Author Correction: A population of luminous accreting black holes with hidden mergers.

In this Letter, the spelling of author Benny Trakhtenbrot was corrected; the affiliation for author Sylvain Veilleux was amended; and a new ref. 9 was added to the Abstract with subsequent references renumbered; these errors have been corrected online.

A population of luminous accreting black holes with hidden mergers.

Major galaxy mergers are thought to play an important part in fuelling the growth of supermassive black holes1. However, observational support for this hypothesis is mixed, with some studies showing a correlation between merging galaxies and luminous quasars2,3 and others showing no such association4,5. Recent observations have shown that a black hole is likely to become heavily obscured behind merger-driven gas and dust, even in the early stages of the merger, when the galaxies are well separated6-8 (5 to 40 kiloparsecs). Merger simulations further suggest that such obscuration and black-hole accretion peaks in the final merger stage, when the two galactic nuclei are closely separated9 (less than 3 kiloparsecs). Resolving this final stage requires a combination of high-spatial-resolution infrared imaging and high-sensitivity hard-X-ray observations to detect highly obscured sources. However, large numbers of obscured luminous accreting supermassive black holes have been recently detected nearby (distances below 250 megaparsecs) in X-ray observations10. Here we report high-resolution infrared observations of hard-X-ray-selected black holes and the discovery of obscured nuclear mergers, the parent populations of supermassive-black-hole mergers. We find that obscured luminous black holes (bolometric luminosity higher than 2 × 1044 ergs per second) show a significant (P < 0.001) excess of late-stage nuclear mergers (17.6 per cent) compared to a sample of inactive galaxies with matching stellar masses and star formation rates (1.1 per cent), in agreement with theoretical predictions. Using hydrodynamic simulations, we confirm that the excess of nuclear mergers is indeed strongest for gas-rich major-merger hosts of obscured luminous black holes in this final stage.

The close environments of accreting massive black holes are shaped by radiative feedback.

The majority of the accreting supermassive black holes in the Universe are obscured by large columns of gas and dust. The location and evolution of this obscuring material have been the subject of intense research in the past decades, and are still debated. A decrease in the covering factor of the circumnuclear material with increasing accretion rates has been found by studies across the electromagnetic spectrum. The origin of this trend may be driven by the increase in the inner radius of the obscuring material with incident luminosity, which arises from the sublimation of dust; by the gravitational potential of the black hole; by radiative feedback; or by the interplay between outflows and inflows. However, the lack of a large, unbiased and complete sample of accreting black holes, with reliable information on gas column density, luminosity and mass, has left the main physical mechanism that regulates obscuration unclear. Here we report a systematic multi-wavelength survey of hard-X-ray-selected black holes that reveals that radiative feedback on dusty gas is the main physical mechanism that regulates the distribution of the circumnuclear material. Our results imply that the bulk of the obscuring dust and gas is located within a few to tens of parsecs of the accreting supermassive black hole (within the sphere of influence of the black hole), and that it can be swept away even at low radiative output rates. The main physical driver of the differences between obscured and unobscured accreting black holes is therefore their mass-normalized accretion rate.

360° inverted internal limiting membrane flap technique for idiopathic macular holes ≤ 250 µm, > 250 and ≤ 400 µm, and > 400 µm.

PURPOSE: To study the functional and morphological results of the inverted internal limiting membrane (ILM) flap technique for the treatment of idiopathic macular holes (MHs) sized ≤ 250 µm, > 250 and ≤ 400 µm, and > 400 µm. METHODS: Retrospective, nonrandomized interventional study of 65 eyes with primary idiopathic MHs who underwent pars plana vitrectomy (PPV) with the inverted ILM flap technique. Closure rate, best-corrected visual acuity (BCVA), and integrity of external limiting membrane (ELM) and ellipsoid zone (EZ) were analyzed by optical coherence tomography (OCT). RESULTS: Total closure rate was 96.9% with 100% in the ≤ 250 µm group, 100% in the > 250 and ≤ 400 µm group, and 91.7% in the > 400 µm group. Mean BCVA significantly improved after treatment: from 0.7 to 0.3 LogMAR in the ≤ 250 µm group (n = 15, p < 0.001), from 0.9 to 0.4 LogMAR in the > 250 and ≤ 400 µm group (n = 26, p < 0.001), and from 1.0 to 0.5 LogMAR in the > 400 µm group (n = 24, p < 0.001). A total of 16 patients had follow-up over 14 months: BCVA increased from 0.9 LogMAR preoperatively to 0.4 after 1 month (p < 0.00001) and to 0.3 LogMAR after 14 months (p = 0.03). A recovered ELM could be observed in 56.3% after 1 month and in 87.5% after 14 months. A recovered EZ could be observed in 18.8% after 1 month and in 68.8% after 14 months. CONCLUSION: The study demonstrates a high closure rate with corresponding restitution of outer retinal layers. In addition to its importance for the treatment of MHs > 400 µm, the inverted ILM flap technique also appears to be effective and safe for the treatment of MHs < 400 µm. TRIAL REGISTRATION: WHO: DRKS00021241.

Novel probabilistic model of core vitreous traction using microsurgical vitrectomy tools.

PURPOSE: Traction exerted on the vitreous base during vitrectomy poses a risk for retinal tears. We aimed to quantify core vitreous traction during vitrectomy using spring return and pneumatic cutters. METHODS: Juvenile porcine vitreous was vacuum held in a vitreous bath while traction was measured using precision force gauge during vitrectomy. The parameters included were aspiration rate, cut-rate, cutter size, and machine types. RESULTS: An empirical probabilistic model was developed. The traction was proportional to the aspiration rate but insignificantly dependent on the cut-rate. The traction probability was inversely proportional to the exponential function of the traction (p < 0.05). The traction was < 0.003 N for 99% of the time using either 23- or 25-gauge cutters. CONCLUSION: The tractions measured were considered similar to the causative forces of an iatrogenic retinal tear during a pars plana vitrectomy. The results provide a safety reference matrix of instrumental parameters during vitrectomy.

[Closure of Persisting Full Thickness Macular Holes by Subretinal Fluid Application: Technical Approach and Surgical Considerations]. / Verschluss von persistierenden Makulalöchern durch subretinale Flüssigkeitsapplikation: technisches Vorgehen und chirurgische Überlegungen.

INTRODUCTION: Firm adhesions between the retina and adjacent retinal pigment epithelium (RPE) may prevent the closure of macular holes (MH) after chromovitrectomy. Controlled application of subretinal (SR) fluid with BSS may release these adhesions leading to closure of the retracted retina in large and or refractory macular holes. METHODS: For a standardized procedure, it is recommended to exclude residues of epiretinal membranes on the retinal surface preoperatively at OCT or intraoperatively by means of vital dyes. Intraoperatively, a perfluorocarbon (PFO) bubble is placed above the MH and lowers the infusion bottle of 20 mmHg. Subsequently, SR-fluid blebs are applied in the upper, temporal and inferior quadrants with a subretinal 41-gauge cannula. After removing decalin bubble, the SR-detachment is enlarged toward the foveal center. This is essential to achieve a complete detachment of the outer macular edges from the RPE. The MH can be closed by a temporary gas endotamponade. RESULTS: With a standardized procedure, the operation can be carried out safely and with minimal effort. Additional measures, such as care for bubble-free SR-fluid sands or machine assistance, were added. In a pilot study, experienced VR surgeons performed the SR-fluid application safely and without complications. The preoperative diameter of the MH was 1150 µm (651 - 2350 µm). The secondary closure rate for our PMH was 80.9%. CONCLUSION: SR-adhesions seem to have a previously unnoticed component in persistent macular holes. An SR-fluid application can be carried out quickly, safely and with minimal material effort. The initial results show a high secondary closure rate.

Application of subretinal fluid to close refractory full thickness macular holes: treatment strategies and primary outcome: APOSTEL study.

INTRODUCTION: Persisting macular holes (PMH) after surgical release of any epiretinal traction of the vitreous and adjacent membrane may rely on secondary firm adhesions between the retracted retina and adjacent retinal pigment epithelium. Secondary application of subretinal (SR)-fluid may release these adhesions followed by an anatomical closure. METHODS: Twelve surgeons applied in a consecutive case series SR-fluid in 41 eyes with PMH and reported retrospectively their initial surgical, anatomical and functional experience with this approach. RESULTS: The mean duration of the MH prior to SR-fluid application was 17 months (6-96 months). The mean age of the patients at the time of surgery was 72 years (54-88). The mean preoperative aperture diameter of the opening was 1212 µm (239-4344 µm), base diameter 649 µm (SD 320 µm). The mean preoperative BCVA prior to surgery was 0.1 (0.01-0.3). All patients (41/41) complained about reduced BCVA and a significant central scotoma (negative scotoma) in their central field of vision. The secondary closure rate for our PMH was 85.36% (35 out of 41 eyes) at 6 weeks after surgery. The postoperative BCVA improved to 0.22 (0.02-0.5). The application of SR-fluid was not associated with major intraoperative adverse effects. CONCLUSION: Remaining SR-adhesions may inhibit PMH closure. Their release by application of SR-fluid will lead to a fast and immediate anatomical closure in many cases without serious adverse events.

Subretinal Implantation of a Human Embryonic Stem Cell-Derived Retinal Pigment Epithelium Monolayer in a Porcine Model.

The goal of this study was to quantitatively assess retinal thickness using spectral domain optical coherence tomography (SD-OCT) after subretinal implantation of human embryonic stem cell-derived retinal pigment epithelium in a porcine model. The implant is called CPCB-RPE1 for the California Project to Cure Blindness-Retinal Pigment Epithelium 1. Data were derived from previous experiments on 14 minipigs that received either subretinal implantation of CPCB-RPE1 (n = 11) or subretinal bleb formation alone (sham; n = 3) using previously described methods and procedures (Brant Fernandes et al. Ophthalmic Surg Lasers Imaging Retina 47:342-51, 2016; Martynova et al. (2016) Koss et al. Graefes Arch Clin Exp Ophthalmol 254:1553-65, 2016; Hu et al. Ophthalmic Res 48:186-91, 2016; Martynova et al. ARVO Abstract 2016. SD-OCT retinal thickness (RT) and sublayer thickness over the implant were compared with topographically similar preimplantation regions as described previously Martynova et al. ARVO Abstract 2016. Imaging results were compared to postmortem histology using hematoxylin-eosin staining. RT overlying the CPCB-RPE1 postimplantation was not significantly different from preimplantation (308 ± 72 µm vs 292 ± 41 µm; p = 0.44). RT was not significantly different before and after implantation in any retinal sublayer at 1 month. Histology demonstrated grossly normal retinal anatomy as well as photoreceptor interdigitation with RPE.

Reprint of: The pathology of pulmonary sarcoidosis: update.

Sarcoidosis is a multi-system disease of unknown etiology, usually affecting the respiratory tract and other organs, and is characterized by the formation of nonnecrotizing epithelioid granulomas. The diagnosis depends on a combination of a typical clinicoradiological presentation, the finding of nonnecrotizing epithelioid granulomas in a tissue biopsy, and exclusion of other possible diseases, especially those of infectious etiology. The granulomas contain epithelioid cells, giant cells, CD4+ T cells in their center, and CD8+ T lymphocytes and B lymphocytes at their periphery. The granulomas are present in a lymphatic pattern around bronchovascular structures and, because of this, may show angioinvasion. The bronchial involvement produces a high diagnostic yield for transbronchial and endobronchial biopsies in this disease. Finally, small amounts of fibrinoid necrosis may occur within granulomas of sarcoidosis and do not exclude the diagnosis. Larger amounts suggest either infection or the rare disease necrotizing sarcoid granulomatosis (NSG). A number of cytoplasmic structures/inclusions can be identified within the granulomas of sarcoidosis, including asteroid bodies, Schaumann's bodies, calcium oxalate crystals, and Hamazaki-Wesenberg bodies; the last two of these can cause difficulties in differential diagnosis. Extra-pulmonary sarcoid can be an important factor in prognosis. Involved sites include (in decreasing frequency): skin, endocrine organs, extra-thoracic lymph nodes, neurologic sites, eyes, liver, spleen, bone marrow, cardiac, ear/nose/throat, parotid/salivary, muscles, bones/joint, and kidney. NSG is a controversial variant of sarcoidosis consisting of granulomatous pneumonitis with sarcoid-like granulomas, variable amounts of necrosis, and granulomatous vasculitis. The lesions are most often confined to lung, and they usually appear as multiple nodules or nodular infiltrates, but occasionally as solitary or unilateral nodules ranging up to 5 cm in diameter. Nodular sarcoidosis is rare, varying from 1.6% to 4% of patients with sarcoidosis, and, as the name suggests, it shows radiographic nodules measuring 1 to 5 cm in diameter that typically consist of coalescent granulomas. Lung transplantation can be used in selected patients with fibrotic late-stage sarcoidosis. There is a high reported frequency of recurrence of disease in the pulmonary allograft, ranging from 47% to 67%, but recurrence is usually not clinically significant. Studies of the pathogenesis of sarcoidosis suggest that it is a chronic immunological response produced by a genetic susceptibility and exposure to specific environmental factors.

The predictability of ocriplasmin treatment effects: is there consensus among retinal experts? Results from the EXPORT study.

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.

VITRECTOMY FOR PERSISTENT MACULAR HOLES FOLLOWING OCRIPLASMIN INJECTION: A Comparative Multicenter Study.

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.

IMPACT OF VITREORETINAL INTERFACE ARCHITECTURE ON SUCCESSFUL VITREOMACULAR TRACTION RESOLUTION IN EYES SCHEDULED FOR INTRAVITREAL OCRIPLASMIN THERAPY.

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.

Intravitreal Sustained-Release Steroid Implants for the Treatment of Macular Edema following Surgical Removal of Epiretinal Membranes.

PURPOSE: To evaluate the efficacy of intravitreal dexamethasone implant for the treatment of postoperative persistent cystoid macular edema (CME) following macular pucker surgery. METHODS: In this multicenter study, we retrospectively reviewed the data of 37 patients (39 eyes) who had been treated with intravitreal dexamethasone implant (Ozurdex®) for persistent CME following macular pucker surgery. Main outcome measures were change in best-corrected visual acuity (BCVA) and central retinal thickness (CRT). RESULTS: All eyes underwent spectral domain optical coherence tomography examination within 130 days after implantation. We observed a significant decrease in mean CRT from 519.9 to 392.9 µm (p < 0.0001). By this time, mean BCVA had improved from 0.60 to 0.43 logMAR (p = 0.003). Seventeen eyes (43.6%) required at least 1 repeat injection of dexamethasone. Of these, 8 (47%) eyes received a total number of 3 or more dexamethasone injections. CONCLUSION: Intravitreal dexamethasone implant injection is an effective treatment option for persistent CME following macular pucker surgery.

Proteomics of vitreous in neovascular age-related macular degeneration.

Neovascular age-related macular degeneration (nAMD) has been described as a predominantly inflammatory and proangiogenic retino-choroidal disease. Vitreous humor (VH) is the adjacent and accessible compartment which, due to the vicinity to the retina, might best represent changes of protein-based mediators of nAMD. The aim of this clinical-experimental study was to analyze the nAMD associated VH proteome of previously untreated patients whilst taking different groups of nAMD into account, based on their clinical presentation (clinical diagnosis groups). Electrophoresis coupled online to mass spectrometry (CE-MS) as well as liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) were used to analyze VH of 108 nAMD patients and 24 controls with idiopathic floaters. A total of 101 different proteins with at least two unique peptides could be identified. Using a stringent statistical analysis with implementation of the closed test principle, we were able to identify four proteins that may be involved in the pathophysiology of nAMD: Clusterin, opticin, pigment epithelium-derived factor and prostaglandin-H2 d-isomerase. Using independent samples, ROC-Area under the curve was determined proving the validity of the results: Clusterin 0.747, opticin 0.656, pigment epithelium-derived factor 0.514, prostaglandin-H2 d-isomerase 0.712. In addition, validation through ELISA measurements was performed. The identified proteins may serve as potential biomarkers or even targets of therapy for nAMD.

Vancomycin in infusion during vitrectomy in surgical treatment of acute postoperative and posttraumatic endophthalmitis.

BACKGROUND: Endophthalmitis is potentially devastating intraocular inflammation following eye trauma or surgery. We describe the visual outcomes and causative pathogens in acute bacterial postoperative and posttraumatic endophthalmitis treated with immediate pars plana vitrectomy (PPV) with Vancomycin dissolved in the infusion fluid. METHODS: Clinical records of consecutive 30 patients with postoperative endophthalmitis and 15 patients with posttraumatic endophthalmitis were evaluated. Vancomycin was administered constantly in the infusion fluid at the time of complete PPV. Cultures were prepared from anterior chamber paracentesis. The mean follow-up period was 13 months. RESULTS: The visual acuities were improved in 38 cases (84 %) and remained stable in seven cases (16 %). Median post-PPV visual acuity was 1.0 logMAR in a group with postoperative endophthalmitis and 1.3 logMAR in a group with posttraumatic endophthalmitis (p < 0.05). Twenty cases (44 %) were culture-positive (Staphylococcus, Streptococcus, Enterococcus and Bacillus spp). CONCLUSIONS: Early PPV with Vanomycin in infusion leads to vision improvement in patients with both posttraumatic and postoperative endophthalmitis. In our series of 45 cases culture was positive only in half of the cases.

Subretinal implantation of a monolayer of human embryonic stem cell-derived retinal pigment epithelium: a feasibility and safety study in Yucatán minipigs.

PURPOSE: A subretinal implant termed CPCB-RPE1 is currently being developed to surgically replace dystrophic RPE in patients with dry age-related macular degeneration (AMD) and severe vision loss. CPCB-RPE1 is composed of a terminally differentiated, polarized human embryonic stem cell-derived RPE (hESC-RPE) monolayer pre-grown on a biocompatible, mesh-supported submicron parylene C membrane. The objective of the present delivery study was to assess the feasibility and 1-month safety of CPCB-RPE1 implantation in Yucatán minipigs, whose eyes are similar to human eyes in size and gross retinal anatomy. METHODS: This was a prospective, partially blinded, randomized study in 14 normal-sighted female Yucatán minipigs (aged 2 months, weighing 24-35 kg). Surgeons were blinded to the randomization codes and postoperative and post-mortem assessments were performed in a blinded manner. Eleven minipigs received CPCB-RPE1 while three control minipigs underwent sham surgery that generated subretinal blebs. All animals except two sham controls received combined local (Ozurdex™ dexamethasone intravitreal implant) and systemic (tacrolimus) immunosuppression or local immunosuppression alone. Correct placement of the CPCB-RPE1 implant was assessed by in vivo optical coherence tomography and post-mortem histology. hESC-RPE cells were identified using immunohistochemistry staining for TRA-1-85 (a human marker) and RPE65 (an RPE marker). As the study results of primary interest were nonnumerical no statistical analysis or tests were conducted. RESULTS: CPCB-RPE1 implants were reliably placed, without implant breakage, in the subretinal space of the minipig eye using surgical techniques similar to those that would be used in humans. Histologically, hESC-RPE cells were found to survive as an intact monolayer for 1 month based on immunohistochemistry staining for TRA-1-85 and RPE65. CONCLUSIONS: Although inconclusive regarding the necessity or benefit of systemic or local immunosuppression, our study demonstrates the feasibility and safety of CPCB-RPE1 subretinal implantation in a comparable animal model and provides an encouraging starting point for human studies.

INTRAOCULAR PRESSURE CHANGES DURING VITRECTOMY USING CONSTELLATION VISION SYSTEM'S INTRAOCULAR PRESSURE CONTROL FEATURE.

PURPOSE: To evaluate intraocular pressure (IOP) changes during experimental vitrectomy and the efficacy of Constellation Vision System's IOP control (IOPc) feature in reestablishing baseline pressure. METHODS: Using a pressure transducer in freshly enucleated porcine eyes, a broad range of parameters (baseline pressures, aspiration levels, and cut rates) were tested with 23- and 25-gauge probes and IOPc turned ON versus OFF. RESULTS: IOPc turned ON was significantly more effective than IOPc turned OFF in controlling IOP drop and stabilizing pressure during vitrectomy using a wide range of baseline pressures (20-70 mmHg). The 23-gauge system consistently presented a reduced drop from baseline compared with the 25-gauge system. The overall average drop for the 23- and 25-gauge systems was 12.79 mmHg and 21.17 mmHg, respectively. Both gauge sizes reestablished baseline pressure approximately 1.6 seconds after the initial pressure drop generated at the beginning of aspiration. A peak of IOP (overshooting) was observed when the pressure was returning to baseline using both 23- and 25-gauge systems. CONCLUSION: Using IOPc feature turned ON, 23- and 25-gauge probes were effective in reestablishing and sustaining baseline infusion pressures, although 23-gauge probes showed less IOP fluctuation than did 25-gauge probes.

LYSOPHOSPHATIDIC ACIDS AND AUTOTAXIN IN RETINAL VEIN OCCLUSION.

PURPOSE: To analyze the levels of lysophosphatidic acids (LPAs) and autotaxin (ATX) in undiluted vitreous of untreated patients with retinal vein occlusion (RVO). METHODS: Sixty-four vitreous samples (40 RVO, 24 controls with idiopathic floaters) were analyzed in this retrospective case series using LC/MS for LPAs 16:0, 18:0, 18:1, 20:4, and ELISA kits or Luminex technology for ATX, angiopoetin-1 (ANG-1), interleukin-6 (IL-6), interleukin-7 (IL-7), interleukin-8 (IL-8), monocyte chemoattractant protein-1 (MCP-1), pigment epithelium-derived factor (PEDF), and vascular endothelial growth factor (VEGF). LPA and ATX levels were correlated with the visual acuity, central macular thickness (CMT), average retinal thickness (AvT), vitreal cytokine levels and with each other. RESULTS: Levels of every LPA species tested and ATX were significantly increased in the vitreous fluid from all patients with RVO (total LPAs: 968.0 ± 842.3 nM; ATX: 2.5 ± 1.02 nM) compared with controls (total LPAs: 225.2 ± 292.8 nM, P < 0.0001; ATX: 1.9 ± 1.00 nM, P = 0.005). There were strong positive correlations between the vitreal levels of IL-6, IL-8, MCP-1, VEGF and LPAs. CONCLUSION: Levels of LPAs and ATX were positively correlated with proinflammatory cytokines and VEGF and might thus play an important role in the development of macular edema secondary to RVO.

Current treatment modalities in diabetic macular edema.

Diabetic macular edema is the major cause of vision impairment in the diabetic population. Its treatment requires a multidisciplinary approach and the use of both systemic and local therapies. Current management includes the vascular endothelial growth factor inhibitors and steroids administered as intravitreal injections, as well as laser therapy and surgical treatment. Treatment modalities in diabetic macular edema have changed in recent years, after the introduction of vascular endothelial growth factor inhibitors, which are gradually replacing laser photocoagulation. All anti-VEGF agents tested so far showed efficacy in the treatment of diabetic macular edema. Due to structural differences, the therapeutic efficacy of different anti-VEGF products varies. According to recent results, 2,0 mg of aflibercept is more effective than 0,3 mg of ranibizumab in patients with lower visual acuity at baseline. Additionally, its superiority was shown in reducing the number of required macular laser photocoagulation procedures. This article provides a comprehensive overview of available therapeutic modalities based on laser photocoagulation, anti-VEGF agents, steroid injections or surgical interventions, and discusses their efficacy in patients with diabetic macular edema.

Genome-scale analysis of DNA methylation in lung adenocarcinoma and integration with mRNA expression.

Lung cancer is the leading cause of cancer death worldwide, and adenocarcinoma is its most common histological subtype. Clinical and molecular evidence indicates that lung adenocarcinoma is a heterogeneous disease, which has important implications for treatment. Here we performed genome-scale DNA methylation profiling using the Illumina Infinium HumanMethylation27 platform on 59 matched lung adenocarcinoma/non-tumor lung pairs, with genome-scale verification on an independent set of tissues. We identified 766 genes showing altered DNA methylation between tumors and non-tumor lung. By integrating DNA methylation and mRNA expression data, we identified 164 hypermethylated genes showing concurrent down-regulation, and 57 hypomethylated genes showing increased expression. Integrated pathways analysis indicates that these genes are involved in cell differentiation, epithelial to mesenchymal transition, RAS and WNT signaling pathways, and cell cycle regulation, among others. Comparison of DNA methylation profiles between lung adenocarcinomas of current and never-smokers showed modest differences, identifying only LGALS4 as significantly hypermethylated and down-regulated in smokers. LGALS4, encoding a galactoside-binding protein involved in cell-cell and cell-matrix interactions, was recently shown to be a tumor suppressor in colorectal cancer. Unsupervised analysis of the DNA methylation data identified two tumor subgroups, one of which showed increased DNA methylation and was significantly associated with KRAS mutation and to a lesser extent, with smoking. Our analysis lays the groundwork for further molecular studies of lung adenocarcinoma by identifying novel epigenetically deregulated genes potentially involved in lung adenocarcinoma development/progression, and by describing an epigenetic subgroup of lung adenocarcinoma associated with characteristic molecular alterations.