Differential Vulnerability and Response to Injury among Brain Cell Types Comprising the Neurovascular Unit.

The neurovascular unit (NVU) includes multiple different cell types, including neurons, astrocytes, endothelial cells, and pericytes, which respond to insults on very different time or dose scales. We defined differential vulnerability among these cell types, using response to two different insults: oxygen-glucose deprivation (OGD) and thrombin-mediated cytotoxicity. We found that neurons are most vulnerable, followed by endothelial cells and astrocytes. After temporary focal cerebral ischemia in male rats, we found significantly more injured neurons, compared with astrocytes in the ischemic area, consistent with differential vulnerability in vivo. We sought to illustrate different and shared mechanisms across all cell types during response to insult. We found that gene expression profiles in response to OGD differed among the cell types, with a paucity of gene responses shared by all types. All cell types activated genes relating to autophagy, apoptosis, and necroptosis, but the specific genes differed. Astrocytes and endothelial cells also activated pathways connected to DNA repair and antiapoptosis. Taken together, the data support the concept of differential vulnerability in the NVU and suggest that different elements of the unit will evolve from salvageable to irretrievable on different time scales while residing in the same brain region and receiving the same (ischemic) blood flow. Future work will focus on the mechanisms of these differences. These data suggest future stroke therapy development should target different elements of the NVU differently.

Before, during, and after: An Argument for Safety and Improved Outcome of Thrombolysis in Acute Ischemic Stroke with Direct Oral Anticoagulant Treatment.

Direct oral anticoagulants are the primary stroke prevention option in patients with atrial fibrillation. Anticoagulant use before stroke, however, might inhibit clinician comfort with thrombolysis if a stroke does occur. Resuming anticoagulants after ischemic stroke is also problematic for fear of hemorrhage. We describe extensive literature showing that thrombolysis is safe after stroke with direct anticoagulant use. Early reinstitution of direct anticoagulant treatment is associated with lower risk of embolic recurrence and lower hemorrhage risk. The use of direct anticoagulants before, during, and after thrombolysis appears to be safe and is likely to promote improved outcomes after ischemic stroke. ANN NEUROL 2024.

MicroRNA-494 augments fibrotic transformation of human retinal pigment epithelial cells and targets p27 with cell-type specificity.

Epiretinal membranes (ERMs) are the result of fibro-cellular proliferation that cause distortion and impairment of central vision. We hypothesized that select microRNAs (miRs) regulate retinal fibro-proliferation and ERM formation. Following IRB approval, a pilot study was performed in patients presenting for retina surgery with and without clinical ERMs. Total RNA was isolated from ERM tissue and controls from non-ERM vitreous and subjected to miR profiling via microarray analysis. MiR-494 was identified as the only miR selectively expressed at significantly greater levels, and in silico analysis identified p27 as a putative fibroproliferative gene target of miR-494. In vitro testing of miR-494 and p27 in fibrotic transformation was assessed in spontaneously immortalized human retinal pigment epithelial (RPE) and human Müller cell lines, stimulated to transform into a fibroproliferative state via transforming growth factor beta (TGFß). Fibroproliferative transformation was characterized by de novo cellular expression of alpha smooth muscle actin (αSMA). In both RPE and Müller cells, both TGFß and miR-494 mimic decreased p27 expression. In parallel experiments, transfection with p27 siRNA augmented TGFß-induced αSMA expression, while only in RPE cells did co-transfection with miR-494 inhibitor decrease αSMA levels. These results demonstrate that miR-494 augments fibrotic transformation in both Müller cells and RPEs, however only in RPEs does miR-494 mediate fibrotic transformation via p27. As p27 is known to regulate cellular proliferation and differentiation, future studies should extend clinical testing of miR-494 and/or p27 as a potential novel non-surgical therapy for ERMs, as well as identify relevant miR-494 targets in Müller cells.

"En-glove" lysis of lower eyelid retractors with AlloDerm and dermis-fat grafts in lower eyelid retraction surgery.

PURPOSE: To describe a minimally invasive surgical technique using AlloDerm or dermis-fat grafts for lower eyelid retraction. METHODS: A retrospective review of all patients undergoing lower eyelid retraction surgery via a minimal invasive, "en-glove" technique from 2005 through 2009. Charts were reviewed for the type of graft (AlloDerm or dermis-fat) used, the etiology of lower eyelid retraction, and the follow-up time. Outcome measures included lower eyelid height (measured from the corneal light reflex to the lower eyelid margin, or MRD2), reduction of lagophthalmos, cosmetic appearance, complications, and need for further surgery. Presurgery and postreconstruction photographs were reviewed and graded for functional and cosmetic outcome. RESULTS: A total of 8 patients underwent successful lower eyelid retraction surgery using this minimally invasive technique. Etiologies included thyroid eye disease and cicatricial paralytic lower eyelid retraction. Mean improvement in MRD2 was 1.5 mm for the AlloDerm group (4 patients, 7 eyelids) and 1.0 mm for the dermis-fat group (4 patients, 4 eyelids) after a minimum of 3 months' follow-up. The cosmetic result was satisfactory in all cases. CONCLUSIONS: "En-glove" lower eyelid retraction surgical technique offers a minimally invasive approach for the release of the lower eyelid retractors and allows for volume augmentation using either AlloDerm or dermis-fat spacer graft.