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Macrophages are rapidly conditioned by cognate and soluble signals to acquire phenotypes that deliver specific functions during inflammation, wound healing and angiogenesis. Whether inhibitory CD200R signaling regulates pro-angiogenic macrophage phenotypes with the potential to suppress ocular neovascularization is unknown. CD200R-deficient bone marrow derived macrophages (BMMΦ) were used to demonstrate that macrophages lacking this inhibitory receptor exhibit enhanced levels of Vegfa, Arg-1 and Il-1β when stimulated with PGE 2 or RPE-conditioned (PGE 2 -enriched) media. Endothelial tube formation in HUVECs was increased when co-cultured with PGE 2 -conditioned CD200R −/− BMMΦ, and laser-induced choroidal neovascularization was enhanced in CD200R-deficient mice. In corroboration, signaling through CD200R results in the down-regulation of BMMΦ angiogenic and pro-inflammatory phenotypes. Translational potential of this pathway was investigated in the laser-induced model of choroidal neovascularization. Local delivery of a CD200R agonist mAb to target myeloid infiltrate alters macrophage phenotype and inhibits pro-angiogenic gene expression, which suppresses pathological angiogenesis and CNV development.

To determine the feasibility of a novel intraocular lens (IOL) designed to improve retinal image quality at up to 10° of retinal eccentricity and optionally provide retinal magnification in patients with macular disease. In this prospective, interventional pilot study, 8 eyes of 7 patients with bilateral dry age-related macular degeneration and 1+ or less cataract underwent phacoemulsification and capsular bag implantation of a single, injectable, hydrophobic acrylic IOL. Safety and efficacy were assessed by monitoring logMAR corrected distance and near visual acuity, intraocular pressure, specular microscopy, 80-point visual field testing, and anterior segment and macular optical coherence tomography at baseline and 1 week, 1 month, and 2 months postoperatively. Microperimetry was undertaken at baseline and 1 and/or 2 months postoperatively. Reading performance was assessed at baseline and 1 month postoperatively using the Minnesota low vision reading chart (MNREAD; Precision Vision, LaSalle, IL). Safety outcomes were equivalent to standard monofocal IOLs. Visual acuities improved in all patients. Mean corrected distance visual acuity improved from 0.93 ± 0.22 preoperatively to 0.59 ± 0.25 at 2 months postoperatively. Mean reading speed increased from 28 ± 19 to 44 ± 31 words per minute. Mean microperimetry threshold sensitivities increased from 8.2 ± 4.6 to 12 ± 5.6 dB. Mean percentage of fixation points within a 4° circle increased from 77% ± 17% to 91% ± 11% with evidence for progressive movement of preferred retinal loci away from areas of geographic atrophy. Initial results indicate this novel IOL has a safety profile comparable with standard IOLs. Visual benefits may exceed those obtained with existing technologies in patients with macular disease. Further work is required to determine the full potential of extended macular vision technology. [J Refract Surg. 2018;34(11):718-725.].

Long-term follow-up of 12 persons with Leber's congenital amaurosis treated with gene therapy showed that about half of them had improvements in retinal sensitivity (although the extent varied markedly among patients), followed by a decline. Leber’s congenital amaurosis is a group of inherited, early-onset, severe retinal dystrophies that cause substantial sight impairment in childhood. 1 One of the causes of this condition is mutations in the gene encoding RPE65 (retinal pigment epithelium–specific protein 65 kDa). The encoded retinoid isomerase converts all- trans retinyl esters to 11- cis retinal for the regeneration of visual pigment after exposure to light. RPE65 deficiency causes photoreceptor-cell dysfunction and impaired vision from birth. Severe dysfunction of rod photoreceptor cells, which are wholly reliant on retinal pigment epithelium–derived RPE65, causes severely impaired night vision. The function of cone photoreceptor cells, which mediate . . .

If we attempt to summarise data from our study, the Southampton Study and that by Berler to examine whether or not age greater than 88 is a risk factor for intraoperative complications using meta-analysis techniques, we find that there is significant inconsistency between the studies (test for heterogeneity Χ2 = 7.54, p = 0.02, I2 = 73.5%).

Uveitis is a sight threatening inflammatory disorder that remains a significant cause of visual loss. We investigated lentiviral gene delivery of interleukin 1 receptor antagonist (IL-1ra) or interleukin (IL)-10 to ameliorate murine endotoxin-induced uveitis (EIU). An human immunodeficiency virus-1-based vector containing the mIL-1ra or mIL-10 cDNA demonstrated high expression of biologically active cytokine. Following administration of Lenti.GFP into the anterior chamber, transgene expression was observed in corneal endothelial cells, trabecular meshwork and iris cells. To treat EIU, mice were injected with Lenti.IL-1ra, Lenti.IL-10 or a combination of these. EIU was induced 14 days after vector administration and mice were culled 12 h following disease induction. Lenti.IL-1ra or Lenti.IL-10-treated eyes showed significantly lower mean inflammatory cell counts in the anterior and posterior chambers compared with controls. The aqueous total protein content was also significantly lower in treated eyes, demonstrating better preservation of the blood-ocular barrier. Furthermore, the treated eyes showed less in vivo fluorescein leakage from inner retinal vessels compared with controls. The combination of both IL-1ra and IL-10 had no additive effect. Thus, lentiviral gene delivery of IL-1ra or IL-10 significantly reduces the severity of experimental uveitis, suggesting that lentiviral-mediated expression of immunomodulatory genes in the anterior chamber offers an opportunity to treat uveitis.

Despite impressive progress, more than 50% of patients treated with CD19-targeting chimeric antigen receptor T cells (CAR19) experience progressive disease. Ten of 16 patients with large B cell lymphoma (LBCL) with progressive disease after CAR19 treatment had absent or low CD19. Lower surface CD19 density pretreatment was associated with progressive disease. To prevent relapse with CD19 − or CD19 lo disease, we tested a bispecific CAR targeting CD19 and/or CD22 (CD19-22.BB.z-CAR) in a phase I clinical trial ( NCT03233854 ) of adults with relapsed/refractory B cell acute lymphoblastic leukemia (B-ALL) and LBCL. The primary end points were manufacturing feasibility and safety with a secondary efficacy end point. Primary end points were met; 97% of products met protocol-specified dose and no dose-limiting toxicities occurred during dose escalation. In B-ALL ( n  = 17), 100% of patients responded with 88% minimal residual disease-negative complete remission (CR); in LBCL ( n  = 21), 62% of patients responded with 29% CR. Relapses were CD19 −/lo in 50% (5 out of 10) of patients with B-ALL and 29% (4 out of 14) of patients with LBCL but were not associated with CD22 −/lo disease. CD19/22-CAR products demonstrated reduced cytokine production when stimulated with CD22 versus CD19. Our results further implicate antigen loss as a major cause of CAR T cell resistance, highlight the challenge of engineering multi-specific CAR T cells with equivalent potency across targets and identify cytokine production as an important quality indicator for CAR T cell potency. Bispecific CAR T cells targeting CD19 and CD22 exhibit clinical activity and low toxicity in patients with large B cell lymphoma and B cell acute lymphoblastic leukemia, with relapses associated with loss of CD19 but not CD22.

Cancer immunotherapies have unique toxicities. Establishment of grading scales and standardized grade-based treatment algorithms for toxicity syndromes can improve the safety of these treatments, as observed for cytokine release syndrome (CRS) and immune effector cell associated neurotoxicity syndrome (ICANS) in patients with B cell malignancies treated with chimeric antigen receptor (CAR) T cell therapy. We have observed a toxicity syndrome, distinct from CRS and ICANS, in patients treated with cell therapies for tumors in the central nervous system (CNS), which we term tumor inflammation-associated neurotoxicity (TIAN). Encompassing the concept of ‘pseudoprogression,’ but broader than inflammation-induced edema alone, TIAN is relevant not only to cellular therapies, but also to other immunotherapies for CNS tumors. To facilitate the safe administration of cell therapies for patients with CNS tumors, we define TIAN, propose a toxicity grading scale for TIAN syndrome and discuss the potential management of this entity, with the goal of standardizing both reporting and management. The authors describe a localized toxicity syndrome that is associated with immunotherapy treatment for CNS tumors and propose a new grading scale—with the goal of promoting research and standardizing both reporting and management.

A form of Leber's congenital amaurosis is caused by mutant RPE65 , a critical component of the visual cycle. Two early clinical trials to assess subretinal injection of a viral vector containing RPE65 in young adults with advanced retinal degeneration show that this approach is generally safe in the short term, although one group reported an adverse event: macular hole. The authors observed improvement in some measures of visual function. Two early clinical trials to assess subretinal injection of a viral vector containing RPE65 in young adults with advanced retinal degeneration show that this approach is generally safe in the short term, although one group reported an adverse event: macular hole. The authors observed improvement in some measures of visual function. Leber's congenital amaurosis is a term used to describe a group of recessively inherited, severe, infantile-onset rod–cone dystrophies. 1 Mutation of one of several genes, including RPE65 , causes disease that involves impaired vision from birth 2 , 3 and typically progresses to blindness in the third decade of life. There is no effective treatment. RPE65 is expressed in the retinal pigment epithelium and encodes a 65-kD protein that is a key component of the visual cycle, 1 , 4 – 8 a biochemical pathway that regenerates the visual pigment after exposure to light. 9 – 14 A lack of functional RPE65 results in deficiency of 11- cis . . .