The direct actions of glucocorticoid hormones on protein turnover were studied in isolated soleus muscles. These steroids were found to decrease the rates of both protein synthesis and protein breakdown within 3 h and 4 h respectively. Synthetic steroids (e.g. dexamethasone) were found to be more potent than naturally secreted hormones (e.g. cortisol) in inducing these changes, but only at concentrations in vitro less than 10nm.
Four corticosteroid hormones were administered (5 mg/kg/day) to rats over 6 to 10 days. Both biochemical and microscopic techniques were employed to determine the influence of these corticosteroids on the fine structure and growth of five striated muscles. Throughout, dexamethasone and triamcinalone were more potent than prednisone or cortisone in influencing muscle growth. The corticosteroids' action on the heart was anabolic, increasing its RNA and protein content. In contrast, the same corticosteroids were catabolic against fast-twitch muscles (e.g., extensor digitorum longus), inducing appreciable atrophy. However, slow-twitch muscles (e.g., soleus) were more resistant to these hormones, exhibiting an intermediate response between that of the heart and fast-twitch muscles. Only minor morphological changes were found in both fast and slow muscles 10 days after the corticosteroid treatments. The hormones' atrophic effects on skeletal muscle primarily arose from the corticosteroid's ability to inhibit protein synthesis, via decreases in the muscles' ribosomal capacities. Whole-body protein synthesis was also suppressed by these corticosteroids, but to a lesser extent than in the whole skeletal musculature.
IMPORTANCE Advanced age-related macular degeneration (AMD) is a leading cause of blindness in Western countries. Causal, modifiable risk factors need to be identified to develop preventive measures for advanced AMD.OBJECTIVE To assess whether smoking, alcohol consumption, blood pressure, body mass index, and glycemic traits are associated with increased risk of advanced AMD. DESIGN, SETTING, PARTICIPANTSThis study used 2-sample mendelian randomization. Genetic instruments composed of variants associated with risk factors at genome-wide significance (P < 5 × 10 −8 ) were obtained from published genome-wide association studies. Summary-level statistics for these instruments were obtained for advanced AMD from the International AMD Genomics Consortium 2016 data set, which consisted of 16 144 individuals with AMD and 17 832 control individuals. Data were analyzed from July 2020 to September 2021.EXPOSURES Smoking initiation, smoking cessation, lifetime smoking, age at smoking initiation, alcoholic drinks per week, body mass index, systolic and diastolic blood pressure, type 2 diabetes, glycated hemoglobin, fasting glucose, and fasting insulin. MAIN OUTCOMES AND MEASURESAdvanced AMD and its subtypes, geographic atrophy (GA), and neovascular AMD.RESULTS A 1-SD increase in logodds of genetically predicted smoking initiation was associated with higher risk of advanced AMD (odds ratio [OR], 1.26; 95% CI, 1.13-1.40; P < .001), while a 1-SD increase in logodds of genetically predicted smoking cessation (former vs current smoking) was associated with lower risk of advanced AMD (OR, 0.66; 95% CI, 0.50-0.87; P = .003). Genetically predicted increased lifetime smoking was associated with increased risk of advanced AMD (OR per 1-SD increase in lifetime smoking behavior, 1.32; 95% CI, 1.09-1.59; P = .004). Genetically predicted alcohol consumption was associated with higher risk of GA (OR per 1-SD increase of log-transformed alcoholic drinks per week, 2.70; 95% CI, 1.48-4.94; P = .001). There was insufficient evidence to suggest that genetically predicted blood pressure, body mass index, and glycemic traits were associated with advanced AMD. CONCLUSIONS AND RELEVANCEThis study provides genetic evidence that increased alcohol intake may be a causal risk factor for GA. As there are currently no known treatments for GA, this finding has important public health implications. These results also support previous observational studies associating smoking behavior with risk of advanced AMD, thus reinforcing existing public health messages regarding the risk of blindness associated with smoking.
PurposeAge-related macular degeneration is a common form of vision loss affecting older adults. The etiology of AMD is multifactorial and is influenced by environmental and genetic risk factors. In this study, we examine how 19 common risk variants contribute to drusen progression, a hallmark of AMD pathogenesis.MethodsExome chip data was made available through the International AMD Genomics Consortium (IAMDGC). Drusen quantification was carried out with color fundus photographs using an automated drusen detection and quantification algorithm. A genetic risk score (GRS) was calculated per subject by summing risk allele counts at 19 common genetic risk variants weighted by their respective effect sizes. Pathway analysis of drusen progression was carried out with the software package Pathway Analysis by Randomization Incorporating Structure.ResultsWe observed significant correlation with drusen baseline area and the GRS in the age-related eye disease study (AREDS) dataset (ρ = 0.175, P = 0.006). Measures of association were not statistically significant between drusen progression and the GRS (P = 0.54). Pathway analysis revealed the cell adhesion molecules pathway as the most highly significant pathway associated with drusen progression (corrected P = 0.02).ConclusionsIn this study, we explored the potential influence of known common AMD genetic risk factors on drusen progression. Our results from the GRS analysis showed association of increasing genetic burden (from 19 AMD associated loci) to baseline drusen load but not drusen progression in the AREDS dataset while pathway analysis suggests additional genetic contributors to AMD risk.
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