miR-30a-5p inhibition promotes interaction of Fas+ endothelial cells and FasL+ microglia to decrease pathological neovascularization and promote physiological angiogenesis.

Ischemia-induced angiogenesis contributes to various neuronal and retinal diseases, and often results in neurodegeneration and visual impairment. Current treatments involve the use of anti-VEGF agents but are not successful in all cases. In this study we determined that miR-30a-5p is another important mediator of retinal angiogenesis. Using a rodent model of ischemic retinopathy, we show that inhibiting miR-30a-5p reduces neovascularization and promotes tissue repair, through modulation of microglial and endothelial cell cross-talk. miR-30a-5p inhibition results in increased expression of the death receptor Fas and CCL2, to decrease endothelial cell survival and promote microglial migration and phagocytic function in focal regions of ischemic injury. Our data suggest that miR-30a-5p inhibition accelerates tissue repair by enhancing FasL-Fas crosstalk between microglia and endothelial cells, to promote endothelial cell apoptosis and removal of dead endothelial cells. Finally, we found that miR-30a levels were increased in the vitreous of patients with proliferative diabetic retinopathy. Our study identifies a role for miR-30a in the pathogenesis of neovascular retinal disease by modulating microglial and endothelial cell function, and suggests it may be a therapeutic target to treat ischemia-mediated conditions.

Transcriptome-wide analysis of small RNA expression in early zebrafish development.

During early vertebrate development, a large number of noncoding RNAs are maternally inherited or expressed upon activation of zygotic transcription. The exact identity, expression levels, and function for most of these noncoding RNAs remain largely unknown. miRNAs (microRNAs) and piRNAs (piwi-interacting RNAs) are two classes of small noncoding RNAs that play important roles in gene regulation during early embryonic development. Here, we utilized next-generation sequencing technology to determine temporal expression patterns for both miRNAs and piRNAs during four distinct stages of early vertebrate development using zebrafish as a model system. For miRNAs, the expression patterns for 198 known miRNAs within 122 different miRNA families and eight novel miRNAs were determined. Significant sequence variation was observed at the 5' and 3'ends of miRNAs, with most extra nucleotides added at the 3' end in a nontemplate directed manner. For the miR-430 family, the addition of adenosine and uracil residues is developmentally regulated and may play a role in miRNA stability during the maternal zygotic transition. Similar modification at the 3' ends of a large number of miRNAs suggests widespread regulation of stability during early development. Beside miRNAs, we also identified a large and unexpectedly diverse set of piRNAs expressed during early development.

Atypical Variant of Posterior Reversible Encephalopathy Syndrome in the Setting of Renovascular Hypertension: Case Report and Review of Literature.

Posterior reversible encephalopathy syndrome (PRES) is a clinico-radiologic syndrome resulting in subcortical vasogenic edema appreciated on T2/fluid-attenuated inversion recovery (FLAIR) sequence of magnetic resonance imaging (MRI). PRES classically involves bilateral parieto-occipital lobes and is usually reversible. Atypical variant of PRES includes the involvement of brainstem, basal ganglia, thalami, or periventricular white matter. We report an unusual case of PRES with isolated brainstem involvement with periventricular white matter changes in a patient with renovascular hypertension from unilateral renal artery stenosis. To our knowledge, this is the first case of secondary hypertension from renal artery stenosis resulting in the atypical variant of PRES.

Gastric Volume and Its Relationship to Underlying Pathology or Acid-suppressing Medication.

BACKGROUND: Pulmonary aspiration during sedation is a major concern for sedation providers, making identifying high-risk patients a priority. Gastric fluid volume (GFV), an accepted risk factor for aspiration, has not been well characterized in fasting children. We hypothesized that GFV would increase with gastrointestinal (GI) pathology and decrease with regular acid-suppressor use. AIMS: The primary objective was to determine baseline GFV in fasting children. The secondary objectives were to evaluate the effect of GI pathology and regular use of acid-suppressing medications on GFV. SETTINGS AND STUDY DESIGN: This was prospective, observational study. MATERIALS AND METHODS: We endoscopically aspirated and measured GFV of 212 children fasting for >6 h who were sedated for esophagogastroduodenoscopy (EGD). Inclusion criteria were children up to 21 years of age, with the American Society of Anesthesiologists physical Status I and II presenting for elective EGD. After determining baseline GFV, the effect of GI pathology and effect of regular acid-suppressing medication use on GFV was analyzed. STATISTICAL ANALYSIS: Analysis of variance was used to compare the GFV among ages and pathology and medication groups. Student's t-test was used to compare GFV between genders and also to compare GFV in confounder analyses. RESULTS: For the studied 212 children, average GFV was 0.469 ± 0.448 mL/kg (0-2.663 mL/kg). We found no association between GI pathology and GFV (P = 0.147), or acid-suppressor use and GFV (P = 0.360). CONCLUSIONS: Average GFV in this study falls within the range of prior EGD-measured GFV in fasting children. Contrary to our hypothesis, we found no association between pathologies or regular acid-suppressor use on GFV. On the basis of GFV, children with GI disorders or those using acid-suppressors do not appear to pose an increased risk of aspiration. Future studies should discern differences in effects on GFV of immediate preprocedural versus the regular use of acid-suppressing medications.

Hypoxia-induced metabolic stress in retinal pigment epithelial cells is sufficient to induce photoreceptor degeneration.

Photoreceptors are the most numerous and metabolically demanding cells in the retina. Their primary nutrient source is the choriocapillaris, and both the choriocapillaris and photoreceptors require trophic and functional support from retinal pigment epithelium (RPE) cells. Defects in RPE, photoreceptors, and the choriocapillaris are characteristic of age-related macular degeneration (AMD), a common vision-threatening disease. RPE dysfunction or death is a primary event in AMD, but the combination(s) of cellular stresses that affect the function and survival of RPE are incompletely understood. Here, using mouse models in which hypoxia can be genetically triggered in RPE, we show that hypoxia-induced metabolic stress alone leads to photoreceptor atrophy. Glucose and lipid metabolism are radically altered in hypoxic RPE cells; these changes impact nutrient availability for the sensory retina and promote progressive photoreceptor degeneration. Understanding the molecular pathways that control these responses may provide important clues about AMD pathogenesis and inform future therapies.

Neurovascular crosstalk between interneurons and capillaries is required for vision.

Functional interactions between neurons, vasculature, and glia within neurovascular units are critical for maintenance of the retina and other CNS tissues. For example, the architecture of the neurosensory retina is a highly organized structure with alternating layers of neurons and blood vessels that match the metabolic demand of neuronal activity with an appropriate supply of oxygen within perfused blood. Here, using murine genetic models and cell ablation strategies, we have demonstrated that a subset of retinal interneurons, the amacrine and horizontal cells, form neurovascular units with capillaries in 2 of the 3 retinal vascular plexuses. Moreover, we determined that these cells are required for generating and maintaining the intraretinal vasculature through precise regulation of hypoxia-inducible and proangiogenic factors, and that amacrine and horizontal cell dysfunction induces alterations to the intraretinal vasculature and substantial visual deficits. These findings demonstrate that specific retinal interneurons and the intraretinal vasculature are highly interdependent, and loss of either or both elicits profound effects on photoreceptor survival and function.

Ras pathway inhibition prevents neovascularization by repressing endothelial cell sprouting.

Vascular networks develop from a growing vascular front that responds to VEGF and other guidance cues. Angiogenesis is required for normal tissue function, but, under conditions of stress, inappropriate vascularization can lead to disease. Therefore, inhibition of angiogenic sprouting may prevent neovascularization in patients with blinding neovascular eye diseases, including macular degeneration. VEGF antagonists have therapeutic benefits but also can elicit off-target effects. Here, we found that the Ras pathway, which functions downstream of a wide range of cytokines including VEGF, is active in the growing vascular front of developing and pathological vascular networks. The endogenous Ras inhibitor p120RasGAP was expressed predominately in quiescent VEGF-insensitive endothelial cells and was ectopically downregulated in multiple neovascular models. MicroRNA-132 negatively regulated p120RasGAP expression. Experimental delivery of α-miR-132 to developing mouse eyes disrupted tip cell Ras activity and prevented angiogenic sprouting. This strategy prevented ocular neovascularization in multiple rodent models even more potently than the VEGF antagonist, VEGF-trap. Targeting microRNA-132 as a therapeutic strategy may prove useful for treating multiple neovascular diseases of the eye and for preventing vision loss regardless of the neovascular stimulus.