Temporal sequence of changes in rat retina after UV-A and blue light exposure

AbstractTwo spectral types of retinal light damage were induced in pigmented rats by irradiating small retinal patches at either 380 or 470 nm. The temporal sequence of changes in the retina was followed for up to 2 months by funduscopy and histology. For both damage types, fundus changes were best visible after 3 days. Histology showed that 380 nm specifically damaged photoreceptor cells, particularly the rods. All cell compartments of the rods, including the nucleus were affected already after 3 h. In the next days, damaged rods degenerated. At high doses (2.5×the funduscopic threshold dose) all rods in the irradiated area were lost, resulting in a local photoreceptor lesion, which was still present at 2 months after the irradiation. At 470 nm, damage occurred both in the photoreceptor layer and in the pigment epithelium. Acute changes, at 1 h after irradiation, consisted mainly of damaged mitochondria in these layers. Next, the pigment epithelium showed swelling, an altered melanin distribution and, at high doses (2.5×threshold), interruptions of the monolayer. Degeneration of photoreceptor cells was initially limited to a few scattered cells, but 3 days after high doses focal areas of massive degeneration were seen. At late stages, the cells of the pigment epithelium recovered and the photoreceptor layer showed a loss of cells. The results show that the spectral damage types are distinct in the early phases, indicating that different mechanisms are involved. Yet, the end effect of both damage types after exposure at doses up to 2.5×the funduscopic threshold is remarkably similar and consists of local photoreceptor lesions

Modeling the Mechanical Parameters of Glaucoma

Glaucoma is a major eye disease characterized by a progressive loss of retinal ganglion cells (RGCs). Biomechanical forces as a result of hydrostatic pressure and strain play a role in this disease. Decreasing intraocular pressure is the only available therapy so far, but is not always effective and does not prevent blindness in many cases. There is a need for drugs that protect RGCs from dying in glaucoma; to develop these, we need valid glaucoma and drug screening models. Since in vivo models are unsuitable for screening purposes, we focus on in vitro and ex vivo models in this review. Many groups have studied pressure and strain model systems to mimic glaucoma, to investigate the molecular and cellular events leading to mechanically induced RGC death. Therefore, the focus of this review is on the different mechanical model systems used to mimic the biomechanical forces in glaucoma. Most models use either cell or tissue strain, or fluid- or gas-controlled hydrostatic pressure application and apply it to the relevant cell types such as trabecular meshwork cells, optic nerve head astrocytes, and RGCs, but also to entire eyes. New model systems are warranted to study concepts and test experimental compounds for the development of new drugs to protect vision in glaucoma patients

Plasma GDF-15 concentration is not elevated in open-angle glaucoma

Aim Recently, the level of growth differentiation factor 15 (GDF-15) in blood, was proposed as biomarker to detect mitochondrial dysfunction. In the current study, we evaluate this biomarker in open-angle glaucoma (OAG), as there is increasing evidence that mitochondrial dysfunction plays a role in the pathophysiology of this disease. Methods Plasma GDF-15 concentrations were measured with ELISA in 200 OAG patients and 61 age-matched controls (cataract without glaucoma). The OAG patient group consisted of high tension glaucoma (HTG; n = 162) and normal tension glaucoma (NTG; n = 38). Groups were compared using the Kruskal-Wallis nonparametric test with Dunn’s multiple comparison post-hoc correction. GDF-15 concentration was corrected for confounders identified with forward linear regression models. Results Before correcting for confounders, median plasma GDF-15 levels was significantly lower in the combined OAG group (p = 0.04), but not when analysing HTG and NTG patients separately. Forward linear regression analysis showed that age, gender, smoking and systemic hypertension were significant confounders affecting GDF-15 levels. After correction for these confounders, GDF-15 levels in OAG patients were no longer significantly different from controls. Subgroup analysis of the glaucoma patients did not show a correlation between disease severity and plasma GDF-15, but did reveal that for NTG patients, intake of dietary supplements, which potentially improve mitochondrial function, correlated with lower plasma GDF-15. Conclusion The present study suggests that plasma GDF-15 is not suited as biomarker of mitochondrial dysfunction in OAG patients

The level of hepatic ABCC6 expression determines the severity of calcification after cardiac injury

Because vascular or cardiac mineralization is inversely correlated with morbidity and long-term survival, we investigated the role of ABCC6 in the calcification response to cardiac injury in mice. By using two models of infarction, nonischemic cryoinjury and the pathologically relevant coronary artery ligation, we confirmed a large propensity to acute cardiac mineralization in Abcc6-/- mice. Furthermore, when the expression of ABCC6 was reduced to approximately 38% of wild-type levels in Abcc6+/- mice, no calcium deposits in injured cardiac tissue were observed. In addition, we used a gene therapy approach to deliver a functional human ABCC6 via hydrodynamic tail vein injection to approximately 13% of mouse hepatocytes, significantly reducing the calcification response to cardiac cryoinjury. We observed that the level and distribution of known regulators of mineralization, such as osteopontin and matrix Gla protein, but not osteocalcin, were concomitant to the level of hepatic expression of human and mouse ABCC6. We notably found that undercarboxylated matrix Gla protein precisely colocalized within areas of mineralization, whereas osteopontin was more diffusely distributed in the area of injury, suggesting a prominent association for matrix Gla protein and osteopontin in ABCC6-related dystrophic cardiac calcification. This study showed that the expression of ABCC6 in liver is an important determinant of calcification in cardiac tissues in response to injuries and is associated with changes in the expression patterns of regulators of mineralization. © 2014 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved

The vast complexity of primary open angle glaucoma:Disease genes, risks, molecular mechanisms and pathobiology

<p>Primary open angle glaucoma (POAG) is a complex progressive optic nerve neuropathy triggered by both environmental and genetic risk factors. Several ocular tissues, including the ciliary body, trabecular meshwork and optic nerve head, and perhaps even brain tissues, are involved in a chain of pathological events leading to POAG.</p><p>Genetic risk evidence for POAG came from family linkage-studies implicating a small number of disease genes (MYOC, OPEN, WDR36). Recent Genome Wide Association Studies (GWAS) identified a large number of new POAG loci and disease genes, such as CAV1, CDKN2B and GAS7. In the current study, we reviewed over 120 family and GWA studies. We selected in total 65 (candidate) POAG disease genes and proceeded to assess their function, mRNA expression in POAG relevant eye tissues and possible changes in disease state. We found that the proteins corresponding to these 65 (candidate) POAG disease genes take part in as few as four common functional molecular networks. Functions attributed to these 4 networks were developmental (dys)function, lipid metabolism, and inflammatory processes. For the 65 POAG disease genes, we reviewed the available (transgenic) mouse models of POAG, which may be useful for future functional studies. Finally, we showed that the 65 (candidate) POAG genes substantially increased the specificity and sensitivity of a discriminative POAG risk test. This suggests that personal risk assessment and personalized medicine for POAG are on the horizon. Taken together, the data presented are essential to comprehend the role of genetic variation in POAG, and may provide leads to understand the pathophysiology of POAG as well as other neurodegenerative disorders, such as Alzheimer's disease. (C) 2013 Elsevier Ltd. All rights reserved.</p>