Future directions of glaucoma treatment: emerging gene, neuroprotection, nanomedicine, stem cell, and vascular therapies.

PURPOSE OF REVIEW: The aim of this article is to summarize current research on novel gene, stem cell, neuroprotective, nanomedicine, and vascular therapies for glaucoma. RECENT FINDINGS: Gene therapy using viral vectors and siRNA have been shown to reduce intraocular pressure by altering outflow and production of aqueous humor, to reduce postsurgical fibrosis with few adverse effects, and to increase retinal ganglion cell (RGC) survival in animal studies. Stem cells may treat glaucoma by replacing or stimulating proliferation of trabecular meshwork cells, thus restoring outflow facility. Stem cells can also serve a neuroprotective effect by differentiating into RGCs or preventing RGC loss via secretion of growth factors. Other developing neuroprotective glaucoma treatments which can prevent RGC death include nicotinamide, the NT-501 implant which secretes ciliary neurotrophic factor, and a Fas-L inhibitor which are now being tested in clinical trials. Recent studies on vascular therapy for glaucoma have focused on the ability of Rho Kinase inhibitors and dronabinol to increase ocular blood flow. SUMMARY: Many novel stem cell, gene, neuroprotective, nanomedicine, and vascular therapies have shown promise in preclinical studies, but further clinical trials are needed to demonstrate safety and efficacy in human glaucomatous eyes. Although likely many years off, future glaucoma therapy may take a multifaceted approach.

The Association of Cardiovascular and Neurological Comorbidities in Geriatric Patients Sustaining Ocular Trauma.

Purpose: Falls are associated with ocular trauma in the elderly. However, it is unlikely for a fall to cause ocular injury unless there is a disruption in the protective maneuvers that shield the face. We suspect ocular injury may be an early indicator of systemic or neurologic degeneration. This study investigates the 5-year incidence of cardiovascular and neurodegenerative diseases in older patients who sustained ocular or periorbital injuries. Patients and Methods: This was a retrospective cohort study. The study population included 141 patients over the age of 65 who sustained trauma to the eye, orbit, or eyelid between April 2011 and June 2016. The control population included 141 patients with a similar range of comorbidities who received cataract surgery during the same period. The study measured new diagnoses of various disorders during the 5-year period following presentation. Results: There were a total of 180 females and 102 males in the study. The mean ages of the control and subject group were 76 and 81.8, respectively. Of our twelve tested comorbidity types, patients that suffered a periocular trauma were more likely to develop heart failure (p=0.00244), dementia (p=0.00002), Alzheimer's disease (p=0.00087), and vascular disease (p=0.00037). Conclusion: Geriatric patients who sustained ocular and periocular injuries had a greater incidence of heart failure, dementia, Alzheimer's disease, and atherosclerosis diagnoses in the 5-year period following injury. The findings of this study suggest that periocular trauma may be an early indicator of underlying degenerative or systemic disease. Ophthalmologists should ensure proper primary care follow-up in conjunction with recovery from injury.

Comparison of Time-to-Surgery and Outcomes in Transferred Vs Non-Transferred Open Globe Injuries.

Purpose: It is widely accepted in the field of ophthalmology that closure of open globes within 24 hours of the injury results in the best visual outcomes. This study investigates the time-to-surgery and visual outcomes of open globe injury patients in North Carolina that were transferred to our institution before receiving surgical intervention as compared to those that were not transferred. Patients and methods: This is a retrospective cohort study using data from UNC Hospitals trauma registry. Demographics, time of injury, final clinical outcomes, time to surgical intervention, and transfer history were extracted and analyzed. The study population includes open globe injury patients of all ages that were seen and treated at our institution from 2005 to 2020. Patients were divided based on transfer history. The transfer group consisted of patients who were transferred from an outside hospital to our tertiary care facility for surgical treatment. The non-transfer group consisted of patients who arrived at our tertiary care facility directly after injury. Results: In total, 238 open globe injuries were evaluated. Of those, 197 were transferred and 41 were not transferred. Compared to non-transfer patients, transfer patients had longer delays between injury and surgery, between presentation at the initial ED and surgery, and between injury and arrival at the tertiary care center. On average, the delay between injury and surgical intervention was 3 hours and 51 minutes longer for transfer patients compared to non-transfer patients. Eight patients in the transfer group were delayed >24 hours due to inter-hospital transfer. Additionally, transfer patients on average suffered from poorer final visual acuities, with an average final visual acuity of 1.84 logMAR in the transfer group and 1.35 logMAR in the non-transfer group. Conclusion: Our study found that inter-hospital transfer leads to significant delays in primary closure of open globe injuries. Injuries that were transferred to a tertiary care center before receiving surgical intervention on average resulted in worse final visual acuities.

Citrobacter rodentium-induced colitis: A robust model to study mucosal immune responses in the gut.

Citrobacter rodentium is a natural mouse pathogen which reproducibly infects mice and causes intestinal disease. The C. rodentium model of infection is very useful for investigating host-pathogen immune interactions in the gut, and can also be used to understand the pathogenesis of several important human intestinal disorders, including Crohn's disease, ulcerative colitis, dysbiosis and colon tumorigenesis. Both innate and adaptive immune responses play a critical role in protection against C. rodentium. Here, we summarize the role of immune components in protection against C. rodentium and describe techniques for the analysis of innate and adaptive mucosal immune responses, including setting up the infection, analysis of colonic hyperplasia and bacterial dissemination, evaluation of antibody responses, and purification and analysis of intestinal epithelial and lymphoid cells.

Beneficial effect of probiotics in IBD: are peptidogycan and NOD2 the molecular key effectors?

Although the beneficial capacities of probiotics are more and more substantiated, their effects clearly depend on the strains used and their mechanisms of action remain poorly understood. Recent evidences have highlighted the potential role of cell-wall components in the anti-inflammatory capacity of selected lactobacilli. In this addendum, we summarize our recent results concerning the role of peptidoglycan (PGN) and NOD2 signaling in the regulation of intestinal inflammation. We showed that the protective effect of Lactobacillus PGN is strain-specific and linked to the induction of diverse immune regulatory pathways. Moreover the beneficial effect of Lactobacillus PGN correlated with the release of a specific muropeptide sensed by NOD2. These findings allow for a better understanding of how probiotic lactobacilli exert their beneficial effect and will help guide for more successful strain selection.

Anti-inflammatory capacity of selected lactobacilli in experimental colitis is driven by NOD2-mediated recognition of a specific peptidoglycan-derived muropeptide.

BACKGROUND AND AIMS: Inflammatory bowel disease (IBD) has been linked to a loss of tolerance towards the resident microflora. Therapeutic use of probiotics is known to be strain specific, but precise mechanisms remain unclear. The role of NOD2 signalling and the protective effect of Lactobacillus peptidoglycan (PGN) and derived muropeptides in experimental colitis were evaluated. METHODS: The anti-inflammatory capacity of lactobacilli and derived bacterial compounds was evaluated using the 2,4,6-trinitrobenzene sulfonic acid (TNBS) colitis model. The role of NOD2, MyD88 and interleukin 10 (IL-10) in this protection was studied using Nod2(-/-), MyD88(-/-) and Il10-deficient mice, while induction of regulatory dendritic cells (DCs) was monitored through the expansion of CD103(+) DCs in mesenteric lymph nodes or after adoptive transfer of bone marrow-derived DCs. The development of regulatory T cells was investigated by following the expansion of CD4(+)FoxP3(+) cells. High-performance liquid chromatography and mass spectrometry were used to analyse the PGN structural differences. RESULTS: The protective capacity of strain Lactobacillus salivarius Ls33 was correlated with a local IL-10 production and was abolished in Nod2-deficient mice. PGN purified from Ls33 rescued mice from colitis in an IL-10-dependent manner and favoured the development of CD103(+) DCs and CD4(+)Foxp3(+) regulatory T cells. In vitro Ls33 PGN induced IL-10-producing DCs able to achieve in vivo protection after adoptive transfer in a NOD2-dependent way. This protection was also correlated with an upregulation of the indoleamine 2,3-dioxygenase immunosuppressive pathway. The protective capacity was not obtained with PGN purified from a non-anti-inflammatory strain. Structural analysis of PGNs highlighted in Ls33 the presence of an additional muropeptide, M-tri-Lys. The synthesised ligand protected mice from colitis in a NOD2-dependent but MyD88-independent manner. CONCLUSIONS: The results indicated that PGN and derived muropeptides are active compounds in probiotic functionality and might represent a useful therapeutic strategy in IBD.