2% and A‐V difference was 26.5 ± 7.8%.

Conclusion

We confirmed an increase in oxygen saturation in both retinal artery and vein in relation to degree of diabetic retinopathy.
Novel techniques in corneal regeneration and bioscaffold engineering
Authors: Lagali N. , Rafat M. , Xeroudaki M. , Koulikovska M. , Fagerholm P.
Published: September 2015

Restoration of corneal transparency and a functioning epithelium and stroma may involve multiple procedures that are limited by availability of donor tissue and an inability of host tissue to self‐regenerate. We present a tissue‐engineered collagen‐based hydrogel bioscaffolds for regenerating a transparent stroma and providing the additional possibility of carrying and delivering corneal stem cells to the stroma or epithelium. We present in vitro results of bioscaffold compatibility with epithelial and stem cells, and techniques for the optimal implantation of scaffolds using femtosecond laser surgery. Using models of in vivo bioscaffold implantation in the rabbit, we evaluate transparency, stability, and controlled degradation characteristics of the scaffolds. Tissue engineering provides the opportunity to tune the size, thickness, transparency, homogeneity and degradation rate for specific applications. For example, the bioscaffold may be used to substantially thicken the stroma or allow non‐invasive in vivo tracking of its controlled degradation as it releases therapeutic cells. In vitro and in vivo results with bioscaffolds are presented that provide the basis for further preclinical and clinical development.
The link with the EBO: the glaucoma subspecialty diploma
Authors: Sunaric Megevand G.
Published: September 2015

The EBO has gained worldwide respect for its efforts on harmonizing education and training in general ophthalmology within Europe. The comprehensive EBO Diploma examination, awards successful candidates the title of the Fellow of the European Board of Ophthalmology (FEBO), and is the most evident result of such efforts. More recently the EBO has established a Subspecialty European Board of Ophthalmology Diploma Examination (FEBOS) with the goal to increase standards of knowledge and care in various subspecialties. The first of these subspecialty examinations to be introduced is in the field of glaucoma and is developed in close collaboration with the European Glaucoma Society (EGS). The FEBOS‐Glaucoma examination and diploma represent a logical continuation of the efforts in providing sustainable education and glaucoma care within Europe led by the EGS.

The goals, the organisation and requirements to sit the subspecialty exam as well as the first experience with the FEBO‐Glaucoma exam and Diploma will be presented.
Pharmacokinetics of anti‐VEGF and steroid agents in vitrectomized eyes with diabetic macular edema
Authors: Papastefanou V.
Published: September 2015

Anti‐VEGF and steroid agents for diabetic macular edema (DME) in a vitrectomized eye is fraught with difficulties, bearing in mind the numerous confounding factors in DME. The pharmacokinetic parameters are affected as the vitreous cavity milieu is altered and the vitreous consistency is not reformed post vitrectomy (PPV). Pharmacokinetic data are largely based on experimental animal models.

VEGF clearance is increased in the vitrectomized eye compared to the non‐vitrectomized eye, but there is little direct evidence that the protein expression profile in the vitreous cavity is altered after vitrectomy. Whilst some studies have demonstrated longer intravitreal retention for Bevacizumab compared to Ranibizumab and reduced half‐life for both agents after PPV, other studies have found no changes. There is a characteristic lack of pharmacokinetic data for anti‐VEGF agents in human vitrectomized eyes.

The vitreous half‐life of triamcinolone acetonide (TA) after intravitreal injection was reduced in vitrectomized eyes in both animal models and human eyes. No pharmacokinetic differences between vitrectomized and non‐vitrectomized eyes are noted in animal eyes following the injection of the Dexamethasone implant (Ozurdex, Allergan).
Choroidal blood flow and thickness measurements
Authors: Schmidl D.
Published: September 2015

Most of the ocular blood supply goes into the choroidal circulation. Intensive research has been directed towards choroidal structure and function in health and disease. Indeed, choroidal blood flow and its regulation has been found to be altered in several ocular diseases, such as age‐related macular degeneration. Several techniques for the assessment of choroidal blood flow have been developed including laser Doppler flowmetry, laser speckle flowgraphy, laser interferometric measurement of fundus pulsation amplitude or pneumotonometric measurement of pulsatile ocular blood flow. All these techniques have significant limitations and currently no gold standard method for the assessment of choroidal blood flow exists.

With the introduction of enhanced depth imaging optical coherence tomography (OCT) systems, it is now possible to image choroidal thickness in vivo. Alterations in choroidal thickness have been observed in several ocular diseases. The correlation between functional and structural choroidal parameters is, however, weak. Further research is required to better understand the results obtained in patients with ocular pathologies and to investigate whether choroidal thickness is a good biomarker for choroidal disease.
Scleral lenses in the management of exposure/neurotrophic keratopathy in patients with cranial nerve palsy
Authors: Schornack M.
Published: September 2015

Scleral lenses are increasingly being recognized as a viable option for management of exposure keratopathy. Unlike more aggressive surgical interventions, the lenses can provide complete protection of the ocular surface without compromising visual clarity or restricting visual field. Preservation of corneal epithelial integrity is of utmost importance when lid function is compromised or absent. The fluid reservoir between the posterior surface of a scleral lens and the anterior corneal surface provides continuous hydration of the corneal epithelium and allows for healing of any epithelial defects. Furthermore, the lens itself protects fragile epithelial tissue from shear forces arising from lid movement over the cornea during the blink. Preservation of visual function is also important for these patients. Those who suffer from decreased vision due to irregularity of a desiccated ocular surface frequently note improvement in visual function with scleral lens wear, because the lens provides a smooth optical surface and neutralizes any corneal irregularity. This presentation will review and summarize visual and ocular outcomes of scleral lens therapy for management of exposure keratopathy at the Mayo Clinic.
Understanding the molecular genetic causes of inherited corneal disorders
Authors: Davidson A.
Published: September 2015

Inherited corneal diseases comprise a group of clinically and genetically heterogeneous disorders that can lead to bilateral severely impaired vision and/or blindness. Advances in next generation sequencing (NGS) technologies have revolutionised clinical genetics over the past five years. The application of NGS, in combination with genome wide association studies, to the field of inherited corneal disorders has provided significant insights into the genetics of corneal diseases and their underlying aetiology. An overview of our current understanding of the genetics of monogenic corneal dystrophies, as well as the contribution of genetic factors to complex conditions such as keratoconus and Fuchs endothelial corneal dystrophy (FECD), will be provided. Examples from our laboratory exploiting NGS platforms, in combination with careful phenotyping of patient sub‐groups, to identify novel genetic causes and mechanisms of inherited corneal disorders such as; posterior polymorphous corneal dystrophy, epithelial recurrent erosion dystrophy, and X‐linked megalocornea, will be highlighted. Furthermore the impact of these findings on clinical care and their potential to provide translational outcomes will be discussed.
Mutation in the Ercc2 gene of the mouse causes cataracts
Authors: Graw J. , Kunze S. , Dalke C. , Fuchs H. , Klaften M. , Sabrautzki S. , Hrabe de Angelis M.
Published: September 2015

Cataracts have been associated with many mutations. In a large‐scale high‐throughput ENU mutagenesis screen we analyzed the offspring of paternally treated C3HeB/FeJ mice for obvious ocular dysmorphologies.

We identified a mutant suffering from rough coat and small eyes only in homozygotes; homozygous females turned out to be sterile. The mutation was mapped to chromosome 7 between the markers 116J6.1 and D7Mit294. The critical interval (8.6 Mb) contains 3 candidate genes (Apoe, Six5, Opa3); none of them showed a mutation. Using exome sequencing, we identified a c.2209T>C mutation in the Xpd/Ercc2 gene leading to a Ser737Pro exchange.

During embryonic development, the mutant eyes did not show major changes. Postnatal histological analyses demonstrated small cortical vacuoles; later, cortical cataracts developed. Since XPD/ERCC2 is involved in DNA repair, we checked also for the presence of the repair‐associated histone γH2AX in the lens. During the time, when primary lens fiber cell nuclei are degraded, γH2AX was strongly expressed in the cell nuclei; later, it demarcates clearly the border of the lens cortex to the organelle‐free zone.

These findings demonstrate the importance of XPD/ERCC2 for lens fiber cell differentiation.
Mutations in Connexin‐encoding genes
Authors: Beyer E. , Berthoud V.
Published: September 2015

Gap junctions formed of connexin46 (Cx46) and connexin50 (Cx50) facilitate lens function and survival. Mutations of the connexin‐encoding genes (GJA3 and GJA8) have been linked to inherited cataracts. We expressed these mutants in vitro to elucidate abnormalities that contribute to cataractogenesis. Most of the mutants reduce intercellular communication due to alterations of channel function or impaired connexin synthesis/assembly/stability. One unusual mutant (Cx50P88S) forms cytoplasmic accumulations that may act as light scattering particles. Another unusual mutant (Cx50G46V) exhibits increased hemichannel function that may cause cell injury and death. We have studied mice expressing two different connexin mutants (Cx50D47A and Cx46 fs380) that mimic cataract‐linked human mutations. Both mouse lines develop cataracts (although with different time courses) and have reduced connexin levels (mutant and co‐expressed wild type) likely due to protein degradation. Our studies suggest that reduction of intercellular communication is a common feature that contributes to connexin mutant‐linked cataractogenesis, but individual mutants cause additional abnormalities that contribute to differences in phenotypes.
Ocular autonomic dysfunction in glaucoma
Authors: Vandewalle E.
Published: September 2015

The retina relies primarily upon autoregulation of the retinal vasculature in cases of increased metabolic demand or reduced ocular perfusion pressure. The choroidal blood vessels are highly innervated by the autonomic nervous system, but are separated too far from the retina to respond to the local accumulation of vaso‐active metabolites. It could therefore be hypothesized that conditions interfering with either the autoregulation or the autonomic nervous regulation could render the retina at a higher risk of ischemic damage. Glaucoma has been associated with disturbances in both types of regulation. Retinal oximetry is capable of providing reproducible in vivo, non‐invasive measurements of the retinal vessel oxygen saturation and with the advent of enhanced depth imaging optical coherence tomography (EDI‐OCT), allowing a detailed non‐invasive evaluation of the choroid in‐vivo, renewed interest in the role of the choroid in the pathogenesis of glaucoma has grown.
Longterm restoration of ocular surface function with scleral lenses
Authors: Carrasquillo K.G.
Published: September 2015

The ocular surface ecosystem is altered when any of its components becomes compromised. In order to have a stable and healthy ocular surface, there has to be good lid function, healthy and functioning lacrimal and accessory glands, healthy and functional limbal stem cells to allow corneal regeneration and prevention of corneal conjunctivalization, a healthy tear film, and adequate sensory innervation. Without these, the ocular surface, in particular the cornea is vulnerable to severe desiccation, vascularization, opacification, conjunctivalization, chronic epithelial breakdowns, chronic exposure, amongst other sequela; ultimately resulting in compromised vision, severe forms of pain, and light sensitivity. Scleral lenses play an important role in restoring the ocular surface function of compromised ocular surfaces, even when other topical or surgical approaches have failed. Not only are they a viable option, but they are able to provide long‐term support of the ocular surface. We report on various cases where long‐term restoration of ocular surface function was achieved with the use of prosthetic replacement of the ocular surface ecosystem (PROSE) treatment and use of BostonSight® PROSE devices.
What are the general requirements for candidates to sit the exam
Authors: Midena E.
Published: September 2015

The European Board of Ophthalmology (EBO) has recently decided to promote, at the European level, a subspecialty diploma in some selected areas of Ophthalmology. The first subspecialty diploma is related to Glaucoma. The guidelines for this kind of diploma have been developed with the European Glaucoma Society, because the aim of EBO is to have the already existing European subspecialty Societies (European Glaucoma Society, Euroepan Society of Cataract and Refractive Surgery, EURETINA, …) as the driver of the EBO Subspeciality examination. The characteristics of the examination, and any information related to the curriculum and major requirements to sit the exam will be presented.
Partial thickness Macular holes and pharmaceutical treatment of FTMH
Authors: Pournaras J.A.C.
Published: September 2015

The pathophysiology of full thickness macular hole and lamellar macular hole are different and will be discussed. Oct characteristics will be repeated according to new classification. Taking in account the natural history, indication of treatment will be detailled according to each stage of those diseases. Recently, ocriplasmin has been introduced as an alternative treatment to vitrectomy. Favorable Prognostic factors have been recognized as age inferior to 65 years old, full thickness macular hole < 400 microns, the absence of epiretinal membrane, vitreous adhesion < 1500 microns and phakic status. While management of full thickness macular hole shows good visual prognosis for the patients, the visual result of lamelar macular hole is not so obvious.
Macular surgical diseases in myopia
Authors: Pournaras J.A.C.
Published: September 2015

Macular surgical diseases in myopia are consecutive to vitreoretinal interface disorders associated to stretching forces due to staphyloma on the other side. OCT have largely contributed to the recognition and the understanding of vitreoretinal interface disorders occuring in myopic condition: epiretinal membrane alone or associated to foveoschisis, lamellar or full thickness macular hole and posterior retinal detachment. Surgical management by vitrectomy associated or not to ILM peeling will be discussed according to myopic disorders. Main surgical complications are macular hole formation and foveal atrophy. Fovea‐sparing internal limiting membrane peeling for myopic traction maculopathy may represent an alternative option to avoid these complications. Scleral buckling surgery associated to vitrectomy may represent an other option under investigation.
Ocular tests and interpretation
Authors: Marques‐Neves C.
Published: September 2015

The eye is a richly enervated organ, with a dual supply from both the sympathetic and parasympathetic nervous system. The inputs from these two branches of the autonomic nervous system (ANS) are responsible for a vast number of ocular physiological responses, ranging from pupillary reflexes to accommodation and aqueous humor turnover. Accordingly, any dysfunction in one (or both) of these inputs can have a significant impact on the overall organ physiology and are likely involved in a number of diseases – such as glaucoma.

Accordingly, several ophthalmological tests using specific systemic and ocular stimuli have been developed to determine the integrity and relative contribution from each of these two ANS inputs. Validated normative databases allow for a proper diagnosis of an ANS dysfunction and can provide a valuable input in the diagnostic and treatment algorithm in a number of ocular conditions.

However, interpretation of these signals is usually complex and thus are not regularly used in the clinical setting. The purpose of this talk is to give an insight into the logistics and complexity of these ANS ocular tests and – more importantly – to provide the tools for its interpretation by a clinical researcher.