Expression of the transcriptional regulator Egr-1 in experimental glomerulonephritis: Requirement for mesangial cell proliferation

Expression of the transcriptional regulator Egr-1 in experimental glomerulonephritis: Requirement for mesangial cell proliferation. The early growth response gene-1 (Egr-1), a zinc finger transcriptional regulator, was induced in a rat model of mesangioproliferative glomerulonephritis (GN). Northern blot analysis revealed a maximal 14.9-fold increase in glomerular Egr-1 mRNA at day 6 of GN. By immunohistochemistry Egr-1 protein expression was demonstrated to be mainly confined to glomerular mesangial cells (MC). To test whether Egr-1 directly regulates MC proliferation, cultured MCs were stimulated with platelet-derived growth factor (PDGF) after preincubation with different Egr-1 antisense oligonucleotides (ASOs). PDGF-induced Egr-1 mRNA levels were inhibited by up to 75% and protein levels by up to 91%. In addition Egr-1-specific ASOs blocked PDGF-induced rise in 3H-thymidine uptake by 83% and almost completely abrogated increase in MC number. We conclude that Egr-1 induction is of critical importance for PDGF-induced mitogenic signaling in MCs, and inhibition of Egr-1 in vivo may offer an approach to oppose glomerular MC proliferation in glomerular inflammatory disease

Is the Hexacyanoferrate(II) Anion Stable in Aqueous Solution? A Combined Theoretical and Experimental Study

A combined theoretical and experimental study was performed to elucidate the structural and dynamical properties of the isolated aqueous hexacyanoferrate(II) ion as well as in the presence of potassium counterions. It is shown that in absence of counterions, the highly negatively charged hexacyanoferrate(II) complex is not stable in aqueous solution. However, if the high negative charge is compensated by potassium counterions, a stable complex is observed, which is proven by theoretical simulations as well as by extended X-ray absorption fine structure (EXAFS) experiments. From the simulation it is found that potassium ions surrounding the complex are highly mobile and thus cannot be observed via EXAFS experiments. The structure of aqueous hexacyanoferrate(II) in the presence of potassium ions is identical to that of the solid-state structure, but the mobility of potassium ions is significantly increased in the liquid. These highly mobile potassium ions circulating the complex are the reason for the very short lifetime of hydrogen bonds between solvent water molecules and cyanide ligands being on the femtosecond scale

Robust segmentation of intraretinal layers in the normal human fovea using a novel statistical model based on texture and shape analysis

A novel statistical model based on texture and shape for fully automatic intraretinal layer segmentation of normal retinal tomograms obtained by a commercial 800nm optical coherence tomography (OCT) system is developed. While existing algorithms often fail dramatically due to strong speckle noise, non-optimal imaging conditions, shadows and other artefacts, the novel algorithm’s accuracy only slowly deteriorates when progressively increasing segmentation task difficulty. Evaluation against a large set of manual segmentations shows unprecedented robustness, even in the presence of additional strong speckle noise, with dynamic range tested down to 12dB, enabling segmentation of almost all intraretinal layers in cases previously inaccessible to the existing algorithms. For the first time, an error measure is computed from a large, representative manually segmented data set (466 B-scans from 17 eyes, segmented twice by different operators) and compared to the automatic segmentation with a difference of only 2.6% against the inter-observer variability

Highly reproducible swept-source, dispersion-encoded full-range biometry and imaging of the mouse eye

We report a high-speed, dispersion-encoded, full-range (DEFR) swept-source optical coherence tomography system for in vivo ocular imaging and biometry of small animals. The fast DEFR algorithm removes the depth ambiguity, gives access to objects located at the zero delay position, and doubles the sampling depth to 2×5.0 mm (at −101 to −71 dB sensitivity) in a single scan using 2048 samples/depth scan 0.43 nm line width of a light source operating at 1056 nm with 70 nm tuning range. The acquisition speed (frames of 512 depth scans in 18.3 ms) permits precise on-line monitoring during positioning and provides cross-sectional views of the mouse eye. Preliminary studies demonstrate high-throughput, reproducible assessment of multiple biometric features (e.g., day-to-day reproducibility of axial length measurement ±5.3 μm) that is insensitive to eye motion sufficient for long-term monitoring

Receptor for advanced glycation end products (RAGE) regulates sepsis but not the adaptive immune response

This is the publisher's version, also available electronically from http://www.jci.org/articles/view/18704While the initiation of the adaptive and innate immune response is well understood, less is known about cellular mechanisms propagating inflammation. The receptor for advanced glycation end products (RAGE), a transmembrane receptor of the immunoglobulin superfamily, leads to perpetuated cell activation. Using novel animal models with defective or tissue-specific RAGE expression, we show that in these animal models RAGE does not play a role in the adaptive immune response. However, deletion of RAGE provides protection from the lethal effects of septic shock caused by cecal ligation and puncture. Such protection is reversed by reconstitution of RAGE in endothelial and hematopoietic cells. These results indicate that the innate immune response is controlled by pattern-recognition receptors not only at the initiating steps but also at the phase of perpetuation

Three-Dimensional 1060-nm OCT: Choroidal thickness maps in normal subjects and improved posterior segment visualization in cataract patients

Purpose. To evaluate the performance and potential clinical role of three-dimensional (3D) 1060-nm OCT by generating choroidal thickness (ChT) maps in patients of different ages with different degrees of ametropia and axial lengths and to investigate the effect of cataract grade on OCT retinal imaging quality. Methods. Axial lengths (ALs) and 45° fundus photographs were acquired from 64 eyes (34 healthy subjects, 19 to 80 years, ametropia +3 to −10 D). 3D 1060-nm OCT was performed over a 36° × 36° field of view with ∼7-μm axial resolution and up to 70 frames/s (512 A-scans/frame). ChT maps between retinal pigment epithelium and the choroidal–scleral interface, were generated and statistically analyzed. A further 30 eyes (19 subjects), with cataracts assessed with the LOCS III scale, were imaged with 3D 1060-nm OCT and 800-nm OCT, and visualization of the posterior segment was compared qualitatively. Results. In 64 eyes, ChT maps displayed a thickness decrease with increasing AL. Subfoveal ChT was 315 ± 106 μm (mean ± SD), negatively correlated with AL (R2 = −0.47, P 24.5 mm showed a larger variation and a thicker ChT superiorly than inferiorly. Reduced signal strength in cataractous eyes was found in 65% of the 800-nm OCT images, but in only 10% of the 1060-nm OCT images. Conclusions. The imaging performance of 3D 1060-nm OCT is unique, producing maps that show the variation in ChT over the entire field of view, in relation to axial length. This imaging system has the potential of visualizing a novel clinical diagnostic biomarker. Compared with 800-nm OCT, it provides superior visualization of the posterior pole in cataractous eyes

Mapping choroidal and retinal thickness variation in Type 2 diabetes using three-dimensional 1060-nm optical coherence tomography

Purpose. To map choroidal (ChT) and retinal thickness (RT) in healthy subjects and patients with diabetes with and without maculopathy using three dimensional 1060-nm optical coherence tomography (3D-1060nm-OCT). Methods. Sixty-three eyes from 42 diabetic subjects (41–82 years of age; 11 females) grouped according to a custom scheme using Early Treatment Diabetic Retinopathy Study definitions for pathology within 1 disc-diameter of fovea (without pathology [NDR], microaneurysms [M1], exudates [M2], clinically significant macular edema [CSME]) and 16 eyes from 16 healthy age matched subjects (38–79 years of age; 11 females) were imaged by 3D-1060nm-OCT performed over a 36° × 36° field of view. Axial length, 45° fundus photographs, body mass index, plasma glucose, and blood pressure measurements were recorded. The ChT at the subfoveal location and ChT maps between RPE and the choroidal–scleral interface were generated and statistically analyzed. Results. RT maps show thinning in the NDR group but an increase in thickness with increasing maculopathy in the temporal and central regions (unpaired t-test; P < 0.05). ChT mapping of all diabetic patients revealed central and inferior thinning compared to healthy eyes (unpaired t-test; P < 0.001). Subfoveal ChT (mean ± SD) for healthy eyes was 327 ± 74 μm, which was significantly thicker than all diabetic groups (214 ± 55 μm for NDR, 208 ± 49 μm for M1, 205 ± 54 μm for M2, and 211 ± 76 μm for CSME (ANOVA P < 0.001; Tukey P < 0.001)

Selective breeding for susceptibility to myopia reveals a gene-environment interaction

Purpose. To test whether the interanimal variability in susceptibility to visually induced myopia is genetically determined. Methods. Monocular deprivation of sharp vision (DSV) was induced in outbred White Leghorn chicks aged 4 days. After 4 days' DSV, myopia susceptibility was quantified by the relative changes in axial length and refraction. Chicks in the extreme tails of the distribution of susceptibility to DSV were kept and paired for breeding (high- and low-susceptibility lines). A second round of selection was then performed. The third generation of chicks, derived from the selected parents, was assessed after either monocular DSV (4 or 10 days) or lens wear. Results. After two rounds of selective breeding, the chicks from the high-susceptibility line developed approximately twice as much myopia in response to 4 days' DSV as did those from the low-susceptibility line (P < 0.001). All ocular component dimensions differed significantly (P < 0.001) between the two selected lines, both before treatment and in the responses of the treated eye. When DSV was conducted for 10 days, the relative changes in axial length and refractive error were still significantly different between the high and low lines (P < 0.001). The chicks bred for high or low susceptibility to DSV also showed significantly different responses to minus lens wear, but not to plus lens wear. Additive genetic effects explained ∼50% of the interanimal variability in response to DSV. Conclusions. Genes and environment interact to shape refractive development in chicks