Accelerated atherosclerosis in patients with diabetes is a major cause of their morbidity and mortality, and it is unresponsive to therapy aimed at restoring relative euglycemia. In hyperglycemia, nonenzymatic glycation and oxidation of proteins and lipids results in the accumulation of irreversibly formed advanced glycation endproducts. These advanced glycation endproducts engage their receptor in cells of the blood vessel wall, thereby activating mechanisms linked to the development of vascular lesions. We report here a model of accelerated and advanced atherosclerosis in diabetic mice deficient for apolipoprotein E. Treatment of these mice with the soluble extracellular domain of the receptor for advanced glycation endproducts completely suppressed diabetic atherosclerosis in a glycemia- and lipid-independent manner. These findings indicate interaction between the advanced glycation endproducts and their receptor is involved in the development of accelerated atherosclerosis in diabetes, and identify this receptor as a new therapeutic target in diabetic macrovascular disease.

Wearing contact lenses has been identified as a risk factor for the development of eye conditions such as giant papillary conjunctivitis and keratitis. We hypothesized that wearing contact lenses is associated with changes in the ocular microbiota. We compared the bacterial communities of the conjunctiva and skin under the eye from 58 subjects and analyzed samples from 20 subjects (9 lens wearers and 11 non-lens wearers) taken at 3 time points using a 16S rRNA gene-based sequencing technique (V4 region; Illumina MiSeq). We found that using anesthetic eye drops before sampling decreases the detected ocular microbiota diversity. Compared to those from non-lens wearers, dry conjunctival swabs from lens wearers had more variable and skin-like bacterial community structures (UniFrac; P value = <0.001), with higher abundances of Methylobacterium, Lactobacillus, Acinetobacter, and Pseudomonas and lower abundances of Haemophilus, Streptococcus, Staphylococcus, and Corynebacterium (linear discriminant analysis [LDA] score = >3.0). The results indicate that wearing contact lenses alters the microbial structure of the ocular conjunctiva, making it more similar to that of the skin microbiota. Further research is needed to determine whether the microbiome structure provides less protection from ocular infections.

Children with IP-EVA malformations have an excellent prognosis for developing open-set speech perception and using oral communication modes following CI. On the contrary, children with severe malformations or CND may have elevated charge requirements for attaining sound detection alone. These children's prognosis for obtaining open-set speech understanding, using exclusive oral communication, and participating in mainstream education is more limited. These findings have important implications for considering alternative forms of intervention such as auditory brainstem implantation and/or supplementation with visually based communication strategies.

Progressive deposition of amyloid 3-protein In brain, whether A,B has any physiological role is unknown. Studies aimed at elucidating the biological effects of A/3 on the nervous system have yielded equivocal results. Addition of synthetic peptides corresponding to the first 28 or 42 amino acids of the Al3 sequence to culture medium resulted in a dose-dependent effect on survival and neurite outgrowth of rat hippocampal neurons (3, 4). With a similar paradigm, AP-(1-40) peptide was found to be both trophic and toxic to hippocampal neurons, depending on the peptide dose and maturity ofthe neurons in vitro (5). In such systems, increased evidence favors a role of excitatory amino acids in A,B-induced neurotoxicity (6), possibly because A,B destabilizes calcium homeostasis (7). A recent study further suggested that peptide aggregation may enhance A,B toxicity in cultured hippocampal neurons (8). Finally, two reports suggested that transfection of either full-length APP or its C-terminal 100 residues, both ofwhich contain the AP region, into neural cells may result in cell degeneration upon neuronal differentiation (9, 10).Central to many of these studies is the addition of soluble AP3 in relatively high concentrations to culture medium. In one study, acetonitrile and trifluoroacetic acid were used to solubilize A,B before addition to culture medium (5 show that immobilized A,B has no detrimental effect on neurite outgrowth. On the contrary, in the presence of low amounts of extracellular matrix (ECM) components, A,B promotes neurite outgrowth in a dose-dependent manner. MATERIALS AND METHODSPeptides. Six synthetic peptides were used: AP-(1-40),A,B-(1-28), and A,B-(21-37) (all from the human APP sequence) and, as controls, a 40-residue peptide having all A,B amino acids but randomly scrambled (NH2-VIEVLVGE-LDAFDGHVAGFSHDQKGNHVKGGARYMVSIFE), the 37-residue islet amyloid polypeptide (amylin; Peninsula Laboratories), and a 10-residue substance P peptide (Peninsula Laboratories). All peptides were HPLC purified, and the first four peptides were additionally analyzed by mass spectroscopy. All peptides were dissolved in deionized water at a concentration of 1 mg/ml. A sample of AP3 peptide was aggregated before use by dissolving in phosphate-buffered saline at 10 mg/ml, incubating at 37°C for 48 hr, and storing at 4°C for 1 week. The peptide was resuspended in water at 1 mg/ml just before use. On SDS/PAGE, the sample consisted primarily of mono-and dimeric forms, with smaller amounts of tetrameric aggregates. Substrate Preparation. Tissue culture substrates were prepared under sterile conditions by coating 35-mm Petri dishes with a premixed solution consisting of peptide, ECM, or both. All dishes were coated with peptide concentrations ranging from 0.5 to 5.0 pug/cm2. The ECM component con- §To whom reprint requests should be addressed. 4748The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C...

The status of the auditory periphery, particularly of hair cells rather than neural activity, accounts for a large fraction of variability in speech perception outcomes in adults and older children. In younger children, the relationship is weaker, and the elderly differ from other adults. This simple measurement can be applied with high throughput so that peripheral status can be assessed to help manage patient expectations, create individually-tailored treatment plans, and identify subjects performing below expectations based on residual cochlear function.