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In order to proceed along an action sequence, an autonomous agent has to recognize that the intended final condition of the previous action has been achieved. In previous work, we have shown how a sequence of actions can be generated by an embodied agent using a neural-dynamic architecture for behavioral organization, in which each action has an intention and condition of satisfaction. These components are represented by dynamic neural fields, and are coupled to motors and sensors of the robotic agent.Here,we demonstratehowthemappings between intended actions and their resulting conditions may be learned, rather than pre-wired.We use reward-gated associative learning, in which, over many instances of externally validated goal achievement, the conditions that are expected to result with goal achievement are learned. After learning, the external reward is not needed to recognize that the expected outcome has been achieved. This method was implemented, using dynamic neural fields, and tested on a real-world E-Puck mobile robot and a simulated NAO humanoid robot.

Background: Bacterial diarrheagenic heat-stable enterotoxins (STs) induce colon cancer cell cytostasis by targeting guanylyl cyclase C (GCC) signaling. Although the molecular pathway involving cGMP-dependent influx of Ca2+ through cyclic nucleotide-gated (CNG) channels has been elucidated, the long-term kinetics of the antineoplastic effects of these toxins remain undefined.Methods: GCC signaling inducing cytostasis was examined in human colon carcinoma T84 cells employing radioimmunoassay for cGMP, unidirectional 45Ca2+ current, 3H-thymidine incorporation into the DNA and flow cytometry.Results: Prolonged stimulation of GCC produced resistance in tumor cells to ST-induced cytostasis. Resistance reflected rapid (tachyphylaxis) and slow (bradyphylaxis) mechanisms of desensitization induced by cGMP. Tachyphylaxis was mediated by cGMP-dependent protein kinase, which reduced the influx of Ca2+ through CNG channels. In contrast, bradyphylaxis was mediated by cGMP-dependent allosteric activation of phosphodiesterase 5, which shapes the amplitude of ST-dependent cyclic nucleotide accumulation required for cytostasis. Importantly, interruption of tachy- and bradyphylaxis restored cancer cell cytostasis induced by ST.Conclusions: Regimens that incorporate cytostatic bacterial enterotoxins and inhibitors of cGMP-mediated desensitization offer a previously unrecognized therapeutic paradigm for treatment and prevention of colorectal cancer.Clinical Pharmacology & Therapeutics (2005) 79, P13–P13; doi: 10.1016/j.clpt.2005.12.046 [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study is to evaluate the long-term efficacy of a novel minimally invasive glaucoma surgery technique (MIGS), Ab interno Canaloplasty (AbiC)., Material and Methods: For this retrospective cohort study, we analysed the data of 25 eyes of 23 patients with open angle glaucoma who underwent an AbiC (6 eyes) or in case of an additional cataract, a combined cataract-AbiC procedure ("phacocanaloplasty ab interno", 19 eyes), respectively. Postoperatively, we investigated the intraocular pressure (IOP) and the number of still required IOP-lowering medication, as well as surgery-related complications., Results: Overall, the mean baseline IOP of 20.24 mmHg ± 5.92 (n = 25) was reduced to 10.64 mmHg ± 2.77 (n = 25, p < 0.001), 12.55 mmHg ± 3.33 (n = 22, p < 0.001) and 13.67 mmHg ± 2.15 (n = 21, p < 0.001) at 1 day, 1 year and 2 year follow-up visit, respectively. Compared to baseline, this implies a reduction in IOP of 47.4, 37.9 and 32.5%. An average glaucoma medication usage of 1.92 ± 1.04 was registered at baseline visit and was reduced to 0,05 ± 0,23 after 2 years of follow-up. 80% of patients were off medication. In 5 eyes (20%) further antiglaucomatous eye drops or surgical treatment were administered. The only surgical complications were hyphema in 5 eyes (20%) and a localized peripheral detachment of the Descemet's membrane in one eye (4%) with no late sequelae., Conclusion: AbiC performed independently or combined with cataract surgery seems to be a safe and effective MIGS-technique with good long-term regulation of IOP and low risk profile., Competing Interests: The authors declare that they have no conflict of interest./Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht., (Thieme. All rights reserved.)

ARHGAP42 encodes Rho GTPase activating protein 42 that belongs to a member of the GTPase Regulator Associated with Focal Adhesion Kinase (GRAF) family. ARHGAP42 is involved in blood pressure control by regulating vascular tone. Despite these findings, disorders of human variants in the coding part of ARHGAP42 have not been reported. Here, we describe an 8-year-old girl with childhood interstitial lung disease (chILD), systemic hypertension, and immunological findings who carries a homozygous stop-gain variant (c.469G>T, p.(Glu157Ter)) in the ARHGAP42 gene. The family history is notable for both parents with hypertension. Histopathological examination of the proband lung biopsy showed increased mural smooth muscle in small airways and alveolar septa, and concentric medial hypertrophy in pulmonary arteries. ARHGAP42 stop-gain variant in the proband leads to exon 5 skipping, and reduced ARHGAP42 levels, which was associated with enhanced RhoA and Cdc42 expression. This is the first report linking a homozygous stop-gain variant in ARHGAP42 with a chILD disorder, systemic hypertension, and immunological findings in human patient. Evidence of smooth muscle hypertrophy on lung biopsy and an increase in RhoA/ROCK signaling in patient cells suggests the potential mechanistic link between ARHGAP42 deficiency and the development of chILD disorder., Competing Interests: The authors have declared that no competing interests exist.

Reactive oxygen species (ROS) are implicated in triggering cell signalling events and pathways to promote and maintain tumorigenicity. Chemotherapy and radiation can induce ROS to elicit cell death allows for targeting ROS pathways for effective anti-cancer therapeutics. Coenzyme Q 10 is a critical cofactor in the electron transport chain with complex biological functions that extend beyond mitochondrial respiration. This study demonstrates that delivery of oxidized Coenzyme Q 10 (ubidecarenone) to increase mitochondrial Q-pool is associated with an increase in ROS generation, effectuating anti-cancer effects in a pancreatic cancer model. Consequent activation of cell death was observed in vitro in pancreatic cancer cells, and both human patient-derived organoids and tumour xenografts. The study is a first to demonstrate the effectiveness of oxidized ubidecarenone in targeting mitochondrial function resulting in an anti-cancer effect. Furthermore, these findings support the clinical development of proprietary formulation, BPM31510, for treatment of cancers with high ROS burden with potential sensitivity to ubidecarenone.

Striated preferentially expressed gene (SPEG), a member of the myosin light chain kinase family, is localized at the level of triad surrounding myofibrils in skeletal muscles. In humans, SPEG mutations are associated with centronuclear myopathy and cardiomyopathy. Using a striated muscle-specific Speg-knockout (KO) mouse model, we have previously shown that SPEG is critical for triad maintenance and calcium handling. Here, we further examined the molecular function of SPEG and characterized the effects of SPEG deficiency on triad and focal adhesion proteins. We used yeast two-hybrid assay, and identified desmin, an intermediate filament protein, to interact with SPEG and confirmed this interaction by co-immunoprecipitation. Using domain-mapping assay, we defined that Ig-like and fibronectin III domains of SPEG interact with rod domain of desmin. In skeletal muscles, SPEG depletion leads to desmin aggregates in vivo and a shift in desmin equilibrium from soluble to insoluble fraction. We also profiled the expression and localization of triadic proteins in Speg-KO mice using western blot and immunofluorescence. The amount of RyR1 and triadin were markedly reduced, whereas DHPRα1, SERCA1 and triadin were abnormally accumulated in discrete areas of Speg-KO myofibers. In addition, Speg-KO muscles exhibited internalized vinculin and β1 integrin, both of which are critical components of the focal adhesion complex. Further, β1 integrin was abnormally accumulated in early endosomes of Speg-KO myofibers. These results demonstrate that SPEG-deficient skeletal muscles exhibit several pathological features similar to those seen in MTM1 deficiency. Defects of shared cellular pathways may underlie these structural and functional abnormalities in both types of diseases., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Centronuclear myopathies (CNMs) are a subtype of congenital myopathies characterized by skeletal muscle weakness and an increase in the number of central myonuclei. SPEG (striated preferentially expressed protein kinase) has been identified as the sixth gene associated with CNM, and it has been shown that striated muscle-specific Speg-knockout (KO) mice have defective triad formation, abnormal excitation-contraction coupling, and calcium mishandling. The impact of SPEG deficiency on the survival and function of myogenic cells remains to be deciphered. In this study, the authors examined the overall population, proliferation, and differentiation of myogenic cells obtained from striated muscle-specific Speg-KO mice and compared them with wild-type (WT) controls. SPEG-deficient skeletal muscles contained fewer myogenic cells, which on further study demonstrated reduced proliferation and delayed differentiation compared with those from WT muscles. Regenerative response to skeletal muscle injury in Speg-KO mice was compared with that of WT mice, leading to the identification of similar abnormalities including fewer satellite cells, fewer dividing cells, and an increase in apoptotic cells in KO mice. Overall, these results reveal specific abnormalities in myogenic cell number and behavior associated with SPEG deficiency. Similar satellite cell defects have been reported in mouse models of MTM1- and DNM2-associated CNM, suggestive of shared underlying pathways., (Copyright © 2020 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Metabolic reprogramming in cancer cells, vs. non-cancer cells, elevates levels of reactive oxygen species (ROS) leading to higher oxidative stress. The elevated ROS levels suggest a vulnerability to excess prooxidant loads leading to selective cell death, a therapeutically exploitable difference. Co-enzyme Q 10 (CoQ 10 ) an endogenous mitochondrial resident molecule, plays an important role in mitochondrial redox homeostasis, membrane integrity, and energy production. BPM31510 is a lipid-drug conjugate nanodispersion specifically formulated for delivery of supraphysiological concentrations of ubidecarenone (oxidized CoQ 10 ) to the cell and mitochondria, in both in vitro and in vivo model systems. In this study, we sought to investigate the therapeutic potential of ubidecarenone in the highly treatment-refractory glioblastoma. Rodent (C6) and human (U251) glioma cell lines, and non-tumor human astrocytes (HA) and rodent NIH3T3 fibroblast cell lines were utilized for experiments. Tumor cell lines exhibited a marked increase in sensitivity to ubidecarenone vs. non-tumor cell lines. Further, elevated mitochondrial superoxide production was noted in tumor cells vs. non-tumor cells hours before any changes in proliferation or the cell cycle could be detected. In vitro co-culture experiments show ubidecarenone differentially affecting tumor cells vs. non-tumor cells, resulting in an equilibrated culture. In vivo activity in a highly aggressive orthotopic C6 glioma model demonstrated a greater than 25% long-term survival rate. Based on these findings we conclude that high levels of ubidecarenone delivered using BPM31510 provide an effective therapeutic modality targeting cancer-specific modulation of redox mechanisms for anti-cancer effects.

Diamond-Blackfan anemia (DBA) is a rare congenital bone marrow disorder with mutations in ribosomal protein genes. Several animal models have been developed to study the pathological mechanism of DBA. Previously, we reported that the complete knock-out of both Rpl5 and Rps24 alleles were lethal, while heterozygous Rpl5+/- and Rps24+/- mice showed normal phenotype.  To establish a more efficient mouse model for mimicking DBA symptoms, we have taken advantage of RNAi technology to generate an inducible mouse model utilizing tetracycline-induced down-regulation of Rpl5.    After two weeks of treatment with doxycycline in drinking water, a subset of treated shRNA Rpl5+/- adult mice developed mild anemia while control mice had normal complete blood counts. Similarly, treated shRNA Rpl5+/- mice developed reticulocytopenia and bone marrow erythroblastopenia. Detection of DBA symptoms in these mice make them a valuable DBA model for studying the pathological mechanism underlying DBA and for further assessment of the disease and drug testing for novel therapies., Competing Interests: Conflict of interests: The authors declare no competing financial interests., (Copyright: © 2019, Kazerounian et al. and Applied Systems.)

Hbs1 has been established as a central component of the cell's translational quality control pathways in both yeast and prokaryotic models; however, the functional characteristics of its human ortholog (Hbs1L) have not been well-defined. We recently reported a novel human phenotype resulting from a mutation in the critical coding region of the HBS1L gene characterized by facial dysmorphism, severe growth restriction, axial hypotonia, global developmental delay and retinal pigmentary deposits. Here we further characterize downstream effects of the human HBS1L mutation. HBS1L has three transcripts in humans, and RT-PCR demonstrated reduced mRNA levels corresponding with transcripts V1 and V2 whereas V3 expression was unchanged. Western blot analyses revealed Hbs1L protein was absent in the patient cells. Additionally, polysome profiling revealed an abnormal aggregation of 80S monosomes in patient cells under baseline conditions. RNA and ribosomal sequencing demonstrated an increased translation efficiency of ribosomal RNA in Hbs1L-deficient fibroblasts, suggesting that there may be a compensatory increase in ribosome translation to accommodate the increased 80S monosome levels. This enhanced translation was accompanied by upregulation of mTOR and 4-EBP protein expression, suggesting an mTOR-dependent phenomenon. Furthermore, lack of Hbs1L caused depletion of Pelota protein in both patient cells and mouse tissues, while PELO mRNA levels were unaffected. Inhibition of proteasomal function partially restored Pelota expression in human Hbs1L-deficient cells. We also describe a mouse model harboring a knockdown mutation in the murine Hbs1l gene that shared several of the phenotypic elements observed in the Hbs1L-deficient human including facial dysmorphism, growth restriction and retinal deposits. The Hbs1lKO mice similarly demonstrate diminished Pelota levels that were rescued by proteasome inhibition., Competing Interests: The authors have declared that no competing interests exist.

Diamond-Blackfan anemia (DBA) is a rare bone marrow failure disorder that affects 7 out of 1,000,000 live births and has been associated with mutations in components of the ribosome. In order to characterize the genetic landscape of this heterogeneous disorder, we recruited a cohort of 472 individuals with a clinical diagnosis of DBA and performed whole-exome sequencing (WES). We identified relevant rare and predicted damaging mutations for 78% of individuals. The majority of mutations were singletons, absent from population databases, predicted to cause loss of function, and located in 1 of 19 previously reported ribosomal protein (RP)-encoding genes. Using exon coverage estimates, we identified and validated 31 deletions in RP genes. We also observed an enrichment for extended splice site mutations and validated their diverse effects using RNA sequencing in cell lines obtained from individuals with DBA. Leveraging the size of our cohort, we observed robust genotype-phenotype associations with congenital abnormalities and treatment outcomes. We further identified rare mutations in seven previously unreported RP genes that may cause DBA, as well as several distinct disorders that appear to phenocopy DBA, including nine individuals with biallelic CECR1 mutations that result in deficiency of ADA2. However, no new genes were identified at exome-wide significance, suggesting that there are no unidentified genes containing mutations readily identified by WES that explain >5% of DBA-affected case subjects. Overall, this report should inform not only clinical practice for DBA-affected individuals, but also the design and analysis of rare variant studies for heterogeneous Mendelian disorders., (Copyright © 2018 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Background/aims: To evaluate predictive factors for the treatment success of ocriplasmin and to use these factors to generate a multivariate model to calculate the individual probability of successful treatment., Methods: Data were collected in a retrospective, multicentre cohort study. Patients with vitreomacular traction (VMT) syndrome without a full-thickness macular hole were included if they received an intravitreal injection (IVI) of ocriplasmin. Five factors (age, gender, lens status, presence of epiretinal membrane (ERM) formation and horizontal diameter of VMT) were assessed on their association with VMT resolution. A multivariable logistic regression model was employed to further analyse these factors and calculate the individual probability of successful treatment., Results: 167 eyes of 167 patients were included. Univariate analysis revealed a significant correlation to VMT resolution for all analysed factors: age (years) (OR 0.9208; 95% CI 0.8845 to 0.9586; p<0.0001), gender (male) (OR 0.480; 95% CI 0.241 to 0.957; p=0.0371), lens status (phakic) (OR 2.042; 95% CI 1.054 to 3.958; p=0.0344), ERM formation (present) (OR 0.384; 95% CI 0.179 to 0.821; p=0.0136) and horizontal VMT diameter (µm) (OR 0.99812; 95% CI 0.99684 to 0.99941, p=0.0042). A significant multivariable logistic regression model was established with age and VMT diameter., Conclusion: Known predictive factors for VMT resolution after ocriplasmin IVI were confirmed in our study. We were able to combine them into a formula, ultimately allowing the calculation of an individual probability of treatment success with ocriplasmin in patients with VMT syndrome without FTHM., Competing Interests: Competing interests: HH reports personal fees from Allergan, personal fees from Alcon, personal fees from Bayer, personal fees from Heidelberg Engineering, personal fees from Novartis, personal fees from Alimera, outside the submitted work; NF reports personal fees and non-financial support from Allergan, personal fees and non-financial support from Bayer, personal fees from Heidelberg Engineering, personal fees and non-financial support from Novartis, personal fees and non-financial support from Alimera, outside the submitted work; JW reports personal fees from Allergan, personal fees from Bayer, personal fees from Novartis, personal fees from Alcon, outside the submitted work; HK reports personal fees from Abbott Medical Optics, personal fees from Alimera Sciences, personal fees from Alcon, personal fees from Allergan, personal fees from Carl Zeiss Meditec AG, personal fees from Dres. Schlegel + Schmidt, personal fees from Ellex, personal fees from Geuder, personal fees from Novartis, personal fees from Oculentis, personal fees from Oertli Instrumente AG, personal fees from Polytech Domilens, personal fees from Topcon Medical, outside the submitted work; SM reports personal fees from Bayer healthcare, personal fees from Novartis, outside the submitted work; MJK reports personal fees from Allergan, personal fees from Allimera, personal fees from Bayer, personal fees from Insight Instruments, personal fees from Novartis, outside the submitted work; SF reports personal fees from Roche, outside the submitted work; MMM reports personal fees from Allergan, personal fees from Bayer, personal fees from Novartis, personal fees from Heidelberg Engineering, personal fees from Alcon, personal fees from Zeiss, outside the submitted work; RGS reports personal fees from Allergan, personal fees from Novartis, outside the submitted work; SM has nothing to disclose. PC reports personal fees from Novartis, outside the submitted work; PS has nothing to disclose. AL reports personal fees from Alcon, personal fees from Bayer, outside the submitted work; TB reports personal fees from Alcon, personal fees from Novartis, personal fees from Alimera, personal fees from Bayer, personal fees from Heidelberg, outside the submitted work., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Angiogenesis or neovascularization is a complex multi-step physiological process that occurs throughout life both in normal tissues and in disease. It is tightly regulated by the balance between pro-angiogenic and anti-angiogenic factors. The angiogenic switch has been identified as the key step during tumor progression in which the balance between pro-angiogenic and anti-angiogenic factors leans toward pro-angiogenic stimuli promoting the progression of tumors from dormancy to dysplasia and ultimately malignancy. This event can be described as either the outcome of a genetic event occurring in cancer cells themselves, or the positive and negative cross-talk between tumor-associated endothelial cells and other cellular components of the tumor microenvironment. In recent years, the mechanisms underlying the angiogenic switch have been extensively investigated in particular to identify therapeutic targets that can lead to development of effective therapies. In this review, we will discuss the current findings on the regulatory pathways in endothelial cells that are involved in the angiogenic switch with an emphasis on the role of anti-angiogenic protein, thrombospondin-1 (TSP-1) and pro-angiogenic factor, vascular endothelial growth factor (VEGF).

Purpose: To determine functional and anatomical outcomes of pars plana vitrectomy for persistent full-thickness macular hole (MH) after intravitreal injection of ocriplasmin., Methods: This is a multicenter retrospective interventional study of 37 eyes of 37 patients who underwent pars plana vitrectomy with internal limiting membrane peeling for persistent MH after ocriplasmin treatment between December 2013 and December 2015 and comparison with 35 eyes of 35 patients who were offered ocriplasmin injection but underwent pars plana vitrectomy alone without pharmacologic vitreolysis before surgery. In addition, 24 matched pairs (MH diameter at baseline ±5 µm) were analyzed. Clinical data such as visual acuity, intraoperative characteristics, and spectral domain optical coherence tomography images were reviewed. Main outcome measures were visual acuity and MH closure rate., Results: After a mean follow-up period of 9 months, postoperative mean visual acuity showed no significant differences between ocriplasmin-treated eyes (logarithm of minimum angle of resolution 0.37 ± 0.26, Snellen 20/47) and eyes without ocriplasmin treatment (logarithm of minimum angle of resolution 0.39 ± 0.25; Snellen 20/49) (P > 0.9). After ocriplasmin injection, mean MH diameter enlarged from 217 ± 102 µm to 384 ± 239 µm (P < 0.001). Matched-pair analysis revealed no difference in gain of visual acuity between the first visit and the last follow-up (P = 0.29). Macular hole closure was observed in similar proportion in ocriplasmin-treated eyes (97%) and vitrectomy-only eyes (94%) (P > 0.5)., Conlcusion: Eyes with persistent MH after ocriplasmin injection showed significant visual improvement after pars plana vitrectomy. Matched-pair analysis revealed no statistical differences in functional and anatomical postoperative results comparing with eyes of similar MH diameter that proceeded directly to surgery without ocriplasmin pretreatment.

Purpose: To evaluate the agreement and predictability of ocriplasmin treatment effects among retinal experts (raters) by assessment of retinal imaging data of eyes treated for vitreomacular traction in nine different centers in Germany and Austria., Methods: Retrospective cohort study. Combined confocal near-infrared scanning laser ophthalmoscopy and spectral-domain optical coherence tomography images (Spectralis® device, Heidelberg Engineering GmbH, Germany) from 136 eyes of 135 subjects were reviewed by 14 raters using an internet-based grading database and a standardized questionnaire. In addition to the images taken within 2 days prior to treatment, age, gender, and lens status were disclosed to the raters. Treatment success was defined as a complete cleavage of the posterior vitreous cortex at day 28±5. Main outcome was the agreement and predictability among raters for assessment of treatment success., Results: Raters generally accepted starting ocriplasmin treatment (chance for treatment success ≥ 1%) in 22.4 to 69.1% (median 53.2%) of eyes (moderate intra- and interrater agreements with kappa-values of 0.6 and 0.48). The likelihood for a high potential treatment success (equal or higher than 25%) was judged by the raters in 43.4% to 86.0% (median 62.6%) of eyes (moderate intra- and fair interrater agreements with kappa-values of 0.56 and 0.22). Allocating eyes for high potential treatment success overall increased the odds by 3.07, with odds ratios of single raters up to 4.06 to 6.16., Conclusions: These results underscore the importance of training health care providers in the evaluation of retinal imaging data and also to define characteristic morphological features better in the presence of vitreoretinal interface diseases. The better results of single raters in the predictability of treatment success by the allocation of eyes in the high-potential group indicates the high relevance of the meticulous analysis of retinal images.

Purpose: To evaluate the impact of the vitreoretinal interface architecture, in specific the angle between the posterior vitreous cortex and the internal limiting membrane, on vitreomacular traction (VMT) resolution in eyes treated with intravitreally injected ocriplasmin (Jetrea)., Methods: Retrospective, multicenter cohort study and exploratory data analysis. Spectral domain optical coherence tomography assessments were performed before scheduled ocriplasmin injections. General (age and sex) as well as ocular variables (lens status, presence of epiretinal membrane formations, horizontal diameter of VMT, central retinal thickness, and in particular various prespecified angles between the posterior vitreous cortex and internal limiting membrane) were analyzed to evaluate their impact on successful VMT resolution., Results: Fifty-nine eyes of 59 patients were included. Univariate analysis of age (odds ratio [OR]: 0.881; 95% CI: [0.812-0.955]; P = 0.0022) and lens status (OR: 11.03; 95% CI: [2.23-54.57]; P = 0.0033) had a significant impact on successful VMT resolution, whereas sex (OR: 0.668; 95% CI: [0.126-2.065]; P = 0.4906), epiretinal membrane formation (OR: 0.581; 95% CI: [0.168-2.006]; P = 0.3903), horizontal diameter of VMT (OR: 0.99930; 95% CI: [0.99825-1.00035]; P = 0.1886), and central retinal thickness (OR: 0.9985; 95% CI: [0.9934-1.00436]; P = 0.56) failed. The angle at 500 μm apart from the fovea centralis, irrespective if measured nasally (OR: 1.135; 95% CI: [1.013-1.272]; P = 0.0289) or temporally (OR: 1.099; 95% CI: [1.001-1.208]; P = 0.0485), showed a significant correlation with VMT resolution., Conclusion: The angle between the posterior vitreous cortex and the internal limiting membrane 500 μm apart from the fovea centralis correlates with VMT resolution and may be a clinically useful marker for selection of patients to be treated with ocriplasmin. This observation needs to be proven in a prospective confirmatory investigation.

Cytokines are classically thought to stimulate downstream signaling pathways through monotonic activation of receptors. We describe a severe anemia resulting from a homozygous mutation (R150Q) in the cytokine erythropoietin (EPO). Surprisingly, the EPO R150Q mutant shows only a mild reduction in affinity for its receptor but has altered binding kinetics. The EPO mutant is less effective at stimulating erythroid cell proliferation and differentiation, even at maximally potent concentrations. While the EPO mutant can stimulate effectors such as STAT5 to a similar extent as the wild-type ligand, there is reduced JAK2-mediated phosphorylation of select downstream targets. This impairment in downstream signaling mechanistically arises from altered receptor dimerization dynamics due to extracellular binding changes. These results demonstrate how variation in a single cytokine can lead to biased downstream signaling and can thereby cause human disease. Moreover, we have defined a distinct treatable form of anemia through mutation identification and functional studies., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The aim of this study was to evaluate the pupil size of normal subjects at different illumination levels with a novel pupillometer. The pupil size of healthy study participants was measured with an infrared-video PupilX pupillometer (MEye Tech GmbH, Alsdorf, Germany) at five different illumination levels (0, 0.5, 4, 32, and 250 lux). Measurements were performed by the same investigator. Ninety images were executed during a measurement period of 3 seconds. The absolute linear camera resolution was approximately 20 pixels per mm. This cross-sectional study analysed 490 eyes of 245 subjects (mean age: 51.9 ± 18.3 years, range: 6-87 years). On average, pupil diameter decreased with increasing light intensities for both eyes, with a mean pupil diameter of 5.39 ± 1.04 mm at 0 lux, 5.20 ± 1.00 mm at 0.5 lux, 4.70 ± 0.97 mm at 4 lux, 3.74 ± 0.78 mm at 32 lux, and 2.84 ± 0.50 mm at 250 lux illumination. Furthermore, it was found that anisocoria increased by 0.03 mm per life decade for all illumination levels ( R 2 = 0.43). Anisocoria was higher under scotopic and mesopic conditions. This study provides additional information to the current knowledge concerning age- and light-related pupil size and anisocoria as a baseline for future patient studies.

Purpose: To study the visual outcome and change in central macular thickness (CMT) in patients with neovascular age-related macular degeneration (AMD) who were previously treated with aflibercept (VEGF Trap-Eye, Eylea) and were subsequently switched to bevacizumab (Avastin)., Methods: In this observational analysis, 19 eyes initially treated with at least 3 injections of bevacizumab after initial treatment with at least 3 injections of aflibercept are reported. Outcome measures were Snellen visual acuity (best-corrected visual acuity (BCVA) and CMT measured by spectral-domain optical coherence tomography., Results: A total of 19 eyes initially treated with 6.5 ± 2.8 intravitreal injections of aflibercept were switched to 5.4 ± 3.2 injections of bevacizumab. Median BCVA decreased from 20/94 to 20/113 after aflibercept and increased slightly to 20/101 after bevacizumab (p = 0.84, Friedman test). Of all 19 eyes, 36.8% achieved gain in visual acuity of more than 1 line and 21.1% of more than 3 lines. The CMT decreased slightly from 433 ± 229 μm at baseline to 367 ± 198 μm after aflibercept treatment (p = 0.18, Wilcoxon test) and decreased statistically significantly to 335 ± 184 μm after bevacizumab treatment (p = 0.0065, Wilcoxon test)., Conclusions: Switching from aflibercept to bevacizumab treatment has an equivalent anatomical effect in eyes with neovascular AMD as switching from bevacizumab to aflibercept. Therefore, switching back to bevacizumab might represent a reasonable therapy strategy to overcome tachyphylaxis during long-term monotherapy with aflibercept.