Exploring consensus on preventive measures and identification of patients at risk of age-related macular degeneration using the delphi process

Background: Early identification of AMD can lead to prompt and more effective treatment, better outcomes, and better final visual acuity; several risk scores have been devised to determine the individual level of risk for developing AMD. Herein, the Delphi method was used to provide recommendations for daily practice regarding preventive measures and follow-up required for subjects at low, moderate, and high risk of AMD evaluated with the Simplified Test AMD Risk-assessment Scale (STARS® ) questionnaire. Methods: A steering committee of three experts drafted and refined 25 statements on the approach to be recommended in different clinical situations [general recommendations (n = 2), use of evaluation tools (n = 4), general lifestyle advice (n = 3), and AREDS-based nutritional supplementation (n = 5)] with the help of a group of international experts, all co-authors of this paper. Thirty retinal specialists from Europe and the US were chosen based on relevant publications, clinical expertise, and experience in AMD, who then provided their level of agreement with the statements. Statements for which consensus was not reached were modified and voted upon again. Results: In the first round of voting, consensus was reached for 24 statements. After modification, consensus was then reached for the remaining statement. Conclusion: An interprofessional guideline to support preventive measures in patients at risk of AMD based on STARS® scoring has been developed to aid clinicians in daily practice, which will help to optimize preventive care of patients at risk of AMD

Plasma levels of matrix metalloproteinase-2, -3, -10, and tissue inhibitor of metalloproteinase-1 are associated with vascular complications in patients with type 1 diabetes: The EURODIAB Prospective Complications Study

Impaired regulation of extracellular matrix remodeling by matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinase (TIMP) may contribute to vascular complications in patients with type 1 diabetes. We investigated associations between plasma MMP-1, -2, -3, -9, -10 and TIMP-1, and cardiovascular disease (CVD) or microvascular complications in type 1 diabetic patients. We also evaluated to which extent these associations could be explained by low-grade inflammation (LGI) or endothelial dysfunction (ED). Methods: 493 type 1 diabetes patients (39.5 ± 9.9 years old, 51% men) from the EURODIAB Prospective Complications Study were included. Linear regression analysis was applied to investigate differences in plasma levels of MMP-1, -2, -3, -9, -10, and TIMP-1 between patients with and without CVD, albuminuria or retinopathy. All analyses were adjusted for age, sex, duration of diabetes, Hba1c and additionally for other cardiovascular risk factors including LGI and ED. Results: Patients with CVD (n = 118) showed significantly higher levels of TIMP-1 [β = 0.32 SD (95%CI: 0.12; 0.52)], but not of MMPs, than patients without CVD (n = 375). Higher plasma levels of MMP-2, MMP-3, MMP-10 and TIMP-1 were associated with higher levels of albuminuria (p-trends were 0.028, 0.004, 0.005 and 0.001, respectively). Severity of retinopathy was significantly associated with higher levels of MMP-2 (p-trend = 0.017). These associations remained significant after further adjustment for markers of LGI and ED. Conclusions: These data support the hypothesis that impaired regulation of matrix remodeling by actions of MMP-2, -3 and-10 and TIMP-1 contributes to the pathogenesis of vascular complications in type 1 diabetes

Quantitative trait loci and candidate gene mapping of aluminum tolerance in diploid alfalfa

Aluminum (Al) toxicity in acid soils is a major limitation to the production of alfalfa (Medicago sativa subsp. sativa L.) in the USA. Developing Al-tolerant alfalfa cultivars is one approach to overcome this constraint. Accessions of wild diploid alfalfa (M. sativa subsp. coerulea) have been found to be a source of useful genes for Al tolerance. Previously, two genomic regions associated with Al tolerance were identified in this diploid species using restriction fragment length polymorphism (RFLP) markers and single marker analysis. This study was conducted to identify additional Al-tolerance quantitative trait loci (QTLs); to identify simple sequence repeat (SSR) markers that flank the previously identified QTLs; to map candidate genes associated with Al tolerance from other plant species; and to test for co-localization with mapped QTLs. A genetic linkage map was constructed using EST-SSR markers in a population of 130 BC(1)F(1) plants derived from the cross between Al-sensitive and Al-tolerant genotypes. Three putative QTLs on linkage groups LG I, LG II and LG III, explaining 38, 16 and 27% of the phenotypic variation, respectively, were identified. Six candidate gene markers designed from Medicago truncatula ESTs that showed homology to known Al-tolerance genes identified in other plant species were placed on the QTL map. A marker designed from a candidate gene involved in malic acid release mapped near a marginally significant QTL (LOD 2.83) on LG I. The SSR markers flanking these QTLs will be useful for transferring them to cultivated alfalfa via marker-assisted selection and for pyramiding Al tolerance QTLs

Relationship Between Risk Factors and Mortality in Type 1 Diabetic Patients in Europe: The EURODIAB Prospective Complications Study (PCS)

OBJECTIVE—The purpose of this study was to examine risk factors for mortality in patients with type 1 diabetes

Short NoteForest-type preference of an Afrotropical thrush (East Coast Akalat Sheppardia gunningi sokokensis) in Arabuko-Sokoke Forest, Kenya

No Abstract.OSTRICH 2012, 83(2): 105–10

A multi-technique dating study of two Lower Palaeolithic sites from the Cher Valley (Middle Loire Catchment, France): Lunery-la Terre-des-Sablons and Brinay-la Noira

We present the results of a new dating study carried out at Lunery-la Terre-des-Sablons (LTS) and Brinay-la Noira (BN), two key Lower Palaeolithic sites located in deposits associated to the Cher River (Middle Loire Catchment, France). These sites preserve abundant Mode 1 and Mode 2 lithic industries, and are considered as among the oldest evidence of hominin presence in Western Europe north of the 45°N latitude. Following a multi-technique approach combining electron spin resonance (ESR), single-grain thermally-transferred optically stimulated luminescence (TT-OSL) dating of quartz grains and palaeomagnetism, we obtained new chronological constraints for the sedimentary sequence, and the associated lithic assemblages, at the two sites. The new independent dating results derived from each method are consistent and in overall agreement with existing ESR and terrestrial cosmogenic nuclide (TCN) burial age estimates, except for the Lowermost Unit 3 at LTS. By integrating all of the previous and new dating results, we derive combined age estimates of 772-735 ka and 665 ± 29 ka for the fluvial sands at LTS (Unit 1) and BN, respectively. These two distinct aggradation phases may tentatively be correlated to interglacial/glacial transitions associated with Marine Isotope Stage (MIS) 19-18 for the former and MIS 17-16 for the latter. At BN, an age range of 638–676 ka may be proposed for the hominin occupation after combining numerical age results and geological evidence. This result is consistent with the initial chronology proposed by Moncel et al. (2013) [Moncel, M.H., Despriée, J., Voinchet, P., Tissoux, H., Moreno, D., Bahain, J. J., Courcimault, G., Falgueres, C. (2013). Early evidence of Acheulean settlement in north-western Europe – la Noira site, a 700 000 year-old occupation in the Centre of France. Plos One, 8(11): 1–22] and confirms that BN is among the oldest Acheulean occurrences in Western Europe. At LTS, the mean age of 710 ± 50 ka obtained for the sandy layer in Unit 3 provides a minimum age constraint for the archaeological level located below. The major sedimentary disconformity observed between the fluvial deposits and the underlying pebble layers hosting the lithic artefacts suggests that the true age of the artefacts might be significantly older, probably Early Pleistocene given their similarities with other Mode 1 assemblages identified in Western Europe. However, further refinement of the Mode 1 chronological inference at LTS remains difficult at this stage. Finally, these new dating results show the importance of using the Multiple Centre approach for ESR dating of quartz grains, and confirm the value of combining different dating methods in order to build more robust chronologies for Lower Palaeolithic sites in Europe. From a methodological point of view, the dating results presented here are especially encouraging for the reliability of the ESR method applied to optically bleached quartz grains. This is one of the very first studies demonstrating that quartz samples independently dated by two different laboratories may produce generally reproducible ESR age results.Mathieu Duval, Pierre Voinchet, Lee J.Arnold, Josep M.Parés, Walter Minnella, Verónica Guilarte ... et al

Pathogenicity of new BEST1 variants identified in Italian patients with best vitelliform macular dystrophy assessed by computational structural biology

Background: Best vitelliform macular dystrophy (BVMD) is an autosomal dominant macular degeneration. The typical central yellowish yolk-like lesion usually appears in childhood and gradually worsens. Most cases are caused by variants in the BEST1 gene which encodes bestrophin-1, an integral membrane protein found primarily in the retinal pigment epithelium. Methods: Here we describe the spectrum of BEST1 variants identified in a cohort of 57 Italian patients analyzed by Sanger sequencing. In 13 cases, the study also included segregation analysis in affected and unaffected relatives. We used molecular mechanics to calculate two quantitative parameters related to calcium-activated chloride channel (CaCC composed of 5 BEST1 subunits) stability and calcium-dependent activation and related them to the potential pathogenicity of individual missense variants detected in the probands. Results: Thirty-six out of 57 probands (63% positivity) and 16 out of 18 relatives proved positive to genetic testing. Family study confirmed the variable penetrance and expressivity of the disease. Six of the 27 genetic variants discovered were novel: p.(Val9Gly), p.(Ser108Arg), p.(Asn179Asp), p.(Trp182Arg), p.(Glu292Gln) and p.(Asn296Lys). All BEST1 variants were assessed in silico for potential pathogenicity. Our computational structural biology approach based on 3D model structure of the CaCC showed that individual amino acid replacements may affect channel shape, stability, activation, gating, selectivity and throughput, and possibly also other features, depending on where the individual mutated amino acid residues are located in the tertiary structure of BEST1. Statistically significant correlations between mean logMAR best-corrected visual acuity (BCVA), age and modulus of computed BEST1 dimerization energies, which reflect variations in the in CaCC stability due to amino acid changes, permitted us to assess the pathogenicity of individual BEST1 variants. Conclusions: Using this computational approach, we designed a method for estimating BCVA progression in patients with BEST1 variants

A Screening Tool for Self-Evaluation of Risk for Age-Related Macular Degeneration:Validation in a Spanish Population

PURPOSE: The objectives of this study were the creation and validation of a screening tool for age-related macular degeneration (AMD) for routine assessment by primary care physicians, ophthalmologists, other healthcare professionals, and the general population. METHODS: A simple, self-administered questionnaire (Simplified Théa AMD Risk-Assessment Scale [STARS] version 4.0) which included well-established risk factors for AMD, such as family history, smoking, and dietary factors, was administered to patients during ophthalmology visits. A fundus examination was performed to determine presence of large soft drusen, pigmentary abnormalities, or late AMD. Based on data from the questionnaire and the clinical examination, predictive models were developed to estimate probability of the Age-Related Eye Disease Study (AREDS) score (categorized as low risk/high risk). The models were evaluated by area under the receiving operating characteristic curve analysis. RESULTS: A total of 3854 subjects completed the questionnaire and underwent a fundus examination. Early/intermediate and late AMD were detected in 15.9% and 23.8% of the patients, respectively. A predictive model was developed with training, validation, and test datasets. The model in the test set had an area under the curve of 0.745 (95% confidence interval [CI] = 0.705–0.784), a positive predictive value of 0.500 (95% CI = 0.449–0.557), and a negative predictive value of 0.810 (95% CI = 0.770–0.844). CONCLUSIONS: The STARS questionnaire version 4.0 and the model identify patients at high risk of developing late AMD. TRANSLATIONAL RELEVANCE: The screening instrument described could be useful to evaluate the risk of late AMD in patients >55 years without having an eye examination, which could lead to more timely referrals and encourage lifestyle changes