Incidence of visual impairment in Canada: the Canadian Longitudinal Study on Aging.

OBJECTIVE: Determine the 3-year incidence of visual impairment (VI) in Canada and its risk factors. DESIGN: Prospective 3-year cohort study PARTICIPANTS: Data from 23 973 adults taking part in the Canadian Longitudinal Study on Aging Comprehensive Cohort baseline and 3-year follow-up exams were included. METHODS: Inclusion criteria were 45 to 85 years of age, community-dwelling, and living near one of the 11 data collection sites across 7 Canadian provinces. Presenting binocular visual acuity was measured using the Early Treatment of Diabetic Retinopathy study chart. Incidence of VI was defined as the development at follow-up of visual acuity worse than 20/40 in those with acuity better than or equal to 20/40 at baseline. RESULTS: 3.88% (95% confidence interval [CI] 3.61-4.17) of Canadian adults developed VI over a 3-year period. There was a high degree of variability in the incidence between Canadian provinces with a low of 1.42% in Manitoba and a high of 7.33% in Nova Scotia. Uncorrected refractive error was the leading cause. Risk factors for incident VI included older age (odds ratio [OR] = 1.07, 95% CI 1.06-1.07), Black race (OR = 2.64, 95% CI 1.36-5.14), lower household income (OR = 1.73 for those making less than $20,000 per year, 95% CI 1.24-2.40), current smoker (OR = 1.78, 95% CI 1.37-2.32), and province. CONCLUSION: The incidence of visual impairment is common in older Canadian adults, varies markedly between provinces, and is largely owing to treatable causes. Risk factors for VI suggest subgroups that may benefit from interventions to improve access to eye care.

Vision, Eye Disease, and the Onset of Balance Problems: The Canadian Longitudinal Study on Aging.

PURPOSE: To understand the relationship between visual impairment, self-reported eye disease, and the onset of balance problems. DESIGN: Population-based prospective cohort study. METHODS: Baseline and 3-year follow-up data were used from the Canadian Longitudinal Study on Aging. The Comprehensive Cohort included 30,097 adults aged 45 to 85 years recruited from 11 sites across 7 provinces. Balance was measured using the 1-leg balance test. Those who could not stand on 1 leg for at least 60 seconds failed the balance test. Presenting visual acuity was measured using the Early Treatment of Diabetic Retinopathy Study chart. Participants were asked about a previous diagnosis of cataract, macular degeneration, or glaucoma. Logistic regression was used. RESULTS: Of the 12,158 people who could stand for 60 seconds on 1 leg at baseline, 18% were unable to do the same 3 years later. For each line worse of visual acuity, there was a 15% higher odds of failing the balance test at follow-up (odds ratio [OR] = 1.15, 95% confidence interval [CI] 1.10, 1.20) after adjustment. Those with a report of a former (OR = 1.59, 95% CI 1.17, 2.16) or current cataract (OR = 1.31, 95% CI 1.01, 1.68) were more likely to fail the test at follow-up. Age-related macular degeneration and glaucoma were not associated with failure on the balance test. CONCLUSION: These data provide longitudinal evidence that vision loss increases the odds of balance problems over a 3-year period. Efforts to prevent avoidable vision loss are needed, as are efforts to improve the balance of visually impaired people.

Liposome Imaging in Optically Cleared Tissues.

Three-dimensional (3D) optical microscopy can be used to understand and improve the delivery of nanomedicine. However, this approach cannot be performed for analyzing liposomes in tissues because the processing step to make tissues transparent for imaging typically removes the lipids. Here, we developed a tag, termed REMNANT, that enables 3D imaging of organic materials in biological tissues. We demonstrated the utility of this tag for the 3D mapping of liposomes in intact tissues. We also showed that the tag is able to monitor the release of entrapped therapeutic agents. We found that liposomes release their cargo >100-fold faster in tissues in vivo than in conventional in vitro assays. This allowed us to design a liposomal formulation with enhanced ability to kill tumor associated macrophages. Our development opens up new opportunities for studying the chemical properties and pharmacodynamics of administered organic materials in an intact biological environment. This approach provides insight into the in vivo behavior of degradable materials, where the newly discovered information can guide the engineering of the next generation of imaging and therapeutic agents.

Characterization of Redox-Responsive LXR-Activating Nanoparticle Formulations in Primary Mouse Macrophages.

Activation of the transcription factor liver X receptor (LXR) has beneficial effects on macrophage lipid metabolism and inflammation, making it a potential candidate for therapeutic targeting in cardiometabolic disease. While small molecule delivery via nanomedicine has promising applications for a number of chronic diseases, questions remain as to how nanoparticle formulation might be tailored to suit different tissue microenvironments and aid in drug delivery. In the current study, we aimed to compare the in vitro drug delivering capability of three nanoparticle (NP) formulations encapsulating the LXR activator, GW-3965. We observed little difference in the base characteristics of standard PLGA-PEG NP when compared to two redox-active polymeric NP formulations, which we called redox-responsive (RR)1 and RR2. Moreover, we also observed similar uptake of these NP into primary mouse macrophages. We used the transcript and protein expression of the cholesterol efflux protein and LXR target ATP-binding cassette A1 (ABCA1) as a readout of GW-3956-induced LXR activation. Following an initial acute uptake period that was meant to mimic circulating exposure in vivo, we determined that although the induction of transcript expression was similar between NPs, treatment with the redox-sensitive RR1 NPs resulted in a higher level of ABCA1 protein. Our results suggest that NP formulations responsive to cellular cues may be an effective tool for targeted and disease-specific drug release.

Delivery of MicroRNAs by Chitosan Nanoparticles to Functionally Alter Macrophage Cholesterol Efflux in Vitro and in Vivo.

The prevention and treatment of cardiovascular diseases (CVD) has largely focused on lowering circulating LDL cholesterol, yet a significant burden of atherosclerotic disease remains even when LDL is low. Recently, microRNAs (miRNAs) have emerged as exciting therapeutic targets for cardiovascular disease. miRNAs are small noncoding RNAs that post-transcriptionally regulate gene expression by degradation or translational inhibition of target mRNAs. A number of miRNAs have been found to modulate all stages of atherosclerosis, particularly those that promote the efflux of excess cholesterol from lipid-laden macrophages in the vessel wall to the liver. However, one of the major challenges of miRNA-based therapy is to achieve tissue-specific, efficient, and safe delivery of miRNAs in vivo. We sought to develop chitosan nanoparticles (chNPs) that can deliver functional miRNA mimics to macrophages and to determine if these nanoparticles can alter cholesterol efflux and reverse cholesterol transport in vivo. We developed chNPs with a size range of 150-200 nm via the ionic gelation method using tripolyphosphate (TPP) as a cross-linker. In this method, negatively charged miRNAs were encapsulated in the nanoparticles by ionic interactions with polymeric components. We then optimized the efficiency of intracellular delivery of different formulations of chitosan/TPP/miRNA to mouse macrophages. Using a well-defined miRNA with roles in macrophage cholesterol metabolism, we tested whether chNPs could deliver functional miRNAs to macrophages. We find chNPs can transfer exogenous miR-33 to naïve macrophages and reduce the expression of ABCA1, a potent miR-33 target gene, both in vitro and in vivo, confirming that miRNAs delivered via nanoparticles can escape the endosomal system and function in the RISC complex. Because miR-33 and ABCA1 play a key role in regulating the efflux of cholesterol from macrophages, we also confirmed that macrophages treated with miR-33-loaded chNPs exhibited reduced cholesterol efflux to apolipoprotein A1, further confirming functional delivery of the miRNA. In vivo, mice treated with miR33-chNPs showed decreased reverse cholesterol transport (RCT) to the plasma, liver, and feces. In contrast, when efflux-promoting miRNAs were delivered via chNPs, ABCA1 expression and cholesterol efflux into the RCT pathway were improved. Over all, miRNAs can be efficiently delivered to macrophages via nanoparticles, where they can function to regulate ABCA1 expression and cholesterol efflux, suggesting that these miRNA nanoparticles can be used in vivo to target atherosclerotic lesions.