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  • 1
    Keywords: NF-KAPPA-B ; IMMUNE-RESPONSES ; GLYCATION END-PRODUCTS ; CENTRAL-NERVOUS-SYSTEM ; CELL-ADHESION MOLECULE ; TOLL-LIKE RECEPTORS ; RHEUMATOID-ARTHRITIS ; SUSTAINED INTESTINAL INFLAMMATION ; NITRIC-OXIDE PRODUCTION ; PATTERN MOLECULES
    Abstract: Promiscuity of pattern recognition receptors, such as receptor for advanced glycation end products (RAGE), allows for a complex regulatory network controlling inflammation. Scavenging of RAGE ligands by soluble RAGE treatment is effective in reducing delayed-type hypersensitivity (DTH), even in RAGE(-/-) mice by 50% (p 〈 0.001). This has led to the hypothesis that molecules scavenged by soluble RAGE bind to receptors other than RAGE. This study identifies CD166/ALCAM (ALCAM) as a close structural and functional homolog of RAGE, and it shows that binding of S100B to CD166/ALCAM induces dose- and time-dependent expression of members of the NF-kappaB family in wild type (WT) and RAGE(-/-) mouse endothelial cells. Blocking CD166/ALCAM expression using small interfering RNA completely inhibited S100B-induced NF-kappaB activation in RAGE(-/-), but not in WT cells. The in vivo significance of these observations was demonstrated by attenuation of DTH in WT and RAGE(-/-) animals pretreated with CD166/ALCAM small interfering RNA by 50% and 40%, respectively (p 〈 0.001). Experiments in ALCAM(-/-) animals displayed an only slight reduction of 16% in DTH, explained by compensatory reciprocal upregulation of RAGE in animals devoid of CD166/ALCAM, and vice versa. Consistently, ALCAM(-/-) mice, but not WT mice treated with RAGE small interfering RNA show a 35% reduction in DTH, and ALCAM(-/-) RAGE(-/-) double-knockout mice show a 27% reduction in DTH reaction. Thus, S100B is a proinflammatory cytokine bridging RAGE and CD166/ALCAM downstream effector mechanisms, both being compensatory upregulated after genetic deletion of its counterpart.
    Type of Publication: Journal article published
    PubMed ID: 23729438
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  • 2
    Abstract: OBJECTIVE: The aim of this work was to localize and quantify alterations of nerve microstructure in diabetic polyneuropathy (DPN) by magnetic resonance (MR) neurography with large anatomical coverage. METHODS: Patients (N = 25) with mild-to-moderate (Neuropathy-Symptom-Score [NSS]/Neuropathy Deficit Score [NDS] 3.8 +/- 0.3/2.6 +/- 0.5) and patients (n = 10) with severe DPN (6.2 +/- 0.6/7.4 +/- 0.5) were compared to patients (n = 15) with diabetes but no DPN and to age-/sex-matched nondiabetic controls (n = 25). All subjects underwent MR neurography with large spatial coverage and high resolution from spinal nerve to ankle level: four slabs per leg, each with 35 axial slices (T2- and proton-density-weighted two dimensional turbo-spin-echo sequences; voxel size: 0.4 x 0.3 x 3.5 mm(3) ) and a three-dimensional T2-weighted sequence to cover spinal nerves and plexus. Nerve segmentation was performed on a total of 280 slices per subject. Nerve lesion voxels were determined independently from operator input by statistical classification against the nondiabetic cohort. At the site with highest lesion-voxel burden, signal quantification was performed by calculating nerve proton spin density and T2 relaxation time. RESULTS: Total burden of nerve lesion voxels was significantly increased in DPN (p = 0.003) with strong spatial predominance at thigh level, where average lesion voxel load was significantly higher in severe (57 +/- 18.4; p = 0.0022) and in mild-to-moderate DPN (35 +/- 4.0; p 〈 0.001) than in controls (18 +/- 3.6). Signal quantification at the site of predominant lesion burden (thigh) revealed a significant increase of nerve proton spin density in severe (360 +/- 22.9; p = 0.043) and in mild-to-moderate DPN (365 +/- 15.2; p = 0.001) versus controls (288 +/- 13.4), but not of T2 relaxation time (p = 0.49). Nerve proton spin density predicted severity of DPN with an odds ratio of 2.9 (95% confidence interval: 2.4-3.5; p 〈 0.001) per 100 proton spins. INTERPRETATION: In DPN, the predominant site of microstructural nerve alteration is at the thigh level with a strong proximal-to-distal gradient. Nerve proton spin density at the thigh level is a novel quantitative imaging biomarker of early DPN and increases with neuropathy severity. Ann Neurol 2015;78:939-948.
    Type of Publication: Journal article published
    PubMed ID: 26381658
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