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Objective: The objective of this study was to compare the effectiveness of a second tumor necrosis factor inhibitor (TNFi) versus a non-TNFi biologic following discontinuation of a TNFi for patients with polyarticular-course juvenile idiopathic arthritis (pJIA)., Methods: Using the Childhood Arthritis and Rheumatology Research Alliance Registry, patients with pJIA who started receiving a second biologic following a first TNFi were identified. Patients were required to have no active uveitis on the index date and a visit six months after the index date. Outcome measures included Clinical Juvenile Arthritis Disease Activity Score with a maximum of 10 active joints (cJADAS10), cJADAS10 inactive disease (ID; ≤2.5) and cJADAS10 minimal disease activity (MiDA; ≤5). Multiple imputation was used to account for missing data. Adjusted odds ratios (aORs) were calculated using propensity score quintiles to compare outcomes at six months following second biologic initiation., Results: There were 216 patients included, 84% initially received etanercept, and most patients stopped receiving it because of its ineffectiveness (74%). A total of 183 (85%) started receiving a second TNFi, and 33 (15%) started receiving a non-TNFi. Adalimumab was the most common second biologic received (71% overall, 84% of second TNFi), and tocilizumab was the most common non-TNFi second biologic received (9% overall, 58% of non-TNFi). There was no difference between receiving TNFi versus non-TNFi in cJADAS10 ID (29% vs 25%; aOR 1.23, 95% confidence interval [CI] 0.47-3.20) or at least MiDA (43% vs 39%; aOR 1.11, 95% CI 0.47-2.62) at six months., Conclusion: Most patients with pJIA started receiving TNFi rather than non-TNFi as their second biologic, and there were no differences in disease activity at six months., (© 2024 The Authors. Arthritis Care & Research published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Purpose: During lens fiber cell differentiation, organelles are removed in an ordered manner to ensure lens clarity. A critical step in this process is removal of the cell nucleus, but the mechanisms by which this occurs are unclear. In this study, we investigate the role of a cyclin-dependent kinase 1 (CDK1) regulatory loop in controlling lens fiber cell denucleation (LFCD)., Methods: We examined lens differentiation histologically in two different vertebrate models. An embryonic chick lens culture system was used to test the role of CDK1, cell division cycle 25 (CDC25), WEE1, and PP2A in LFCD. Additionally, we used three mouse models that express high levels of the CDK inhibitor p27 to test whether increased p27 levels affect LFCD., Results: Using chick lens organ cultures, small-molecule inhibitors of CDK1 and CDC25 inhibit LFCD, while inhibiting the CDK1 inhibitory kinase WEE1 potentiates LFCD. Additionally, treatment with an inhibitor of PP2A, which indirectly inhibits CDK1 activity, also increased LFCD. Three different mouse models that express increased levels of p27 through different mechanisms show impaired LFCD., Conclusions: Here we define a conserved nonmitotic role for CDK1 and its upstream regulators in controlling LFCD. We find that CDK1 functionally interacts with WEE1, a nuclear kinase that inhibits CDK1 activity, and CDC25 activating phosphatases in cells where CDK1 activity must be exquisitely regulated to allow for LFCD. We also provide genetic evidence in multiple in vivo models that p27, a CDK1 inhibitor, inhibits lens growth and LFCD.

Objectives: Some adults with rheumatic and musculoskeletal diseases (RMDs) are at increased risk of COVID-19-related death. Excluding post-COVID-19 multisystem inflammatory syndrome of children, children and young people (CYP) are overall less prone to severe COVID-19 and most experience a mild or asymptomatic course. However, it is unknown if CYP with RMDs are more likely to have more severe COVID-19. This analysis aims to describe outcomes among CYP with underlying RMDs with COVID-19., Methods: Using the European Alliance of Associations for Rheumatology COVID-19 Registry, the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry, and the CARRA-sponsored COVID-19 Global Paediatric Rheumatology Database, we obtained data on CYP with RMDs who reported SARS-CoV-2 infection (presumptive or confirmed). Patient characteristics and illness severity were described, and factors associated with COVID-19 hospitalisation were investigated., Results: 607 CYP with RMDs <19 years old from 25 different countries with SARS-CoV-2 infection were included, the majority with juvenile idiopathic arthritis (JIA; n=378; 62%). Forty-three (7%) patients were hospitalised; three of these patients died. Compared with JIA, diagnosis of systemic lupus erythematosus, mixed connective tissue disease, vasculitis, or other RMD (OR 4.3; 95% CI 1.7 to 11) or autoinflammatory syndrome (OR 3.0; 95% CI 1.1 to 8.6) was associated with hospitalisation, as was obesity (OR 4.0; 95% CI 1.3 to 12)., Conclusions: This is the most significant investigation to date of COVID-19 in CYP with RMDs. It is important to note that the majority of CYP were not hospitalised, although those with severe systemic RMDs and obesity were more likely to be hospitalised., Competing Interests: Competing interests: RC reports personal AstraZeneca shares, unrelated to this manuscript. IK-P reports personal fees by Novartis, SOBI, Chugai, Pfizer, AbbVie, BMS, all unrelated to this manuscript. FOR reports consulting/speaker’s fees from Abbvie, Novartis, Pfizer and Sobi, all unrelated to this manuscript. NMW reports personal consultant fees from UCB, BMS, all unrelated to this manuscript. AS reports personal fees from lectures for AbbVie, Celltrion, MSD, Janssen, Lilly, Roche, BMS, and Pfizer, all unrelated to this manuscript. EFM reports personal consultant fees from Boehringer Ingelheim Portugal, Lda, all unrelated to this manuscript. LPCDR received support for specific activities: grants from Abbvie, Novartis, Lilly Portugal, Amgen Biofarmacêutica, Grünenthal S.A., MSD, Medac, A. Menarini Portugal - Farmacêutica, S.A., Pfizer, UCB Pharma, Roche Farmacêutica Química, Lda; and non-financial support from Pfizer, and Grünenthal GmbH, all unrelated to this manuscript.PMM has received consulting/speaker’s fees from Abbvie, BMS, Celgene, Eli Lilly, Galapagos, Janssen, MSD, Novartis, Orphazyme, Pfizer, Roche and UCB, all unrelated to this manuscript, and is supported by the National Institute for Health Research (NIHR), University College London Hospitals (UCLH), Biomedical Research Centre (BRC). MN reports funding from Childhood Arthritis & Rheumatology Research Alliance, Inc (CARRA) to his informatics research and operations group at Boston Children’s Hospital in its capacity as the CARRA Data Warehouse and associated work for CARRA and the CARRA Registry and has sponsored the COVID-19 Global Pediatric Rheumatology Database study, of which he is the Principal Investigator. MN also serves as Director of Informatics for CARRA, for which he receives no direct compensation but do receive research sponsorship for CARRA-related research, development, and operations (see above). He is also a co-investigator of the CARRA Registry and site Principal Investigator at Massachusetts General Hospital. KLH reports non-personal speaker’s fees from Abbvie and grant income from BMS, UCB, and Pfizer, all unrelated to this manuscript, and is supported by the NIHR Manchester Biomedical Research Centre. All other authors report no disclosures., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: We aimed to determine the feasibility and efficacy of online strategies to recruit parents of children with pediatric rheumatic diseases (PRDs) for research and to evaluate the degree to which known features of various rheumatic disease groups were present in the online cohort., Methods: We studied two cohorts; the first was composed of respondents from a cross-sectional parental survey of children with PRDs contacted through patient support groups and social media platforms, and the second cohort was composed of participants from the Childhood Arthritis and Rheumatology Research Alliance (CARRA) legacy clinical registry., Results: In the social media cohort, 712 complete surveys were analyzed. Most (65.9%) were referred from Facebook. The most common rheumatic disease was juvenile idiopathic arthritis (JIA) (27.1%), followed by juvenile dermatomyositis (22.1%). In the CARRA registry cohort, 7985 records were included. JIA was the largest disease group (70.3%), followed by systemic lupus erythematosus (12.0%). The age at disease onset for most PRDs was similar between those in the social media and CARRA registry cohorts (mean difference = 1.3 years)., Conclusion: Recruitment through Facebook was the most fruitful. The clinical characteristics of the social media cohort were similar to those of patients recruited through a clinical registry, suggesting the utility of online recruitment for engaging disease-relevant cohorts. Parents of children with rare PRDs were overrepresented in the social media cohort, perhaps reflecting the increased need of those parents to find online information and receive emotional support. Social media recruitment for research studies may help expand the number and diversity of participants in clinical research, especially by including those with rare diseases., (© 2022 The Authors. ACR Open Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Purpose: We hypothesized that exposure to Porphyromonas gingivalis (Pg) increases the risk for early diabetic retinopathy (DR) and that the risk can be modulated., Methods: We identified 116 early DR cases, and 116 non-DR controls were selected randomly by frequency matching for age, sex, race, and education from the US Third National Health and Nutrition Examination Survey. DR was assessed using non-mydriatic fundus photographs and graded by trained graders using the Modified Airlie House Classification scheme and the Early Treatment for Diabetic Retinopathy Study severity scale. Serum Pg immunoglobulin G (IgG) antibody (Ab) was measured in enzyme-linked immunosorbent assay units. Logistic regression was used to relate serum Pg IgG Ab levels to the risk for early DR., Results: Per tenfold increase in Pg IgG Ab levels, there was an over 60% increased risk for early DR (odds ratio = 1.64; 95% confidence interval, 1.36-1.97), and a linear trend was noted for the estimated probabilities of early DR at various Pg IgG Ab levels (P for trend = 0.0053). The analysis also suggested that moderate alcohol consumption (less than 12 drinks in the past 12 months; P for interaction = 0.0003) and maintaining a normal serum glycated hemoglobulin level (HbA1c ≤ 5.7%; P for interaction < 0.0001) helped reduce the Pg-related DR risk., Conclusions: The increased Pg-related DR risk could be alleviated by managing alcohol consumption and maintaining a normal blood glucose level., Translational Relevance: Findings from this study provide new directions for developing novel therapeutics and prevention strategies for DR.

Age-related macular degeneration (AMD) is a major blinding disease, affecting over 14% of the elderly. Risk for AMD is related to age, diet, environment, and genetics. Dietary modulation of AMD risk is a promising treatment modality, but requires appropriate animal models to demonstrate advantages of diet. Mice lacking the antioxidant transcription factor Nrf2 (Nfe2l2) develop age-related retinopathy relevant to human AMD. Here we evaluated the effect of consuming high glycemic (HG) or low glycemic (LG) diets until 18-months of age on development of features relevant to AMD in Nrf2-null mice. Nrf2-null mice that consumed HG diets developed atrophic AMD, characterized by photoreceptor degeneration, retinal pigment epithelium (RPE) atrophy and pigmentary abnormalities, basal laminar deposits, and loss of the choriocapillaris. In contrast, Nrf2-null-mice that consumed LG diets did not develop retinal disease phenotypes. Consumption of HG diets was associated with accumulation of advanced glycation end-products in the RPE and systemically, whereas consumption of the LG diet was associated with increased levels of anti-glycative and anti-oxidative detoxification machinery. Together our data indicate that the Nrf2-null HG mouse is a good model for atrophic AMD studies and that the LG diet can activate protective pathways to prevent AMD, even in a genetically predisposed animal., (Copyright © 2020. Published by Elsevier Inc.)

Advanced glycation end products (AGEs) are formed upon nonenzymatic reactions of sugars or their metabolites with proteins and other cellular constituents. Many AGEs are long lived. Recent findings suggest that AGEs may predict diabetes and its complications and thus may warrant further study. The objective of this study was to assess the validity of our experimental procedures for measuring AGEs in stored blood sample and to conduct a pilot study for developing AGE biomarkers for diabetes and/or age-related changes of glucose metabolism. We conducted a reliability study of the samples and methods using liquid chromatography-tandem mass spectrometry (LC-MS)/MS assays for 10 AGEs (including methylglyoxal-derived hydroimidazolone (MG-H1), glucosepane (GSP) and two oxidation measures, in stored repository blood samples from the Nurses' Health Study and the Health Professionals Follow-up Study. We also analyzed data relating blood GSP levels to type 2 diabetes status in a case-control study (25 cases and 15 controls). Among the AGEs, GSP, and MG-H1 showed the highest reliability across the various measures: reliability in duplicate samples and stability with delayed processing and storage over 1-2 year period. Furthermore, plasma GSP was associated with older age (P = 0.04) and type 2 diabetes status (age-adjusted P = 0.0475). Our findings suggest that analysis of these AGEs may be developed as biomarkers for diabetes and/or age-related changes of glucose metabolism. © 2018 BioFactors, 44(3):281-288, 2018., (© 2018 International Union of Biochemistry and Molecular Biology.)

Age-related macular degeneration (AMD) is the major cause of blindness in developed nations. AMD is characterized by retinal pigmented epithelial (RPE) cell dysfunction and loss of photoreceptor cells. Epidemiologic studies indicate important contributions of dietary patterns to the risk for AMD, but the mechanisms relating diet to disease remain unclear. Here we investigate the effect on AMD of isocaloric diets that differ only in the type of dietary carbohydrate in a wild-type aged-mouse model. The consumption of a high-glycemia (HG) diet resulted in many AMD features (AMDf), including RPE hypopigmentation and atrophy, lipofuscin accumulation, and photoreceptor degeneration, whereas consumption of the lower-glycemia (LG) diet did not. Critically, switching from the HG to the LG diet late in life arrested or reversed AMDf. LG diets limited the accumulation of advanced glycation end products, long-chain polyunsaturated lipids, and their peroxidation end-products and increased C3-carnitine in retina, plasma, or urine. Untargeted metabolomics revealed microbial cometabolites, particularly serotonin, as protective against AMDf. Gut microbiota were responsive to diet, and we identified microbiota in the Clostridiales order as being associated with AMDf and the HG diet, whereas protection from AMDf was associated with the Bacteroidales order and the LG diet. Network analysis revealed a nexus of metabolites and microbiota that appear to act within a gut-retina axis to protect against diet- and age-induced AMDf. The findings indicate a functional interaction between dietary carbohydrates, the metabolome, including microbial cometabolites, and AMDf. Our studies suggest a simple dietary intervention that may be useful in patients to arrest AMD., Competing Interests: The authors declare no conflict of interest.

Purpose: We aimed to visualize the relationship of predominant dietary patterns and their associations with AMD., Methods: A total of 8103 eyes from 4088 participants in the baseline Age-Related Eye Disease Study (AREDS) were classified into three groups: control (n = 2739), early AMD (n = 4599), and advanced AMD (n = 765). Using principle component analysis, two major dietary patterns and eight minor dietary patterns were characterized. Applying logistic regression in our analysis, we related dietary patterns to the prevalence of AMD. Qualitative comparative analysis by operating Boolean algebra and drawing Venn diagrams was used to visualize our findings., Results: In general, the eight minor patterns were subsets or extensions of either one of the two major dietary patterns (Oriental and Western patterns) and consisted of fewer characteristic foods than the two major dietary patterns. Unlike the two major patterns, which were more strongly associated with both early and advanced AMD, none of the eight minors were associated with early AMD and only four minor patterns, including the Steak pattern (odds ratio comparing the highest to lowest quintile of the pattern score = 1.73 [95% confidence interval: 1.24 to 2.41; Ptrend = 0.02]), the Breakfast pattern (0.60 [0.44 to 0.82]; Ptrend = 0.004]), the Caribbean pattern (0.64 [0.47 to 0.89; Ptrend = 0.009]), and the Peanut pattern (0.64 [0.46 to 0.89; Ptrend = 0.03]), were significantly associated with advanced AMD. Our data also suggested several potential beneficial (peanuts, pizza, coffee, and tea) and harmful (salad dressing) foods for AMD., Conclusions: Our data indicate that a diet of various healthy foods may be optimal for reducing AMD risk. The effects of some specific foods in the context of overall diet warrant further study.

The eye lens is unique among tissues: it is transparent, does not form tumors, and the majority of its cells degrade their organelles, including their cell nuclei. A mystery for over a century, there has been considerable recent progress in elucidating mechanisms of lens fiber cell denucleation (LFCD). In contrast to the disassembly and reassembly of the cell nucleus during mitosis, LFCD is a unidirectional process that culminates in destruction of the fiber cell nucleus. Whereas p27 Kip1 , the cyclin-dependent kinase inhibitor, is upregulated during formation of LFC in the outermost cortex, in the inner cortex, in the nascent organelle free zone, p27 Kip1 is degraded, markedly activating cyclin-dependent kinase 1 (Cdk1). This process results in phosphorylation of nuclear Lamins, dissociation of the nuclear membrane, and entry of lysosomes that liberate DNaseIIβ (DLAD) to cleave chromatin. Multiple cellular pathways, including the ubiquitin proteasome system and the unfolded protein response, converge on post-translational regulation of p27 Kip1 . Mutations that impair these pathways are associated with congenital cataracts and loss of LFCD. These findings highlight new regulatory nodes in the lens and suggest that we are close to understanding this fascinating terminal differentiation process. Such knowledge may offer a new means to confront proliferative diseases including cancer., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

It is conceived that specific combinations of periodontal bacteria are associated with risk for the various forms of periodontitis. We hypothesized that such specificity is also related to human cause-specific death rates. We tested this hypothesis in a representative sample of the US population followed for a mean duration of 11 years and found that two specific patterns of 21 serum antibodies against periodontal bacteria were significantly associated with increased all-cause and/or diabetes-related mortalities. These data suggested that specific combinations of periodontal bacteria, even without inducing clinically significant periodontitis, may have a significant impact on human cause-specific death rates. Our findings implied that increased disease and mortality risk could be transmittable via the transfer of oral microbiota, and that developing personalized strategies and maintaining healthy oral microbiota beyond protection against periodontitis would be important to manage the risk.

Failure of lens fiber cell denucleation (LFCD) is associated with congenital cataracts, but the pathobiology awaits elucidation. Recent work has suggested that mechanisms that direct the unidirectional process of LFCD are analogous to the cyclic processes associated with mitosis. We found that lens-specific mutations that elicit an unfolded-protein response (UPR) in vivo accumulate p27(Cdkn1b), show cyclin-dependent kinase (Cdk)-1 inhibition, retain their LFC nuclei, and are cataractous. Although a UPR was not detected in lenses expressing K6W-Ub, they also accumulated p27 and showed failed LFCD. Induction of a UPR in human lens epithelial cells (HLECs) also induced accumulation of p27 associated with decreased levels of S-phase kinase-associated protein (Skp)-2, a ubiquitin ligase that regulates mitosis. These cells also showed decreased lamin A/C phosphorylation and metaphase arrest. The suppression of lamin A/C phosphorylation and metaphase transition induced by the UPR was rescued by knockdown of p27. Taken together, these data indicate that accumulation of p27, whether related to the UPR or not, prevents the phosphorylation of lamin A/C and LFCD in maturing LFCs in vivo, as well as in dividing HLECs. The former leads to cataract and the latter to metaphase arrest. These results suggest that accumulation of p27 is a common mechanism underlying retention of LFC nuclei., (© FASEB.)

Although the ocular lens shares many features with other tissues, it is unique in that it retains its cells throughout life, making it ideal for studies of differentiation/development. Precipitation of proteins results in lens opacification, or cataract, the major blinding disease. Lysines on ubiquitin (Ub) determine fates of Ub-protein substrates. Information regarding ubiquitin proteasome systems (UPSs), specifically of K6 in ubiquitin, is undeveloped. We expressed in the lens a mutant Ub containing a K6W substitution (K6W-Ub). Protein profiles of lenses that express wild-type ubiquitin (WT-Ub) or K6W-Ub differ by only ∼2%. Despite these quantitatively minor differences, in K6W-Ub lenses and multiple model systems we observed a fourfold Ca(2+) elevation and hyperactivation of calpain in the core of the lens, as well as calpain-associated fragmentation of critical lens proteins including Filensin, Fodrin, Vimentin, β-Crystallin, Caprin family member 2, and tudor domain containing 7. Truncations can be cataractogenic. Additionally, we observed accumulation of gap junction Connexin43, and diminished Connexin46 levels in vivo and in vitro. These findings suggest that mutation of Ub K6 alters UPS function, perturbs gap junction function, resulting in Ca(2+) elevation, hyperactivation of calpain, and associated cleavage of substrates, culminating in developmental defects and a cataractous lens. The data show previously unidentified connections between UPS and calpain-based degradative systems and advance our understanding of roles for Ub K6 in eye development. They also inform about new approaches to delay cataract and other protein precipitation diseases.

Minimally invasive surgery has become common in the surgical resection of gastrointestinal submucosal tumors (SMTs). The purpose of this article is to review recent trends in minimally invasive surgery for gastric SMTs. Although laparoscopic resection has been main stream of minimally invasive surgery for gastrointestinal SMTs, recent advances in endoscopic procedures now provide various treatment modalities for gastric SMTs. Moreover, investigators have developed several hybrid techniques that include the advantages of both laparoscopic and endoscopic procedure. In addition, several types of reduced port surgeries, modification of conventional laparoscopic procedures, have been recently applied to the surgical resection of SMTs. Meanwhile, robotic surgery for SMTs requires further evidence and improvement.

Lens epithelial cells and early lens fiber cells contain the typical complement of intracellular organelles. However, as lens fiber cells mature they must destroy their organelles, including nuclei, in a process that has remained enigmatic for over a century, but which is crucial for the formation of the organelle-free zone in the center of the lens that assures clarity and function to transmit light. Nuclear degradation in lens fiber cells requires the nuclease DNase IIβ (DLAD) but the mechanism by which DLAD gains access to nuclear DNA remains unknown. In eukaryotic cells, cyclin-dependent kinase 1 (CDK1), in combination with either activator cyclins A or B, stimulates mitotic entry, in part, by phosphorylating the nuclear lamin proteins leading to the disassembly of the nuclear lamina and subsequent nuclear envelope breakdown. Although most post-mitotic cells lack CDK1 and cyclins, lens fiber cells maintain these proteins. Here, we show that loss of CDK1 from the lens inhibited the phosphorylation of nuclear lamins A and C, prevented the entry of DLAD into the nucleus, and resulted in abnormal retention of nuclei. In the presence of CDK1, a single focus of the phosphonuclear mitotic apparatus is observed, but it is not focused in CDK1-deficient lenses. CDK1 deficiency inhibited mitosis, but did not prevent DNA replication, resulting in an overall reduction of lens epithelial cells, with the remaining cells possessing an abnormally large nucleus. These observations suggest that CDK1-dependent phosphorylations required for the initiation of nuclear membrane disassembly during mitosis are adapted for removal of nuclei during fiber cell differentiation., (© 2014. Published by The Company of Biologists Ltd.)

Aim: To investigate the influence of the resection margin on local recurrence and survival in gastric cancer patients., Methods: We reviewed the medical records of 1788 patients who had undergone gastrectomy for gastric cancer at the Seoul National University Bundang Hospital, South Korea, between May 2003 and July 2009. The patients were divided into early and advanced gastric cancer groups. In each group, we analyzed the relationship between clinicopathologic factors and survival outcomes, and compared the hazard rates of event occurrence between patients with resection margins above and below the cut-off value, using a Cox proportional hazard model., Results: The early and advanced gastric cancer groups included 1001 and 787 patients, respectively. The hazard rates of event occurrence did not significantly differ between the patients with resection margins above the cut-off value and those with resection margins below the cut-off value (P > 0.05, in all comparisons). Based on the multivariable analyses, the proximal and distal resection margins were not significantly associated with survival outcomes and local recurrence (P > 0.05, in all analyses)., Conclusion: The proximal or distal resection margins did not affect the prognosis of patients with gastric cancer if the margins were pathologically negative.

Purpose: To develop a clinical eye-specific prediction model for advanced age-related macular degeneration (AMD)., Design: The Age-Related Eye Disease Study (AREDS) cohort followed up for 8 years served as the training dataset, and the Blue Mountains Eye Study (BMES) cohort followed up for 10 years served as the validation dataset., Participants: A total of 4507 AREDS participants (contributing 1185 affected vs. 6992 unaffected eyes) and 2169 BMES participants (contributing 69 affected vs. 3694 unaffected eyes)., Methods: Using Bayes' theorem in a logistic model, we used 8 baseline predictors-age, sex, education level, race, smoking status, and presence of pigment abnormality, soft drusen, and maximum drusen size-to devise and validate a macular risk scoring system (MRSS). We assessed the performance of the MRSS by calculating sensitivity, specificity, and the area under the receiver operating characteristic curve (i.e., c-index)., Main Outcome Measures: Advanced AMD., Results: The internally validated c-indexAREDS (0.88; 95% confidence interval, 0.87-0.89) and the externally validated c-indexBMES (0.91; 95% confidence interval, 0.88-0.95) suggested excellent performance of the MRSS. The sensitivity and specificity at the optimal macular risk score cutoff point of 0 were 87.6% and 73.6%, respectively. An application for the iPhone and iPad also was developed as a practical tool for the MRSS., Conclusions: The MRSS was developed and validated to provide satisfactory accuracy and generalizability. It may be used to screen patients at risk of developing advanced AMD., (Copyright © 2014 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: We hypothesized that major American dietary patterns are associated with risk for age-related macular degeneration (AMD)., Design: Cross-sectional study., Methods: We classified 8103 eyes in 4088 eligible participants in the baseline Age-Related Eye Disease Study (AREDS). They were classified into control (n = 2739), early AMD (n = 4599), and advanced AMD (n = 765) by the AREDS AMD Classification System. Food consumption data were collected by using a 90-item food frequency questionnaire., Results: Two major dietary patterns were identified by factor (principal component) analysis based on 37 food groups and named Oriental and Western patterns. The Oriental pattern was characterized by higher intake of vegetables, legumes, fruit, whole grains, tomatoes, and seafood. The Western pattern was characterized by higher intake of red meat, processed meat, high-fat dairy products, French fries, refined grains, and eggs. We ranked our participants according to how closely their diets line up with the 2 patterns by calculating the 2 factor scores for each participant. For early AMD, multivariate-adjusted odds ratio (OR) from generalized estimating equation logistic analysis comparing the highest to lowest quintile of the Oriental pattern score was ORE5O = 0.74 (95% confidence interval (CI): 0.59-0.91; Ptrend =0.01), and the OR comparing the highest to lowest quintile of the Western pattern score was ORE5W = 1.56 (1.18-2.06; Ptrend = 0.01). For advanced AMD, the ORA5O was 0.38 (0.27-0.54; Ptrend < 0.0001), and the ORA5W was 3.70 (2.31-5.92; Ptrend < 0.0001)., Conclusions: Our data indicate that overall diet is significantly associated with the odds of AMD and that dietary management as an AMD prevention strategy warrants further study., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Ubiquitin is a tag that often initiates degradation of proteins by the proteasome in the ubiquitin proteasome system. Targeted expression of K6W mutant ubiquitin (K6W-Ub) in the lens results in defects in lens development and cataract formation, suggesting critical functions for ubiquitin in lens. To study the developmental processes that require intact ubiquitin, we executed the most extensive characterization of the lens proteome to date. We quantified lens protein expression changes in multiple replicate pools of P1 wild-type and K6W-Ub-expressing mouse lenses. Lens proteins were digested with trypsin, peptides were separated using strong cation exchange and reversed-phase liquid chromatography, and tandem mass (MS/MS) spectra were collected with a linear ion trap. Transgenic mice that expressed low levels of K6W-Ub (low expressers) had normal, clear lenses at birth, whereas the lenses that expressed high levels of K6W-Ub (higher expressers) had abnormal lenses and cataracts at birth. A total of 2052 proteins were identified, of which 996 were reliably quantified and compared between wild-type and K6W-Ub transgenic mice. Consistent with a delayed developmental program, fiber-cell-specific proteins, such as γ-crystallins (γA, γB, γC, and γE), were down-regulated in K6W-Ub higher expressers. Up-regulated proteins were involved in energy metabolism, signal transduction, and proteolysis. The K6W-Ub low expressers exhibited delayed onset and milder cataract consistent with smaller changes in protein expression. Because lens protein expression changes occurred prior to lens morphological abnormalities and cataract formation in K6W-Ub low expressers, it appears that expression of K6W-Ub sets in motion a process of altered protein expression that results in developmental defects and cataract.

Purpose: Age-related macular degeneration (AMD) is a leading cause of visual impairment worldwide. Genetics and diet contribute to the relative risk for developing AMD, but their interactions are poorly understood. Genetic variations in Complement Factor H (CFH), and dietary glycemic index (GI) are major risk factors for AMD. We explored the effects of GI on development of early AMD-like features and changes to central nervous system (CNS) inflammation in Cfh-null mice., Methods: Aged 11-week-old wild type (WT) C57Bl/6J or Cfh-null mice were group pair-fed high or low GI diets for 33 weeks. At 10 months of age, mice were evaluated for early AMD-like features in the neural retina and RPE by light and electron microscopy. Brains were analyzed for Iba1 macrophage/microglia immunostaining, an indicator of inflammation., Results: The 10-month-old WT mice showed no retinal abnormalities on either diet. The Cfh-null mice, however, showed distinct early AMD-like features in the RPE when fed a low GI diet, including vacuolation, disruption of basal infoldings, and increased basal laminar deposits. The Cfh-null mice also showed thinning of the RPE, hypopigmentation, and increased numbers of Iba1-expressing macrophages in the brain, irrespective of diet., Conclusions: The presence of early AMD-like features by 10 months of age in Cfh-null mice fed a low GI diet is surprising, given the apparent protection from the development of such features in aged WT mice or humans consuming lower GI diets. Our findings highlight the need to consider gene-diet interactions when developing animal models and therapeutic approaches to treat AMD.

Objective: Because retina-damaging angiogenesis is controlled by vascular endothelial growth factor (VEGF) and people with higher glucose intakes are more susceptible to retinal complications that may be due to increased VEGF, it is crucial to elucidate relations between glucose exposure and VEGF expression. We aimed to determine if a carbohydrate response element binding protein (ChREBP) plays a role in the transcriptional up-regulation of hypoxia-inducible factor-1α (HIF-1α) and the downstream VEGF expression in retinal pigment epithelial (RPE) cells exposed to high glucose under normoxic conditions., Methods: ARPE19 cells were exposed to 5.6, 11, 17, 25 and 30 mM glucose for 48 h in serum-free culture media under normoxic (21 % O2) conditions. Protein and mRNA expression of indicated genes were determined by immunoblot analyses and real-time RT-PCR, respectively. An enzyme-linked immunosorbent assay (ELISA) was used to detect the concentrations of VEGF in the media. Immunofluorescence (IF) and chromatin immunoprecipitation (ChIP) for ChREBP were used to demonstrate nuclear translocation and HIF-1α gene promoter association, respectively., Results: Immunoblot analyses showed that HIF-1α levels were positively related to levels of glucose exposure between 5.6-25 mM in the RPE cells, indicating the induction and stabilization of HIF-1α by elevated glucose under normoxic conditions. Human lens epithelial cells and HeLa cells did not respond to high glucose, implying that this phenomenon is cell type-specific. Real-time RT-PCR for HIF-1α and VEGF and ELISA for VEGF indicated that high glucose is associated with elevated production of HIF-1α-induced VEGF, an established inducer of neovascularization, in the RPE cells. IF analyses showed that, although ChREBP was expressed under both low (5.6 mM) and high (25 mM) glucose conditions, it appeared more in the nuclear region than in the cytosol of the RPE cells after the high glucose treatment. ChIP analyses suggested a HIF-1α gene promoter association with ChREBP under the high glucose condition. These results imply that RPE cells use cytosolic ChREBP as a glucose sensor to up-regulate HIF-1α expression., Conclusion: These results suggest a high glucose-induced, ChREBP-mediated, and normoxic HIF-1α activation that may be partially responsible for neovascularization in both diabetic and age-related retinopathy.

Oral submucous fibrosis (OSF) is a precancerous condition of the oral cavity. It is a collagen-related disorder induced by betel quid chewing, a habit that is common in Taiwan. However, the cumulative exposure to betel quids varies in OSF patients. It seems that there is individual susceptibility to betel quid-induced OSF. This study compared the association of OSF and polymorphisms of six collagen-related genes, collagen 1A1 and 1A2 (COL1A1 and COL1A2), collagenase-1 (COLase), transforming growth factor beta1 (TGF-beta1), lysyl oxidase (LYOXase), and cystatin C (CST3), between patients with low and high exposure to betel quids. A total of 166 patients with OSF from a medical center and 284 betel quid chewers who were free of OSF and oral cancer, from the same hospital and five townships, were recruited. PCR-based restriction fragment length polymorphism assays were used to determine the genotypes of the six collagen-related genes situated on different chromosomes. We found that the genotypes associated with the highest OSF risk for collagen 1A1, collagen 1A2, collagenase-1, transforming growth factor beta1, lysyl oxidase, and cystatin C were CC, AA, TT, CC, AA, and AA, respectively, for the low-exposure group, and TT, BB, AA, CC, GG, and AA, respectively, for the high-exposure group. A trend was noted for an increased risk of OSF with increasing number of high-risk alleles for those with both high and low exposures for betel quid. The cell selection mechanism of oral fibroblasts is proposed to explain the effect of the modification of cumulative betel quid exposure on the risk profiles of collagen-related genes. These results imply that susceptibility to OSF could involve multigenic mechanisms modified by the betel quid-exposure dose.