MAP1B rescues LRRK2 mutant-mediated cytotoxicity

Leucine-rich repeat kinase 2 (LRRK2) mutations are the most common cause of dominant and sporadic Parkinson’s disease (PD), a common neurodegenerative disorder. Yeast-two-hybrid screening using human LRRK2 kinase domain as bait identified microtubule associated protein 1B (MAP1B) as a LRRK2 interactor. The interacting domains were LRRK2 kinase and the light chain portion of MAP1B (LC1). LRRK2 + LC1 interaction resulted in LRRK2 kinase inhibition. LRRK2 mutants (R1441C, G2019S and I2020T) exhibited decreased endogenous LC1 expression and its co-expression with LC1 rescued LRRK2 mutant-mediated toxicity. This study presented the first data on the effects of LRRK2 + LC1 interaction and also suggested that LCI possibly rescued LRRK2 mutant-induced cytotoxicity by inhibiting LRRK2 kinase activity. Compounds that upregulate LC1 expression may therefore hold therapeutic potential for LRRK2-linked diseases

California's Early Coverage Expansion under the Affordable Care Act: A County-Level Analysis

Objective: To assess the coverage effects of California's 2011 Low-Income Health Program (LIHP), enacted as an “early expansion” under the Affordable Care Act (ACA), and to demonstrate the feasibility of using Census data to measure county-level coverage changes. Data Sources/Study Setting: 2008–2012 American Community Survey (ACS). The sample contained California adults ages 19–64 years (n = 237,876) and children 0–18 years (n = 113,159) with incomes below 200 percent of the federal poverty level. Study Design: Differences-in-differences analysis comparing public coverage, private insurance, and the uninsured rate in counties that expanded the LIHP in 2011 versus California counties not expanding during this time. Additional analyses tested for heterogeneous impacts of the LIHP and spillover effects on children. Principal Findings: Compared to nonexpansion counties, public coverage for adults increased by 1.8 percentage points (p = .02) in expanding counties, while the uninsured rate declined by 2.1 percentage points (p = .01). There was no significant change in private coverage. Public coverage gains were largest for Latinos and those with limited English proficiency. The expansion produced a positive spillover effect on children's Medicaid enrollment. Conclusions: California's 2011 expansion produced significant increases in public coverage for low-income individuals, particularly Latinos. Substate coverage analyses with the ACS can add valuable detail to future assessments of the ACA

Eye size and shape in newborn children and their relation to axial length and refraction at 3 years

10.1111/opo.12212Ophthalmic and Physiological Optics354414-423GUSTO (Growing up towards Healthy Outcomes

Mapping genetic determinants of the cell-culture growth phenotype of enterovirus 71

Enterovirus 71 (EV71) is a member of the species Human enterovirus A within the family Picornaviridae and is a major causative agent of epidemics of hand, foot and mouth disease associated with severe neurological disease. Three EV71 genogroups, designated A, B and C, have been identified, with 75–84 % nucleotide sequence similarity between them. Two strains, EV71-26M (genogroup B) and EV71-6F (genogroup C), were found to have distinct cell-culture growth (26M, rapid; 6F, slow) and plaque-formation (26M, large; 6F, small) phenotypes. To identify the genome regions responsible for the growth phenotypes of the two strains, a series of chimeric viruses was constructed by exchanging the 5′ untranslated region (UTR), P1 structural protein or P2/P3 non-structural protein gene regions plus the 3′UTR using infectious cDNA clones of both virus strains. Analysis of reciprocal virus chimeras revealed that the 5′UTRs of both strains were compatible, but not responsible for the observed phenotypes. Introduction of the EV71-6F P1 region into the EV71-26M clone resulted in a small-plaque and slow-growth phenotype similar to that of EV71-6F, whereas the reciprocal chimera displayed intermediate-growth and intermediate-sized plaque phenotypes. Introduction of the EV71-26M P2–P3–3′UTR regions into the EV71-6F clone resulted in a large-plaque and rapid-growth phenotype identical to that of strain EV71-26M, whereas the reciprocal chimera retained the background strain large-plaque phenotype. These results indicate that, although both the P1 and P2–P3–3′UTR genome regions influence the EV71 growth phenotype in cell culture, phenotype expression is dependent on specific genome-segment combinations and is not reciprocal

The association of female reproductive factors with glaucoma and related traits: A systematic review

TOPIC: This systematic review summarizes the existing evidence for the association between female reproductive factors (age at menarche, parity, oral contraceptive (OC) use, age at menopause, and postmenopausal hormone (PMH) use) and intraocular pressure (IOP) or open-angle glaucoma (OAG). CLINICAL RELEVANCE: Understanding the association between female reproductive factors and glaucoma may shed light on disease pathogenesis and aid clinical prediction and personalized treatment strategies. Importantly, some factors are modifiable which may lead to new therapies. METHODS: Two reviewers independently extracted articles in Medline, Embase, Cochrane Database of Systematic Reviews, and Cochrane Central Register of Controlled Trials databases to identify relevant studies. Eligibility criteria included studies with human subjects over 18 years of age; a measured exposure of at least one of the following: age at menarche, parity, OC use, age at menopause, PMH use; a measured outcome of either IOP or OAG; a cohort, case-control, cross-sectional or randomized-controlled trial design; and a reported measure of association including hazard, risk or odds ratio or mean difference with associated confidence intervals. RESULTS: We included a total of 27 studies. Substantial differences in study design, exposure and treatment levels, treatment duration and variable reporting precluded meaningful quantitative synthesis of the identified studies. Overall, relatively consistent associations between PMH use and lower IOP were identified. With respect to OAG, estrogen-only PMH use may be associated with lower OAG risk and this association may be modified by race. No significant associations were found with combined estrogen + progesterone PMH use. No strong associations between parity, or age at menarche and glaucoma were found, but a younger age at menopause was associated with increased glaucoma risk, and adverse associations were identified with longer duration of OC use, though no overall association with OC use was found. CONCLUSION: The association between PMH use and lower IOP/OAG risk is a potentially clinically relevant and modifiable risk factor and should be investigated further, although this needs to be interpreted in the context of a high risk of bias across included studies. There is a need for future research examining associations with IOP specifically, and how the relationship between genetic factors and OAG risk may be influenced by female reproductive factors

Relative contribution of risk factors for early-onset myopia in young Asian children

10.1167/iovs.15-16577Clinical and Epidemiologic Research56138101-8107GUSTO (Growing up towards Healthy Outcomes

Axial length/corneal radius of curvature ratio and myopia in 3-year-old children

10.1167/tvst.5.1.5Translational Vision Science & Technology511-6GUSTO (Growing up towards Healthy Outcomes

Relationships between retinal layer thickness and brain volumes in the UK Biobank cohort

Background and purpose: Current methods to diagnose neurodegenerative diseases are costly and invasive. Retinal neuroanatomy may be a biomarker for more neurodegenerative processes and can be quantified in vivo using optical coherence tomography (OCT), which is inexpensive and noninvasive. We examined the association of neuroretinal morphology with brain MRI image-derived phenotypes (IDPs) in a large cohort of healthy older people. Methods: UK Biobank participants aged 40 to 69 years old underwent comprehensive examinations including ophthalmic and brain imaging assessments. Macular retinal nerve fibre layer (mRNFL), macular ganglion cell-inner plexiform layer (mGCIPL), macular ganglion cell complex (mGCC) and total macular thicknesses were obtained from OCT. Magnetic resonance imaging (MRI) IDPs assessed included total brain, grey matter, white matter and hippocampal volume. Multivariable linear regression models were used to evaluate associations between retinal layers thickness and brain MRI IDPs, adjusting for demographic factors and vascular risk factors. Results: A total of 2131 participants (mean age 55 years; 51% women) with both gradable OCT images and brain imaging assessments were included. In multivariable regression analysis, thinner mGCIPL, mGCC and total macular thickness were all significantly associated with smaller total brain (p < 0.001), grey matter and white matter volume (p < 0.01), and grey matter volume in the occipital pole (p < 0.05). Thinner mGCC and total macular thicknesses were associated with smaller hippocampal volume (p < 0.02). No association was found between mRNFL and the MRI IDPs. Conclusions: Markers of retinal neurodegeneration are associated with smaller brain volumes. Our findings suggest that retinal structure may be a biomarker providing information about important brain structure in healthy older adults

Alcohol, intraocular pressure and open-angle glaucoma: A systematic review and meta-analysis

TOPIC: This systematic review and meta-analysis summarizes the existing evidence for the association of alcohol use with intraocular pressure (IOP) and open-angle glaucoma (OAG). CLINICAL RELEVANCE: Understanding and quantifying these associations may aid clinical guidelines or treatment strategies and shed light on disease pathogenesis. The role of alcohol, a modifiable factor, in determining IOP and OAG risk may also be of interest from an individual or public health perspective. METHODS: The study protocol was pre-registered in the Open Science Framework Registries (https://osf.io/z7yeg). Eligible articles (as of 14 May 2021) from three databases (PubMed, Embase, Scopus) were independently screened and quality assessed by two reviewers. All case-control, cross-sectional and cohort studies reporting a quantitative effect estimate and 95% confidence interval (CI) for the association between alcohol use and either IOP or OAG were included. The evidence for the associations with both IOP and OAG were qualitatively summarized. Effect estimates for the association with OAG were pooled using random effects meta-analysis. Studies not meeting formal inclusion criteria for systematic review, but with pertinent results, were also appraised and discussed. Certainty of evidence was assessed using the GRADE framework. RESULTS: Thirty four studies were included in the systematic review. Evidence from 10 studies reporting an association with IOP suggest that habitual alcohol use is associated with higher IOP and prevalence of ocular hypertension (IOP >21mmHg), although absolute effect sizes were small. Eleven of 26 studies, comprising 173 058 participants, that tested for an association with OAG met inclusion criteria for meta-analysis. Pooled effect estimates indicated a positive association between any use of alcohol and OAG (1.18; 95% CI, 1.02-1.36; p=0.03; I2=40.5%), with similar estimates for both prevalent and incident OAG. The overall GRADE certainty of evidence was very low. CONCLUSION: While this meta-analysis suggests a harmful association between alcohol use and OAG, our results should be interpreted cautiously given the weakness and heterogeneity of the underlying evidence base, the small absolute effect size and the borderline statistical significance. Nonetheless, these findings may be clinically relevant and future research should focus on improving the quality of evidence

Calcium Channel Blocker Use and Associated Glaucoma and Related Traits Among UK Biobank Participants

IMPORTANCE: Calcium channel blocker (CCB) use has been associated with an increased risk of glaucoma in exploratory studies. OBJECTIVE: To examine the association of systemic CCB use with glaucoma and related traits among UK Biobank participants. DESIGN, SETTING, AND PARTICIPANTS: This population-based cross-sectional study included UK Biobank participants with complete data (2006-2010) for analysis of glaucoma status, intraocular pressure (IOP), and optical coherence tomography (OCT)-derived inner retinal layer thicknesses. Data analysis was conducted in January 2023. EXPOSURE: Calcium channel blocker use was assessed in a baseline touchscreen questionnaire and confirmed during an interview led by a trained nurse. MAIN OUTCOMES AND MEASURES: The primary outcome measures included glaucoma status, corneal-compensated IOP, and 2 OCT-derived inner retinal thickness parameters (macular retinal nerve fiber layer [mRNFL] and macular ganglion cell-inner plexiform layer [mGCIPL] thicknesses). We performed logistic regression and linear regression analyses to test for associations with glaucoma status and IOP and OCT-derived inner retinal thickness parameters, respectively. RESULTS: This study included 427 480 adults. Their median age was 58 (IQR, 50-63) years, and more than half (54.1%) were women. There were 33 175 CCB users (7.8%). Participants who had complete data for glaucoma status (n = 427 480), IOP (n = 97 100), and OCT-derived inner retinal layer thicknesses (n = 41 023) were eligible for respective analyses. After adjustment for key sociodemographic, medical, anthropometric, and lifestyle factors, use of CCBs (but not other antihypertensive agents) was associated with greater odds of glaucoma (odds ratio [OR], 1.39 [95% CI, 1.14 to 1.69]; P = .001). Calcium channel blocker use was also associated with thinner mGCIPL (-0.34 μm [95% CI, -0.54 to -0.15 μm]; P = .001) and mRNFL (-0.16 μm [95% CI, -0.30 to -0.02 μm]; P = .03) thicknesses but not IOP (-0.01 mm Hg [95% CI, -0.09 to 0.07 mm Hg]; P = .84). CONCLUSIONS AND RELEVANCE: In this study, an adverse association between CCB use and glaucoma was observed, with CCB users having, on average, 39% higher odds of glaucoma. Calcium channel blocker use was also associated with thinner mGCIPL and mRNFL thicknesses, providing a structural basis that supports the association with glaucoma. The lack of association of CCB use with IOP suggests that an IOP-independent mechanism of glaucomatous neurodegeneration may be involved. Although a causal relationship has not been established, CCB replacement or withdrawal may be considered should glaucoma progress despite optimal care