Microglia, the resident immune cells of the central nervous system, can display a pro-inflammatory M1 phenotype or an anti-inflammatory M2 phenotype. Arginase (Arg)-1 expressed in interleukin-4 (IL-4)-induced M2 microglia reduces nitric oxide (NO) production by competing with inducible NO synthase for L-arginine, which contributes to the attenuation of brain inflammation. Although previous studies have indicated that brain zinc promotes M1 activation, the effect of zinc on M2 microglial activation remains to be determined. In the present study, murine primary microglia treated with 10 ng mL⁻¹ IL-4 exhibited increased Arg-1 mRNA expression and levels of intracellular free zinc. Chelation of this increased intracellular free zinc by the cell permeable zinc chelator N,N,N′,N′-tetrakis-(2-pyridylmethyl)ethylenediamine (TPEN) aggravated the IL-4-induced mRNA expression and enzymatic activity of Arg-1. However, the cell impermeable zinc chelator CaEDTA had no effect on Arg-1 expression or cytosolic levels of free zinc in IL-4-induced M2-polarized microglia. Furthermore, treatment with IL-4 resulted in upregulation of phagocytic activity in microglia, while administration of TPEN abolished IL-4-induced phagocytic activity. Moreover, this effect was reversed viaL-arginine supplementation. These findings suggest that IL-4 induces an increase in intracellular free zinc in microglia, which may act as a negative regulator of IL-4-induced Arg-1 expression, and that such negative regulation is essential for microglial phagocytic activity.

Background/Objectives: Non-saccular aneurysms are a rare subtype of intracranial aneurysms with complex morphologies. Although treatment strategies for ruptured non-saccular and saccular aneurysms differ significantly, large-scale comparisons of the outcomes between the two types remain limited. We aimed to compare the clinical characteristics, procedure-related complications, and functional outcomes between patients with subarachnoid hemorrhage (SAH) caused by non-saccular or saccular aneurysms. Methods: We retrospectively analyzed 1176 consecutive patients with aneurysmal SAH from a population-based stroke registry in Kochi Prefecture, Japan. Aneurysms were classified as saccular or non-saccular based on the morphology, and clinical variables, radiological features, and treatment modalities were compared. Additionally, 840 patients who underwent intervention for their aneurysms within 3 days of onset were further investigated to evaluate the impact of the non-saccular aneurysm shape on poor functional outcomes, defined as a modified Rankin Scale score ≥ 3 at discharge. Results: Non-saccular aneurysms were more common in younger patients and located in the posterior circulation. Procedure-related ischemic complications were more likely to occur in non-saccular aneurysms than in saccular aneurysms (odds ratio [OR]: 2.57, 95% confidence interval [CI]: 1.56–4.97, p < 0.001). In a multivariable logistic regression analysis, a non-saccular morphology was an independent risk factor of poor outcomes (OR: 2.92, 95% CI: 1.34–6.32, p = 0.007) after adjustment for potential confounders. Interaction and subgroup analyses revealed that the negative effects of non-saccular aneurysms on functional outcomes were more prominent in younger patients aged ≤ 60 years. Conclusions: Non-saccular aneurysms are independently associated with ischemic complications and poor outcomes after SAH, particularly in younger patients.

Background/Objectives: Aneurysmal subarachnoid hemorrhage (SAH) requires prompt treatment, yet hospital admission is occasionally delayed, and the optimal treatment strategy for such patients remains to be established. We aimed to investigate treatment modality, treatment timing, and outcomes in patients with SAH with respect to early versus delayed admission. Methods: A total of 1080 patients with SAH and a defined onset date were included in this prefecture-wide, multicenter, registry-based study. Baseline characteristics, late SAH complications (including vasospasm), and functional outcomes were compared between early and delayed admission groups at Day 4 or later (Day 0 = SAH onset). Additionally, the association of treatment choice (endovascular therapy or direct surgery) with treatment timing was analyzed in the delayed admission group. Results: Delayed admission was observed in 69 (6.4%) patients. The neurological status upon admission was significantly better in the delayed admission group, with more World Federation of Neurological Societies grades I–II (89.8% vs. 56.2% in the early admission group). Delayed admission was significantly associated with an increased incidence of symptomatic vasospasm by multivariable logistic regression analysis (odds ratio 2.51: 95% confidence interval 1.26–5.00, p = 0.009), while a significant difference in poor functional outcomes (modified Rankin scale 3–6) was not revealed. Although endovascular therapy use did not increase in the delayed admission group, the interval from admission to endovascular therapy was significantly shorter than that in the direct surgery group (0 [0–1] days vs. 1 [1–8] days: median [interquartile range], p = 0.007, Mann–Whitney U test). Conclusions: Delayed admission was a risk factor for symptomatic vasospasm; however, functional outcomes were not exacerbated. These results were obtained under the treatment strategy of multiple institutions, where the timing of endovascular therapy was earlier than that of direct surgery in patients with delayed admission.