Saccular Aneurysm Models Featuring Growth and Rupture: A Systematic Review.

BACKGROUND Most available large animal extracranial aneurysm models feature healthy non-degenerated aneurysm pouches with stable long-term follow-ups and extensive healing reactions after endovascular treatment. This review focuses on a small subgroup of extracranial aneurysm models that demonstrated growth and potential rupture during follow-up. METHODS The literature was searched in Medline/Pubmed to identify extracranial in vivo saccular aneurysm models featuring growth and rupture, using a predefined search strategy in accordance with the PRISMA guidelines. From eligible studies we extracted the following details: technique and location of aneurysm creation, aneurysm pouch characteristics, time for model creation, growth and rupture rate, time course, patency rate, histological findings, and associated morbidity and mortality. RESULTS A total of 20 articles were found to describe growth and/or rupture of an experimentally created extracranial saccular aneurysm during follow-up. Most frequent growth was reported in rats (n = 6), followed by rabbits (n = 4), dogs (n = 4), swine (n = 5), and sheep (n = 1). Except for two studies reporting growth and rupture within the abdominal cavity (abdominal aortic artery; n = 2) all other aneurysms were located at the neck of the animal. The largest growth rate, with an up to 10-fold size increase, was found in a rat abdominal aortic sidewall aneurysm model. CONCLUSIONS Extracranial saccular aneurysm models with growth and rupture are rare. Degradation of the created aneurysmal outpouch seems to be a prerequisite to allow growth, which may ultimately lead to rupture. Since it has been shown that the aneurysm wall is important for healing after endovascular therapy, it is likely that models featuring growth and rupture will gain in interest for preclinical testing of novel endovascular therapies

Usefulness and Reliability of the Bispectral Index during Balanced Anesthesia for Neurovascular Surgery in New Zealand White Rabbits

Few data about the electroencephalogram and its calculated indices, such as the bispectral index (BIS), have been reported in rabbits. We aimed to evaluate whether a clinically stable anesthesia was mirrored by consistent and stable BIS values and to investigate the effects of modified cerebral blood supply, due to bilateral carotid clamping and re-opening, on BIS values. We also investigated the effects of fentanyl, as an antinociceptive drug, on the BIS. Sixty-eight rabbits undergoing general anesthesia for surgical creation of carotid bifurcation aneurysms were enrolled. The BIS values were recorded at nine selected time points (TPs) during each procedure and before and after fentanyl administration. The BIS values over time were compared with two-way repeated-measures analysis of variance followed by Tukey test, while the Wilcoxon signed rank test was performed to compare values at clamping and re-opening of the carotids as well as before and after fentanyl administration. The BIS values were significantly lower during anesthesia than at the end of anesthesia and at tracheal extubation; no significant differences were found among other TPs. Adequate depth of anesthesia was mirrored by consistent BIS values among rabbits, and alteration of cerebral blood supply did not modify BIS values, except once. Following fentanyl, BIS values did not change in a clinically relevant way

Levosimendan, a new therapeutic approach to prevent delayed cerebral vasospasm after subarachnoid hemorrhage?

BACKGROUND Under physiological cerebral conditions, levosimendan, a calcium-channel sensitizer, has a dose-dependent antagonistic effect on prostaglandin F2alpha (PGF)-induced vasoconstriction. This circumstance could be used in antagonizing delayed cerebral vasospasm (dCVS), one of the main complications after subarachnoid hemorrhage (SAH), leading to delayed cerebral ischemia and ischemic neurological deficits. Data already exist that identified neuroprotective effects of levosimendan in a traumatic brain injury model and additionally, it has been proven that this compound prevents narrowing of the basilar artery (BA) luminal area after SAH in an in vitro rabbit model. Takotsubo cardiomyopathy, a severe ventricular dysfunction, is also a well-known complication after SAH, associated with pulmonary edema and prolonged intubation. METHODS The polypeptide endothelin-1 (ET-1) plays a key role in the development of dCVS after SAH. Therefore, the aim of the present investigation was to detect functional interactions between the calcium-sensitizing and the ET-1-dependent vasoconstriction after experimental-induced SAH; interactions between levosimendan and a substrate-specific vasorelaxation in the BA were also examined. It was reviewed whether levosimendan has a beneficial influence on endothelin(A) and/or endothelin(B1) receptors (ET-(A) and ET-(B1) receptors) in cerebral vessels after SAH. We also examined whether this drug could have antagonistic effects on a PGF-induced vasoconstriction. RESULTS Under treatment with levosimendan after SAH, the endothelin system seems to be affected. The ET-1-induced contraction is decreased, not significantly. In addition, we detected changes in the nitric oxide-cyclic guanosine monophosphate (NO-cGMP) pathway. Preincubation with levosimendan causes a modulatory effect on the ET-(B1) receptor-dependent vasorelaxation. It induces an upregulation of the NO-cGMP pathway with a significantly increased relaxation. Even after PGF-induced precontraction a dose-dependent relaxation was registered, which was significantly higher (Emax) and earlier (pD2) compared to the concentration-effect curve without levosimendan. CONCLUSIONS After experimental-induced dCVS, levosimendan seems to restore the well-known impaired function of the vasorelaxant ET-(B1) receptor. Levosimendan also reversed the PGF-induced contraction dose-dependently. Both of these mechanisms could be used for antagonizing dCVS in patients suffering SAH. Levosimendan could even be used additionally in treating patients developing takotsubo cardiomyopathy

Parent artery-initiated and stent-mediated neointima formation in a rat saccular side wall model.

BACKGROUND Unlike clipping that forms an immediate barrier of blood flow into intracranial aneurysms, endovascular treatments rely on thrombus organization and neointima formation. Therefore, a continuous endothelial cell layer is crucial to prevent blood flow in the former aneurysm. This study investigates the origin of endothelial cells in the neointima of endovascular treated aneurysms, specifically whether cells from the parent artery play a role in neointima formation. METHODS In male rats, decellularized and vital side wall aneurysms were treated by coil (n=16) or stent embolization (n=15). The cell tracer CM-Dil dye was injected into the clamped aorta before aneurysm suture to mark initial endothelial cells in the parent artery and enable tracking of their proliferation during follow-up. Aneurysms were analyzed for growth, thrombus formation, and recurrence. Histological evaluation followed with cell counts for specific regions-of-interest. RESULTS During follow-up, none of the 31 aneurysms ruptured. Macroscopic residual perfusion was observed in 12/16 rats after coiling and in 1/15 after stenting. Amounts of CM-Dil +cells in coiled versus stented decellularized aneurysms significantly decreased in the thrombus on day 7 (p=0.01) and neointima on day 21 (p=0.04). For vital aneurysms, the number of CM-Dil +cells in the neointima on day 21 showed no significant difference. CONCLUSIONS Healing patterns were worse in coil-treated than stent-treated aneurysms. Cell migration forming a neointima seemed mainly dependent on the adjacent vessel in decellularized aneurysms, but appeared buoyed by recruitment from aneurysm wall cells in vital aneurysms. Therefore, a cell-rich parent artery might be crucial

Topographic distribution of inflammation factors in a healing aneurysm.

BACKGROUND Healing of intracranial aneurysms following endovascular treatment relies on the organization of early thrombus into mature scar tissue and neointima formation. Activation and deactivation of the inflammation cascade plays an important role in this process. In addition to timely evolution, its topographic distribution is hypothesized to be crucial for successful aneurysm healing. METHODS Decellularized saccular sidewall aneurysms were created in Lewis rats and coiled. At follow-up (after 3 days (n = 16); 7 days (n = 19); 21 days (n = 8)), aneurysms were harvested and assessed for healing status. In situ hybridization was performed for soluble inflammatory markers (IL6, MMP2, MMP9, TNF-α, FGF23, VEGF), and immunohistochemical analysis to visualize inflammatory cells (CD45, CD3, CD20, CD31, CD163, HLA-DR). These markers were specifically documented for five regions of interest: aneurysm neck, dome, neointima, thrombus, and adjacent vessel wall. RESULTS Coiled aneurysms showed enhanced patterns of thrombus organization and neointima formation, whereas those without treatment demonstrated heterogeneous patterns of thrombosis, thrombus recanalization, and aneurysm growth (p = 0.02). In coiled aneurysms, inflammation markers tended to accumulate inside the thrombus and in the neointima (p < 0.001). Endothelial cells accumulated directly in the neointima (p < 0.0001), and their presence was associated with complete aneurysm healing. CONCLUSION The presence of proinflammatory cells plays a crucial role in aneurysm remodeling after coiling. Whereas thrombus organization is hallmarked by a pronounced intra-thrombotic inflammatory reaction, neointima maturation is characterized by direct invasion of endothelial cells. Knowledge concerning topographic distribution of regenerative inflammatory processes may pave the way for future treatment modalities which enhance aneurysm healing after endovascular therapy

Aspirin treatment prevents inflammation in experimental bifurcation aneurysms in New Zealand White rabbits.

BACKGROUND Aneurysm wall degeneration is linked to growth and rupture. To address the effect of aspirin (ASA) on aneurysm formation under various wall conditions, this issue was analyzed in a novel rabbit bifurcation model. METHODS Bifurcation aneurysms created in 45 New Zealand White rabbits were randomized to vital (n=15), decellularized (n=13), or elastase-degraded (n=17) wall groups; each group was assigned to a study arm with or without ASA. At follow-up 28 days later, aneurysms were evaluated for patency, growth, and wall inflammation at macroscopic and histological levels. RESULTS 36 rabbits survived to follow-up at the end of the trial. None of the aneurysms had ruptured. Patency was visualized in all aneurysms by intraoperative fluorescence angiography and confirmed in 33 (92%) of 36 aneurysms by MRI/MRA. Aneurysm size was significantly increased in the vital (without ASA) and elastase-degraded (with and without ASA) groups. Aneurysm thrombosis was considered complete in three (50%) of six decellularized aneurysms without ASA by MRI/MRA. Locoregional inflammation of the aneurysm complex was significantly reduced in histological analysis among all groups treated with ASA. CONCLUSION ASA intake prevented inflammation of both the periadventitial tissue and aneurysm wall, irrespective of initial wall condition. Although ASA prevented significant growth in aneurysms with vital walls, this preventive effect did not have an important role in elastase-degraded pouches. In possible translation to the clinical situation, ASA might exert a potential preventive effect during early phases of aneurysm formation in patients with healthy vessels but not in those with highly degenerative aneurysm walls

Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders

Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pleiotropic effects remain unclear. We performed analyses of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hyper-activity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, and Tourette syndrome. Genetic correlation analyses revealed a meaningful structure within the eight disorders, identifying three groups of inter-related disorders. Meta-analysis across these eight disorders detected 109 loci associated with at least two psychiatric disorders, including 23 loci with pleiotropic effects on four or more disorders and 11 loci with antagonistic effects on multiple disorders. The pleiotropic loci are located within genes that show heightened expression in the brain throughout the lifespan, beginning prenatally in the second trimester, and play prominent roles in neurodevelopmental processes. These findings have important implications for psychiatric nosology, drug development, and risk prediction.Peer reviewe

Using a web-based SDSS for siting solar power plants

The paper demonstrates the application of a GIS-based spatial Multi-Criteria Decision Analysis (MCDA) approach to assess sites’ suitability for utility-scale solar power plants by implementing and evaluating a Site Ranking tool. The tool gets evaluated by two conducted case studies trying to match and explain the existing spatial distribution of existing solar power plants in the study areas

The Role of Sartans in the Treatment of Stroke and Subarachnoid Hemorrhage: A Narrative Review of Preclinical and Clinical Studies.

Background: Delayed cerebral vasospasm (DCVS) due to aneurysmal subarachnoid hemorrhage (aSAH) and its sequela, delayed cerebral ischemia (DCI), are associated with poor functional outcome. Endothelin-1 (ET-1) is known to play a major role in mediating cerebral vasoconstriction. Angiotensin-II-type-1-receptor antagonists such as Sartans may have a beneficial effect after aSAH by reducing DCVS due to crosstalk with the endothelin system. In this review, we discuss the role of Sartans in the treatment of stroke and their potential impact in aSAH. Methods: We conducted a literature research of the MEDLINE PubMed database in accordance with PRISMA criteria on articles published between 1980 to 2019 reviewing: "Sartans AND ischemic stroke". Of 227 studies, 64 preclinical and 19 clinical trials fulfilled the eligibility criteria. Results: There was a positive effect of Sartans on ischemic stroke in both preclinical and clinical settings (attenuating ischemic brain damage, reducing cerebral inflammation and infarct size, increasing cerebral blood flow). In addition, Sartans reduced DCVS after aSAH in animal models by diminishing the effect of ET-1 mediated vasoconstriction (including cerebral inflammation and cerebral epileptogenic activity reduction, cerebral blood flow autoregulation restoration as well as pressure-dependent cerebral vasoconstriction). Conclusion: Thus, Sartans might play a key role in the treatment of patients with aSAH