Evan Thielen

Spina bifida, known more commonly as myelomeningocele, is a neural tube defect that results in herniation of the cerebellum through the foramen magnum into the central canal as part of the Chiari II malformation. Effects stemming from the herniated cerebellum and its metabolic profile have not been extensively studied. The objective of this study is to examine the metabolic effects of this disease on the cerebellum in utero through the utilization of a retinoid acid-induced Spina bifida rat model. Analysis of this model at mid-late (day 15) and term (day 20) of gestation in comparison to both non-exposed and retinoic acid-exposed non-myelomeningocele controls, the observed metabolic changes suggest that mechanisms of oxidative stress and energy depletion are at play in this neuro tissue. These notable mechanisms are likely to result in further damage to neural tissue as the fetus grows and the compressed cerebellum develops and herniates more due to myelomeningocele.

Background and purpose Flow diverters (FD) can cause rare but devastating delayed aneurysm ruptures in which matrix metalloproteinases (MMPs) have been potentially implicated. Concomitant coiling or anti-inflammatory medications have been proposed to prevent the risk of delayed ruptures. The aim of this study was to evaluate concomitant coiling and ciclosporin in regulating the expression of MMPs in FD-treated aneurysms. Materials and methods Elastase-induced aneurysms were created in 20 rabbits. Aneurysms were treated with (1) FD alone; (2) FD with concomitant coiling; (3) FD+ ciclosporin; or (4) left untreated as controls. At sacrifice, MMP levels were analyzed by zymography. Kruskal–Wallis one-way non-parametric ANOVA was performed for each enzyme. If significant results were observed for the Kruskal–Wallis test, pairwise group comparisons were performed using Dunn's test with Bonferroni multiple-testing correction. Results Significant differences were observed among groups for pro-MMP9 (p=0.0337). Pairwise comparison demonstrated higher levels of pro-MMP9 with concomitant coiling compared with untreated aneurysms (p=0.012), with higher though not significantly different levels of pro-MMP9 in FD with concomitant coiling versus FD alone. While not statistically significant, trends were noted regarding differences in active-MMP9 across groups, with a lower level of active-MMP9 with concomitant coiling compared with the other FD groups. No significant differences were observed for pro- or active-MMP2 across groups, or for FD + ciclosporin compared with FD alone. Conclusions FD implantation increases the level of pro-MMP9 expression in aneurysms. Provocative trends regarding modulation of active-MMP9 expression with concomitant coiling suggest the need for larger confirmatory preclinical studies. Anti-inflammatory treatment with ciclosporin appears to have a minimal biological effect. Trial registration number R01NS076491

BACKGROUND AND PURPOSE: The biologic mechanisms leading to aneurysm healing or rare complications such as delayed aneurysm ruptures after flow-diverter placement remain poorly understood. We used RNA sequencing following implantation of coils or flow diverters in elastase aneurysms in rabbits to identify genes and pathways of potential interest. MATERIALS AND METHODS: Aneurysms were treated with coils (n = 5) or flow diverters (n = 4) or were left untreated for controls (n = 6). Messenger RNA was isolated from the aneurysms at 4 weeks following treatment. RNA samples were processed by using RNA-sequencing technology and were analyzed by using the Ingenuity Pathway Analysis tool. RESULTS: With RNA sequencing for coiled versus untreated aneurysms, 464/9990 genes (4.6%) were differentially expressed (58 down-regulated, 406 up-regulated). When we compared flow-diverter versus untreated aneurysms, 177/10,041 (1.8%) genes were differentially expressed (8 down-regulated, 169 up-regulated). When we compared flow-diverter versus coiled aneurysms, 13/9982 (0.13%) genes were differentially expressed (8 down-regulated, 5 up-regulated). Keratin 8 was overexpressed in flow diverters versus coils. This molecule may potentially play a critical role in delayed ruptures due to plasmin production. We identified overregulation of apelin in flow diverters, supporting the preponderance of endothelialization, whereas we found overexpression of molecules implicated in wound healing (dectin 1 and hedgehog interacting protein) for coiled aneurysms. Furthermore, we identified metallopeptidases 1, 12, and 13 as overexpressed in coiled versus untreated aneurysms. CONCLUSIONS: We observed different physiopathologic responses after endovascular treatment with various devices. Flow diverters promote endothelialization but express molecules that could potentially explain the rare delayed ruptures. Coils promote wound healing and express genes potentially implicated in the recurrence of coiled aneurysms.