Types of Damages in Fission-Neutron Irradiated Cu and Cu Dilute Alloys at 200℃

The damage structures in Cu and Cu based alloys neutron-irradiated at 200℃ were examined by transmission electron microscopy. Large dislocation loops of complex structure and small dot defects were formed in the specimens. The large dislocation loops were interstitial type. On the other hand, the small dot defects were vacancy type. They were stacking faulted tetrahedra. The damage structure in these metals evolves as follows. Interstitial atoms produced by neutron irradiation aggregate and grow to large complicated loops which will become finally dislocation lines by intersection of them with further irradiation, by absorbing interstitials subsequently produced. By the consumption of the interstitials to the sinks, vacancy concentration increases locally to be high enough to form vacancy defects

An angiogenic role for adrenomedullin in choroidal neovascularization.

PURPOSE: Adrenomedullin (ADM) has been shown to take part in physiological and pathological angiogenesis. The purpose of this study was to investigate whether ADM signaling is involved in choroidal neovascularization (CNV) using a mouse model. METHODS AND RESULTS: CNV was induced by laser photocoagulation in 8-week-old C57BL/6 mice. ADM mRNA expression significantly increased following treatment, peaking 4 days thereafter. The expression of ADM receptor (ADM-R) components (CRLR, RAMP2 and RAMP 3) was higher in CD31(+)CD45(-) endothelial cells (ECs) than CD31(-)CD45(-) non-ECs. Inflammatory stimulation upregulated the expression of ADM not only in cell lines but also in cells in primary cultures of the choroid/retinal pigment epithelium complex. Supernatants from TNFα-treated macrophage cell lines potentiated the proliferation of ECs and this was partially suppressed by an ADM antagonist, ADM (22-52). Intravitreous injection of ADM (22-52) or ADM neutralizing monoclonal antibody (mAb) after laser treatment significantly reduced the size of CNV compared with vehicle-treated controls (p<0.01). CONCLUSIONS: ADM signaling is involved in laser-induced CNV formation, because both an ADM antagonist and ADM mAb significantly inhibited it. Suppression of ADM signaling might be a valuable alternative treatment for CNV associated with age-related macular degeneration

An Angiogenic Role for Adrenomedullin in Choroidal Neovascularization

金沢大学医薬保健研究域医学系Purpose: Adrenomedullin (ADM) has been shown to take part in physiological and pathological angiogenesis. The purpose of this study was to investigate whether ADM signaling is involved in choroidal neovascularization (CNV) using a mouse model. Methods and Results: CNV was induced by laser photocoagulation in 8-week-old C57BL/6 mice. ADM mRNA expression significantly increased following treatment, peaking 4 days thereafter. The expression of ADM receptor (ADM-R) components (CRLR, RAMP2 and RAMP 3) was higher in CD31+CD45- endothelial cells (ECs) than CD31-CD45- non-ECs. Inflammatory stimulation upregulated the expression of ADM not only in cell lines but also in cells in primary cultures of the choroid/retinal pigment epithelium complex. Supernatants from TNFα-treated macrophage cell lines potentiated the proliferation of ECs and this was partially suppressed by an ADM antagonist, ADM (22-52). Intravitreous injection of ADM (22-52) or ADM neutralizing monoclonal antibody (mAb) after laser treatment significantly reduced the size of CNV compared with vehicle-treated controls (p&lt;0.01). Conclusions: ADM signaling is involved in laser-induced CNV formation, because both an ADM antagonist and ADM mAb significantly inhibited it. Suppression of ADM signaling might be a valuable alternative treatment for CNV associated with age-related macular degeneration. © 2013 Sakimoto et al

ADM expression after laser treatment.

<p>(A) Time course ADM mRNA expression by qRT–PCR analysis in the RPE/choroid complex after laser treatment. Results are shown as fold-increase in comparison with RPE/choroid complexes from sham-operated eyes. (B) qRT–PCR analysis of ADM mRNA expression in sorted CD31⁺ cells (EC-enriched cell population), CD11b⁺ cells (monocyte/macrophage lineage cells) and cells negative for either CD31 or CD11b (non-EC, non-monocyte/macrophage lineage fraction) 3 days after laser treatment (n≧5). (C) qRT–PCR analysis of ADM mRNA expression in sorted CD31⁺ cells after laser treatment (CNV) compared to sham-treated eye<b>s</b> (sham). (n≧5, *P<0.05) (D) qRT–PCR analysis of ADM mRNA expression in sorted CD11b⁺ cells after laser treatment compared to sham-treated eyes. (n≧5, *P<0.05).</p

Expression of ADM receptors in choroidal ECs.

<p>(A, B) Hematoxylin-eosin-stained light micrograph of normal eye (A) and CNV lesion 7 days after laser treatment (B). Bar, 100 µm. (C) Light micrograph of serial sections of (B). Bar, 100 µm. (D) Immunohistochemistry of (C) with anti-PECAM-1/CD31 antibody. Dotted line indicates the borderline between the neural retina and RPE. Because the CNV lesion did not invade into the retina in this model, we could sort the ECs not from nerural retina but from CNV lesions and choroidal tissue in the following flow cytometry experiments. Bar, 100 µm. (E) Flow cytometric analysis of choroidal ECs from wild-type mice. CD31⁺CD45⁻ cells gated on the right are designated as ECs. (F) Quantitative evaluation of the percentage of choroidal EC 7 days after laser treatment. The number was calculated per cell total (n = ≧5, *P<0.05). (G) qRT–PCR analysis of ADM receptor component expression in choroidal ECs. The value in CD31⁺CD45⁻ECs was compared with that in CD31⁻CD45⁻ non-ECs sorted as gated in (A). Note that the expression level of ADM receptors is not significantly different between ECs and non-ECs in both sham-operated mice (sham) and laser-irradiated CNV mice (CNV). (H) Immunostaining of the CNV 7 days after laser treatment with anti-PECAM-1 (red) and anti-CRLR (green) antibody. High maginification indicate the dotted box in Low magnification. Bar, 100 µm.</p