Fixed Monthly versus Less Frequent Ranibizumab Dosing and Predictors of Visual Response in Exudative Age-Related Macular Degeneration

Purpose. To examine temporal patterns of visual acuity (VA) response to pooled 0.3 mg/0.5 mg ranibizumab treatment in patients with age-related macular degeneration and identify potential baseline predictors of response. Design. Retrospective analysis. Methods. Results from 1824 ranibizumab-treated patients receiving fixed monthly, quarterly, or as-needed dosing after three monthly loading doses in four phase III/IIIb trials (ANCHOR, MARINA, PIER, and SAILOR) were analyzed. Results. At month 3, 14.9% to 29.4% of patients had gained ≥15 letters. Not all patients achieved peak gains at month 3; many continued to have VA increases throughout treatment. After three monthly loading doses, continued monthly dosing resulted in further gains, as there were more delayed 15-letter responders at month 12 (14.7–16.1%) than with less frequent dosing (5.0–6.0%). Monthly dosing also resulted in more patients maintaining VA gains at later time points. Early 15-letter responders had lower baseline mean VA than delayed 15-letter responders in ANCHOR and MARINA; no other differences in baseline characteristics were noted. Conclusions. Although some patients have rapid improvements in VA, others do not experience peak VA until later during treatment. Continued monthly dosing resulted in a greater percentage of patients gaining ≥15 letters than with switching to less frequent dosing regimens

Optical imaging of the chorioretinal vasculature in the living human eye

Detailed visualization of microvascular changes in the human retina is clinically limited by the capabilities of angiography imaging, a 2D fundus photograph that requires an intravenous injection of fluorescent dye. Whereas current angiography methods enable visualization of some retinal capillary detail, they do not adequately reveal the choriocapillaris or other microvascular features beneath the retina. We have developed a noninvasive microvascular imaging technique called phase-variance optical coherence tomography (pvOCT), which identifies vasculature three dimensionally through analysis of data acquired with OCT systems. The pvOCT imaging method is not only capable of generating capillary perfusion maps for the retina, but it can also use the 3D capabilities to segment the data in depth to isolate vasculature in different layers of the retina and choroid. This paper demonstrates some of the capabilities of pvOCT imaging of the anterior layers of choroidal vasculature of a healthy normal eye as well as of eyes with geographic atrophy (GA) secondary to age-related macular degeneration. The pvOCT data presented permit digital segmentation to produce 2D depth-resolved images of the retinal vasculature, the choriocapillaris, and the vessels in Sattler’s and Haller’s layers. Comparisons are presented between en face projections of pvOCT data within the superficial choroid and clinical angiography images for regions of GA. Abnormalities and vascular dropout observed within the choriocapillaris for pvOCT are compared with regional GA progression. The capability of pvOCT imaging of the microvasculature of the choriocapillaris and the anterior choroidal vasculature has the potential to become a unique tool to evaluate therapies and understand the underlying mechanisms of age-related macular degeneration progression

Discovery of Outlying, High-Velocity Oxygen-Rich Ejecta in Cassiopeia A

Hubble Space Telescope images of the young Galactic supernova remnant Cassiopeia A reveal a far larger population of outlying, high-velocity knots of ejecta with a broader range of chemical properties than previously suspected. We identify three main classes of outer ejecta: 1) Knots dominated by [N II] 6548,6583 emission; 2) Knots dominated by oxygen emission lines especially [O II] 7319,7330; and 3) Knots with emission line strengths similar to the [S II] strong FMK ejecta commonly seen in the main emission shell. The discovery of a significant population of O-rich ejecta situated in between the suspected N-rich outer photospheric layer and S-rich FMK-like ejecta suggests that the Cas A progenitor's chemical layers were not completely disrupted by the supernova explosion outside of the remnant's NE and SW high velocity `jet' regions. In addition, we find the majority of O-rich outer ejecta at projected locations out beyond (v = 6500 - 9000 km/s) the remnant's fastest moving Fe-rich X-ray emission material (6000 km/s) seen in Chandra and XMM data along the eastern limb. This suggests that penetration of Fe-rich material up through the S and Si-rich mantle did not extend past the progenitor's N or O-rich outer layers for at least this section of the remnant.Comment: 17 pages including 3 tables and 7 figures. To appear in Ap

Hubble Space Telescope WFPC-2 Imaging of Cassiopeia A

The young SNR Cassiopeia A was imaged with WFPC-2 through four filters selected to capture the complete velocity range of the remnant's main shell in several important emission lines. Primary lines detected were [O III] 4959,5007, [N II] 6583, [S II] 6716,6731 + [O II] 7319,7330 + [O I] 6300,6364, and [S III] 9069,9532. About 3/4th of the remnant's main shell was imaged in all four filters. Considerable detail is observed in the reverse-shocked ejecta with typical knot scale lengths of 0.2"-0.4" (1 - 2 x 10^16 cm). Both bright and faint emission features appear highly clumped. Large differences in [S III] and [O III] line intensities indicating chemical abundance differences are also seen, particularly in knots located along the bright northern limb and near the base of the northeast jet. A line of curved overlapping filament in the remnant's northwestern rim appears to mark the location of the remnant's reverse shock front in this region. Finger-like ejecta structures elsewhere suggest cases where the reverse shock front is encountering the remnant's clumped ejecta. Narrow-band [N II] images of the remnant's circumstellar knots ("QSFs") reveal them to be 0.1"-0.6" thick knots and filaments, often with diffuse edges facing away from the center of expansion. Three color composite images of the whole remnant and certain sections along with individual filter enlargements of selected regions of the bright optical shell are presented and discussed.Comment: 26 pages, 12 figures Accepted to the Astronomical Journa

Fas signaling induces raft coalescence that is blocked by cholesterol depletion in human RPE cells undergoing apoptosis

PURPOSE. To investigate whether the signaling events occurring in Fas-mediated apoptosis alter raft membrane formation in human RPE cells. METHODS. Formation of lipid rafts in cultured human retinal pigment epithelial cells (ARPE-19) was studied by confocal microscopy, with fluorescein-labeled cholera toxin subunit B binding protein (BODIPY)-labeled ganglioside GM1 lipid after Fas-L induction of apoptosis. Apoptosis was assessed by fluorescein-labeled annexin V detection of phosphatidylserine externalization and quadrant analysis with flow cytometry. Membrane rafts were localized into membrane vesicles by passing BODIPY-labeled GM1 RPE cells through a 2-m-pore polycarbonate membrane using an extruder device. The labeled fractions, containing vesicles enriched in GM1, were detected by flow cytometry and then analyzed for the presence of Fas protein. RESULTS. Differential punctate staining of membrane rafts was demonstrated in normal and FasL-induced apoptotic human ARPE-19 cells in culture by confocal microscopy, using cholera toxin B and GM1 labeling of extruded vesicles. The lipid raftassociated vesicles were derived by plasma membrane dissociation, via a newly developed whole-cell extrusion technique that produced 2-m vesicles with both GM1 lipid and Fas protein abundance enriched in a subpopulation of the membrane-derived vesicles. The amount of Fas protein in the vesicles containing raft domains markedly increased in FasL-treated cells. Treatment of human ARPE 19 cells with methyl ␤-cyclodextrin after FasL induction of apoptosis resulted in cellular cholesterol depletion and markedly reduced the incidence of Fas-receptor localization in GM1 rafts. CONCLUSIONS. Human ARPE-19 cells in culture contain membrane rafts with apoptotic signaling effectors uniformly distributed in the native state. The cells stimulated to undergo apoptosis appear to use membrane rafts in the death-signaling process by mobilization of rafts to localized regions of the membrane that are now enriched with apoptotic signaling effectors. Fas signaling induces apoptotic raft formation that results in polar condensation, or capping, of the rafts in the late stages of apoptosis. A novel extrusion technique is described that allows localization and enrichment of rafts into membrane vesicles, which can be assayed by flow cytometry. Cholesterol depletion, after Fas ligand activation of apoptosis, reduced raft formation in cells induced to undergo apoptosis. Therapeutic implications for the treatment of retinal disorders are discussed. (Invest Ophthalmol Vis Sci

The Role of Appearance in Adolescents’ Experiences of Neurofibromatosis Type 1: A Survey of Young People and Parents

© 2016, National Society of Genetic Counselors, Inc. Neurofibromatosis type 1 (NF1) is a genetic condition which can result in varying degrees of visible difference (disfigurement). Adolescence is a time when appearance concerns become more salient for many young people and is acknowledged as a particularly challenging time for individuals with NF1. There is currently little research into the psychosocial impact of the appearance changes associated with NF1 during this stage of life. In order to address this, surveys of young people with NF1 aged 14–24years (n=73), and parents of young people with NF1 (n=55) were developed following interview studies with these groups. The surveys included the Perceived Stigma Questionnaire, Social Comfort Questionnaire, Body Esteem Scale (appearance subscale) and the Subjective Happiness Scale. Young people and parents identified appearance as central to young peoples’ experience of NF1, however no significant difference was found on measures of body esteem, happiness, stigma or social comfort between those young people who reported their NF1 was noticeable to others and those who reported it was not. Findings from the parent survey indicated that their reports of greater perceived noticeability did relate to greater perceived stigma and lower levels of social comfort. Findings highlight the importance of attending to young people’s concerns around appearance in general and managing the possibility of future appearance changes, rather than the current noticeability of NF1

The expansion asymmetry and age of the Cassiopeia A supernova remnant

HST images of the young supernova remnant Cas A are used to explore the expansion and spatial distribution of its highest velocity debris. ACS WFC images taken in 2004 March and December with Sloan F625W, F775W, and F850LP filters were used to identify 1825 high-velocity, outlying ejecta knots through measured proper motions of 0."35 - 0."90 yr(-1), corresponding to V-trans = 5500-14,500 km s(-1) assuming d = 3.4 kpc. The distribution of derived transverse expansion velocities for these ejecta knots shows a striking bipolar asymmetry with the highest velocity knots (V-trans >= 10,500 km s(-1)) confined to nearly opposing northeast and southwest "jets'' at P.A. = 45 degrees-70 degrees and 230 degrees-270 degrees, respectively. The jets have about the same maximum expansion velocity of similar or equal to 14,000 km s(-1) and appear kinematically and chemically distinct in that they are the remnant's only S-rich ejecta with expansion velocities above the 10,000-11,000 km s(-1) exhibited by outer nitrogen-rich ejecta, which otherwise represent the remnant's highest velocity debris. In addition, we find significant gaps in the spatial distribution of outlying ejecta in directions that are approximately perpendicular to the jets (P.A. = 145 degrees-200 degrees and 335 degrees-350 degrees). The remnant's central X-ray point source lies some 700 to the southeast of the estimated expansion center ( P.A. = 169 degrees +/- 8.degrees 4) indicating a projected motion toward the middle of the broad southern ejecta knot gap. Extrapolations of measured 9 month proper motions for all 1825 outer ejecta knots and a selected subsample of 72 bright and compact knots suggest explosion dates (assuming no knot deceleration) of 1662 +/- 27 and 1672 +/- 18, respectively. We find some evidence for nonuniform deceleration in different directions around the remnant and find 126 knots located along the northwestern limb among the least decelerated ejecta, suggesting a convergence date of 1681 +/- 19. A remnant age of around 325 yr would imply a +/- 350 km s(-1) transverse velocity for the central X-ray point source

Slowing and cooling molecules and neutral atoms by time-varying electric field gradients

A method of slowing, accelerating, cooling, and bunching molecules and neutral atoms using time-varying electric field gradients is demonstrated with cesium atoms in a fountain. The effects are measured and found to be in agreement with calculation. Time-varying electric field gradient slowing and cooling is applicable to atoms that have large dipole polarizabilities, including atoms that are not amenable to laser slowing and cooling, to Rydberg atoms, and to molecules, especially polar molecules with large electric dipole moments. The possible applications of this method include slowing and cooling thermal beams of atoms and molecules, launching cold atoms from a trap into a fountain, and measuring atomic dipole polarizabilities.Comment: 13 pages, 10 figures. Scheduled for publication in Nov. 1 Phys. Rev.

Plasma Electronics

Contains reports on twelve research projectsU. S. NavyU.S. Navy (Office of Naval Research) under Contract Nonr-1841(78)U. S. Air Force under Air Force Contract AF 19(604)-7400U. S. ArmyNational Science Foundation (Grant G-24073)Lincoln Laboratory, Purchase Order DDL B-0036

Plasma Dynamics

Contains reports on three research projects.National Science Foundation (Grant G-9330)United States Air Force, Air Force Cambridge Research Center (Contract AF19(604)-5992)United States ArmyUnited States Air Force (Contract AF19(604)-7400)Lincoln Laboratory (Purchase Order B-00306)Flight Accessories Laboratory, Wright-Patterson Air Force Base (WADD Contract AF33(616)-7624)United States Air Force, Air Force Cambridge Research Laboratories (Contract AF19(604)-4551)United States NavyUnited States Atomic Energy Commission (Contract AT(30-1)-1842