Rodent genetically modified models of glaucoma.

Glaucoma, one of the leading causes of irreversible blindness worldwide, is a complex and heterogenous disease. While environmental factors are important, it is well-recognized that the disease has a strong heritable component. With the advent of large-cohort genome wide association studies, a myriad of genetic risk loci has been linked to different forms of glaucoma. Animal models have been an indispensable tool in characterizing these loci, especially if they lie within coding regions in the genome. Not only do these models connect genotype to phenotype, advancing our understanding of glaucoma pathogenesis in the process, they also have valuable utility as a platform for the pre-clinical testing of potential therapies. In this review, we will outline genetic models used for studying the major forms of glaucoma, including primary open angle glaucoma, normal tension glaucoma, primary angle closure glaucoma, pigmentary glaucoma, pseudoexfoliation glaucoma, and early onset glaucoma, including congenital and developmental glaucoma, and how studying these models have helped shed light on human glaucoma.

Association of peripheral anterior synechiae with anterior segment parameters in eyes with primary angle closure glaucoma.

To investigate the association of peripheral anterior synechiae (PAS) with intraocular pressure (IOP) and anterior-segment parameters in subjects with primary angle-closure glaucoma (PACG). A total of 267 subjects with PACG were recruited and underwent gonioscopy and anterior-segment optical coherence tomography (ASOCT). Customized software was used to measure ASOCT parameters, including angle opening distance (AOD750) and trabecular-iris-space-area (TISA750) at 750 µm from the scleral spur, anterior chamber depth, width, area and volume (ACD, ACW, ACA, ACV), iris thickness (IT750), iris area (IAREA), and lens vault (LV). Presenting IOP was defined as the first IOP reading before the initiation of IOP-lowering treatment. The mean age of the 267 subjects was 67.0 ± 8.9 years, 140 (52.4%) were male, and 246 (92.1%) were of Chinese ethnicity. PAS was present in 122 (45.7%) subjects, and was most frequently found in the superior quadrant (79.5%). Subjects with PAS had greater presenting IOP (28.7 ± 12.9 vs 22.4 ± 9.7 mmHg, p < 0.001), narrower AOD750 (p < 0.001), smaller TISA750 (p < 0.001), ACD (p = 0.04), ACA (p = 0.02), ACV (p = 0.01) and larger LV (p = 0.01) compared to PACG eyes without PAS. No significant differences were noted for iris parameters. A multivariate logistic regression analysis showed that higher presenting IOP (ß = 0.20, p < 0.001), worse visual field mean deviation (ß = - 0.20, p = 0.01) and narrower AOD750 (ß = - 0.25, p = 0.03) were the only parameters that significantly correlated with the extent of PAS in clock hours. Almost one-half of the subjects with PACG demonstrated PAS; these eyes were associated with higher presenting IOP, smaller anterior segment dimensions and more severe disease.

Comparing the Safety and Efficacy of Phacogoniosynechialysis With Phacotrabeculectomy in the Management of Refractory Acute Primary Closure Angle Glaucoma With Cataract: A Multicenter Randomized Trial.

PRCIS: Combined phacoemulsification-goniosynechialysis (phaco-GSL) and unaugmented phacotrabeculectomy were both found to be effective in treating eyes with significant cataract and medically unresponsive acute primary angle closure glaucoma (PACG). Phaco-GSL seemed to be safer, with fewer surgical complications, and achieved better visual acuity than phacotrabeculectomy. OBJECTIVES: To compare the results of combined phaco-GSL with unaugmented phacotrabeculectomy in the management of eyes with medically unresponsive acute PACG and cataract. PARTICIPANTS AND RESEARCH METHODS: This was a prospective randomized controlled trial involving patients with significant cataract and acute PACG who were not responsive to maximal medical therapy. Three ophthalmic centers in Hanoi, Vietnam, participated in this trial. Study subjects were randomized into 2 groups: phaco-GSL or phacotrabeculectomy. Of note, mitomycin-C or 5-fluorouracil were not used during trabeculectomy, but postoperative bleb needling with 5-fluorouracil injection(s) was allowed. The primary outcome of the study was the rate of postoperative surgical complications in the first 3 months after surgery. The secondary outcome, determined at 1 year, assessed whether treatment was completely successful [defined as intraocular pressure (IOP)<21 mm Hg without IOP-lowering drops], or partially successful (IOP<21 mm Hg with IOP-lowering drops). Treatment failure was defined as IOP≥21 mm Hg with maximal IOP-lowering drops. RESULTS: In total, 79 eyes from 79 patients (62 females, 17 males) were recruited (42 and 37 eyes in the phaco-GSL and phacotrabeculectomy groups, respectively). There were no statistically significant differences between the 2 groups at baseline in terms of age, visual acuity, IOP, anterior angle width, or preoperative ultrasound biomicroscopy index. Postoperative complications in the first 3 months were seen more frequently in the phacotrabeculectomy group (62.2%) than in the phaco-GSL group (14.3%, P<0.01). At 1 year postsurgery, treatment was 100% successful in both groups, with no difference in the mean IOP (15.38±3.42 vs. 15.72±4.47 mm Hg). The visual field index improved significantly following surgery in both groups, but there was also no significant difference between the 2 groups. However, there was a significant difference in the best corrected visual acuity at 1 year, with patients in the phaco-GSL group achieving better vision (0.45±0.21 logMAR in the phaco-GSL group vs. 0.64±0.27 logMAR in the phacotrabeculectomy group, P=0.04). The mean angle width was also significantly larger in the phaco-GSL group than the phacotrabeculectomy group (2.34±0.33 vs. 1.25±0.41 Shaffer degrees). Similarly, on ultrasound biomicroscopy, the anterior chamber was deeper after 12 months (2.87±0.28 to 2.48±0.33 mm), and the mean trabecular-iris angle area was wider at 12 months (21.88±7.07 vs. 14.95±4.39 degrees) in the phaco-GSL than the phacotrabeculectomy group. CONCLUSIONS: Phaco-GSL and phacotrabeculectomy were both effective in treating medically unresponsive cases of acute PACG with cataracts. However, phaco-GSL showed better visual outcomes, wider drainage angles postsurgery, and fewer complications than phacotrabeculectomy.

Mitochondria maintain controlled activation state of epithelial-resident T lymphocytes.

Epithelial-resident T lymphocytes, such as intraepithelial lymphocytes (IELs) located at the intestinal barrier, can offer swift protection against invading pathogens. Lymphocyte activation is strictly regulated because of its potential harmful nature and metabolic cost, and most lymphocytes are maintained in a quiescent state. However, IELs are kept in a heightened state of activation resembling effector T cells but without cytokine production or clonal proliferation. We show that this controlled activation state correlates with alterations in the IEL mitochondrial membrane, especially the cardiolipin composition. Upon inflammation, the cardiolipin composition is altered to support IEL proliferation and effector function. Furthermore, we show that cardiolipin makeup can particularly restrict swift IEL proliferation and effector functions, reducing microbial containment capability. These findings uncover an alternative mechanism to control cellular activity, special to epithelial-resident T cells, and a novel role for mitochondria, maintaining cells in a metabolically poised state while enabling rapid progression to full functionality.

Inflammation-induced formation of fat-associated lymphoid clusters.

Fat-associated lymphoid clusters (FALCs) are a type of lymphoid tissue associated with visceral fat. Here we found that the distribution of FALCs was heterogeneous, with the pericardium containing large numbers of these clusters. FALCs contributed to the retention of B-1 cells in the peritoneal cavity through high expression of the chemokine CXCL13, and they supported B cell proliferation and germinal center differentiation during peritoneal immunological challenges. FALC formation was induced by inflammation, which triggered the recruitment of myeloid cells that expressed tumor-necrosis factor (TNF) necessary for signaling via the TNF receptors in stromal cells. Natural killer T cells (NKT cells) restricted by the antigen-presenting molecule CD1d were likewise required for the inducible formation of FALCs. Thus, FALCs supported and coordinated the activation of innate B cells and T cells during serosal immune responses.