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Aim: Amitriptyline (AMI) has been used to treat neuropathic pain. However, the clinical outcomes remain unsatisfactory, presumably due to a limited understanding of the underlying molecular mechanisms. Here, we investigated a drug repositioning strategy using a low-dose of AMI encapsulated in poly (D, L lactic-co-glycolic acid) (PLGA) nanoparticles (AMI NPs) for neuropathic pain, since PLGA nanoparticles are known to enhance delivery to microglia. Methods: We evaluated the anti-allodynic effects of AMI and AMI NPs on neuropathic pain by assessing behaviors and inflammatory responses in a rat model of spinal nerve ligation (SNL). While the anti-allodynic effect of AMI (30 μg) drug injection on SNL-induced neuropathic pain persisted for 12 h, AMI NPs significantly alleviated mechanical allodynia for 3 days. Results: Histological and cytokine analyses showed AMI NPs facilitated the reduction of microglial activation and pro-inflammatory mediators in the spinal dorsal horn. This study suggests that AMI NPs can provide a sustained anti-allodynic effect by enhancing the targeting of microglia and regulating the release of pro-inflammatory cytokines from activated microglia. Conclusion: Our findings suggest that the use of microglial-targeted NPs continuously releasing AMI (2 μg) as a drug repositioning strategy offers long-term anti-allodynic effects. Graphical Abstract Article highlights This study investigated a drug repositioning strategy using a low-dose of AMI encapsulated in poly (D, L lactic-co-glycolic acid) (PLGA) nanoparticles (AMI NPs) for neuropathic pain, since PLGA nanoparticles are known to enhance delivery to microglia. While the anti-allodynic effect of AMI (30 μg) drug injection on SNL-induced neuropathic pain persisted for 12 h, AMI NPs significantly alleviated mechanical allodynia for 3 days. This study suggests that AMI NPs can provide a sustained anti-allodynic effect by enhancing the targeting of microglia and regulating the release of pro-inflammatory cytokines from activated microglia. [ABSTRACT FROM AUTHOR]

Background Midcheek lift has been performed for cosmetic or reconstructive surgery of the lower eyelid. For midcheek lift through the subciliary incision, preperiosteal and subperiosteal dissections are the most often implemented, with good clinical outcomes. However, a comparative assessment of the effects of these 2 methods had not been conducted. Objectives In this study we compared the effects of midcheek lift according to preperiosteal or subperiosteal plane and range of midfacial dissection. Methods Forty hemifaces of 20 fresh cadavers were dissected. One side of the hemiface underwent preperiosteal dissection, and the other side underwent subperiosteal dissection. After dissections of 5, 10, 15, 20, and 30 mm and all of the midcheek area from the inferior orbital rim, the length of the elevated lid-cheek junction was measured by placing upward traction on the lateral portion of the lower lid. Results In both methods, the length of the midcheek lift increased as the dissection progressed, and the length of the lift on the lateral side was greater than that on the medial side. The length of the pulled skin in the preperiosteal group was the greatest in most cases. However, in the full dissection cases, the midcheek lift length was not statistically different between the 2 surgical methods, especially on the lateral side. Conclusions Flap elevation in lower blepharoplasty surgery can be predicted based on the surgical method and dissection range. Implementing a surgical plan that takes this into account can enhance both reconstruction and aesthetic surgery outcomes in the midcheek area. [ABSTRACT FROM AUTHOR]

Age-dependent accumulation of amyloid plaques in patients with sporadic Alzheimer's disease (AD) is associated with reduced amyloid clearance. Older microglia have a reduced ability to phagocytose amyloid, so phagocytosis of amyloid plaques by microglia could be regulated to prevent amyloid accumulation. Furthermore, considering the aging-related disruption of cell cycle machinery in old microglia, we hypothesize that regulating their cell cycle could rejuvenate them and enhance their ability to promote more efficient amyloid clearance. First, we used gene ontology analysis of microglia from young and old mice to identify differential expression of cyclin-dependent kinase inhibitor 2A (p16ink4a), a cell cycle factor related to aging. We found that p16ink4a expression was increased in microglia near amyloid plaques in brain tissue from patients with AD and 5XFAD mice, a model of AD. In BV2 microglia, small interfering RNA (siRNA)-mediated p16ink4a downregulation transformed microglia with enhanced amyloid phagocytic capacity through regulated the cell cycle and increased cell proliferation. To regulate microglial phagocytosis by gene transduction, we used poly (D,L-lactic-co-glycolic acid) (PLGA) nanoparticles, which predominantly target microglia, to deliver the siRNA and to control microglial reactivity. Nanoparticle-based delivery of p16ink4a siRNA reduced amyloid plaque formation and the number of aged microglia surrounding the plaque and reversed learning deterioration and spatial memory deficits. We propose that downregulation of p16ink4a in microglia is a promising strategy for the treatment of Alzheimer's disease. [ABSTRACT FROM AUTHOR]

The effect of the reaction between alloy elements and slag on the evolution behavior of non-metallic inclusions in high-Al or Si-alloyed steel melts was investigated at 1873 K (1600 °C). Aluminum (1.5 mass pct) added to the molten steel produces an alumina-rich inclusion by reaction with oxygen, and it reduces FeO by the interfacial reaction with the CaO–Al2O3–FeO–SiO2–MgO slag, resulting in an increase of the alumina content of the slag. On the other hand, silicon (4.0 mass pct) added to the molten steel increases the silica content of the slag by the interfacial reactions with the slag and causing aluminum pick-up from the liquid slag into the molten steel, which changed the existing silica-rich inclusion into aluminum-rich inclusions. The addition of each of the two alloying elements produced alumina-rich inclusions, and the two series of existing alumina inclusions were modified into MgAl2O4 spinel inclusions by picking up magnesium from the slag into the molten steel. Through a population density function (PDF) analysis of inclusion particles, we confirmed that inclusion growth occurred by diffusion of magnesium and aluminum in steel with 1.5 pct Al or 4.0 pct Si. The supersaturation degree for alumina inclusions in the 1.5 pct Al-added steel and 4.0 pct Si-added steel continued to decrease as the reaction time increased. As a result, dendritic or spherical alumina inclusions were observed in both series at 1 minute of alloying, and small, independently present polygonal-shaped MgAl2O4 spinel inclusions were mainly observed at 30 minutes of alloying. [ABSTRACT FROM AUTHOR]