Live Detection of Neural Progenitors and Glioblastoma Cells by an Oligothiophene Derivative.

There is an urgent need for simple and non-invasive identification of live neural stem/progenitor cells (NSPCs) in the developing and adult brain as well as in disease, such as in brain tumors, due to the potential clinical importance in prognosis, diagnosis, and treatment of diseases of the nervous system. Here, we report a luminescent conjugated oligothiophene (LCO), named p-HTMI, for non-invasive and non-amplified real-time detection of live human patient-derived glioblastoma (GBM) stem cell-like cells and NSPCs. While p-HTMI stained only a small fraction of other cell types investigated, the mere addition of p-HTMI to the cell culture resulted in efficient detection of NSPCs or GBM cells from rodents and humans within minutes. p-HTMI is functionalized with a methylated imidazole moiety resembling the side chain of histidine/histamine, and non-methylated analogues were not functional. Cell sorting experiments of human GBM cells demonstrated that p-HTMI labeled the same cell population as CD271, a proposed marker for stem cell-like cells and rapidly migrating cells in glioblastoma. Our results suggest that the LCO p-HTMI is a versatile tool for immediate and selective detection of neural and glioma stem and progenitor cells.

Characterisation of C101248: A novel selective THIK-1 channel inhibitor for the modulation of microglial NLRP3-inflammasome.

Neuroinflammation, specifically the NLRP3 inflammasome cascade, is a common underlying pathological feature of many neurodegenerative diseases. Evidence suggests that NLRP3 activation involves changes in intracellular K+. Nuclear Enriched Transcript Sort Sequencing (NETSseq), which allows for deep sequencing of purified cell types from human post-mortem brain tissue, demonstrated a highly specific expression of the tandem pore domain halothane-inhibited K+ channel 1 (THIK-1) in microglia compared to other glial and neuronal cell types in the human brain. NETSseq also showed a significant increase of THIK-1 in microglia isolated from cortical regions of brains with Alzheimer's disease (AD) relative to control donors. Herein, we report the discovery and pharmacological characterisation of C101248, the first selective small-molecule inhibitor of THIK-1. C101248 showed a concentration-dependent inhibition of both mouse and human THIK-1 (IC50: ∼50 nM) and was inactive against K2P family members TREK-1 and TWIK-2, and Kv2.1. Whole-cell patch-clamp recordings of microglia from mouse hippocampal slices showed that C101248 potently blocked both tonic and ATP-evoked THIK-1 K+ currents. Notably, C101248 had no effect on other constitutively active resting conductance in slices from THIK-1-depleted mice. In isolated microglia, C101248 prevented NLRP3-dependent release of IL-1ß, an effect not seen in THIK-1-depleted microglia. In conclusion, we demonstrated that inhibiting THIK-1 (a microglia specific gene that is upregulated in brains from donors with AD) using a novel selective modulator attenuates the NLRP3-dependent release of IL-1ß from microglia, which suggests that this channel may be a potential therapeutic target for the modulation of neuroinflammation in AD.

Endovascular versus open surgical repair for complicated chronic Type B aortic dissection.

BACKGROUND: Type B aortic dissection can lead to serious and life-threatening complications such as aortic rupture, stroke, renal failure, and paraplegia, all of which require intervention. Traditionally, these complications have been treated with open surgery. Recently however, endovascular repair has been proposed as an alternative. OBJECTIVES: To assess the effectiveness and safety of thoracic aortic endovascular repair versus open surgical repair for treatment of complicated chronic Type B aortic dissection (CBAD). SEARCH METHODS: The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, CINAHL, and AMED databases, as well as the World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov trials registers, to 2 August 2021. We searched references of relevant articles retrieved through the electronic search for additional citations. SELECTION CRITERIA: We considered all randomised controlled trials (RCTs) and controlled clinical trials (CCTs) assessing the effects of thoracic aortic endovascular repair (TEVAR) versus open surgical repair (OSR) for treatment of complicated chronic Type B aortic dissection (CBAD). Outcomes of interest were mortality (all-cause, dissection-related), neurological sequelae (stroke, spinal cord ischaemia/paresis-paralysis, vertebral insufficiency), morphological outcomes (false lumen thrombosis, progression of dissection, aortic diameters), acute renal failure, ischaemic symptoms (visceral ischaemia, limb ischaemia), re-intervention, and health-related quality of life. DATA COLLECTION AND ANALYSIS: Two review authors independently screened all titles and abstracts identified by the searches to identify those that met the inclusion criteria. From title and abstract screening, we did not identify any trials (RCTs or CCTs) that required full-text assessment. We planned to undertake data collection and analysis in accordance with recommendations described in the Cochrane Handbook for Systematic Reviews of Interventions. We planned to assess the certainty of evidence using GRADE. MAIN RESULTS: We did not identify any trials (RCTs or CCTs) that met the inclusion criteria for this review. AUTHORS' CONCLUSIONS: Due to lack of RCTs or CCTs investigating the effectiveness and safety of TEVAR compared to OSR for patients with complicated CBAD, we are unable to provide any evidence to inform decision-making on the optimal intervention for these patients. High-quality RCTs or CCTs addressing this objective are necessary. However, conducting such studies will be challenging for this life-threatening disease.

Surgical and radiological interventions for treating symptomatic extracranial cervical artery dissection.

BACKGROUND: Cervical artery dissection (CeAD) is a pathological bleed or tear, or both, in the wall of the carotid or vertebral arteries as they course through the neck, and is a leading cause of stroke in young people. OBJECTIVES: To assess the effectiveness of surgical and radiological interventions versus best medical treatment alone for treating symptomatic cervical artery dissection. SEARCH METHODS: We performed comprehensive searches of the Cochrane Stroke Group Trials Register (last searched March 2020), the Cochrane Central Register of Controlled Trials (CENTRAL), 2020, Issue 4, in the Cochrane Library (searched March 2020), MEDLINE (1946 to March 2020) and Embase (1974 to March 2020). We searched relevant ongoing trials and research registers (searched March 2020), checked references in all relevant papers for additional eligible studies, and contacted authors and researchers in the field. SELECTION CRITERIA: Randomised controlled trials (RCTs) and controlled clinical trials (CCTs) of either surgical or endovascular intervention for the management of symptomatic CeAD were eligible for inclusion. Only studies with anticoagulants or antiplatelet treatment as the control group were included. Two review authors planned to independently extract data. DATA COLLECTION AND ANALYSIS: Primary outcomes were ipsilateral stroke and disability. Secondary outcomes were death, any stroke, or transient ischaemic attack, residual stenosis (> 50%), recurrence of cervical dissection, expanding pseudoaneurysm, or major bleeding. We analysed the studies according to the first choice of treatment. We planned to assess for risk of bias and apply GRADE criteria for any included studies. MAIN RESULTS: We did not find any completed RCTs or CCTs undertaken in this area of research. AUTHORS' CONCLUSIONS: No RCTs or CCTs compared either surgery or endovascular therapy with control. Thus, there is no available evidence to support their use for the treatment of extracranial cervical artery dissection in addition to antithrombotic therapy in people who continue to have neurological symptoms when treated with antithrombotic therapy alone.

Systematic review of the effectiveness of carotid surgery and endovascular carotid stenting versus best medical treatment in managing symptomatic acute carotid artery dissection.

Cervical artery dissection (CeAD) with an intramural haematoma can lead to stroke risk, especially in young patients. We performed comprehensive searches of the Cochrane Stroke Group Trials Register, the CENTRAL, MEDLINE and EMBASE to review the effectiveness of surgical and endovascular interventions versus best medical treatment alone for symptomatic CeAD. Furthermore, we aim to elaborate on the phenotypic individual disease manifestations of spontaneous Cervical Artery Dissection (sCAD) and how they translate into stroke and risk of dissection recurrence. Primary outcomes were ipsilateral stroke and disability. Secondary outcomes were death, any stroke, or transient ischaemic attack, residual stenosis >50%, recurrence of CeAD, expanding pseudo-aneurysm or major bleeding. Our search yielded no randomised controlled trials and/or controlled clinical trials (CCTs) comparing either carotid surgery or endovascular therapy with optimal medical management; thus there was no evidence to support the use of any specific method for management of extracranial CeAD in patients who fail antithrombotic therapy. However, despite the absence of controlled studies to compare surgery or endovascular therapy in patients who fail antithrombotic therapy, carotid surgery in young patients can be justified as a personalized precision approach given the high morbidity and mortality in this age group.

Hybrid repair versus conventional open repair for aortic arch dissection.

BACKGROUND: A dissection of the aorta is a separation or tear of the intima from the media. This tear allows blood to flow not only through the original aortic flow channel (known as the true lumen), but also through a second channel between the intima and media (known as the false lumen). Aortic dissection is a life-threatening condition which can be rapidly fatal. There is debate on the optimal surgical approach for aortic arch dissection. People with ascending aortic dissection have poor rates of survival. Currently open surgical repair is regarded as the standard treatment for aortic arch dissection. We intend to review the role of hybrid and open repair in aortic arch dissection. OBJECTIVES: To assess the effectiveness and safety of a hybrid technique of treatment over conventional open repair in the management of aortic arch dissection. SEARCH METHODS: The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, Embase, CINAHL and AMED databases and World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov trials registers to 8 February 2021. We also undertook reference checking for additional studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and clinical controlled trials (CCTs), which compared the effects of hybrid repair techniques versus open surgical repair of aortic arch dissection. Outcomes of interest were dissection-related mortality and all-cause mortality, neurological deficit, cardiac injury, respiratory compromise, renal ischaemia, false lumen thrombosis (defined by partial or complete thrombosis) and mesenteric ischaemia. DATA COLLECTION AND ANALYSIS: Two review authors independently screened all records identified by the literature searches to identify those that met our inclusion criteria. We planned to undertake data collection and analysis in accordance with recommendations described in the Cochrane Handbook for Systematic Reviews of Interventions. We planned to assess the certainty of the evidence using GRADE. MAIN RESULTS: We identified one ongoing study and two unpublished studies that met the inclusion criteria for the review. Due to a lack of study data, we could not compare the outcomes of hybrid repair to conventional open repair for aortic arch dissection. AUTHORS' CONCLUSIONS: This review revealed one ongoing RCT and two unpublished RCTs evaluating hybrid versus conventional open repair for aortic arch surgery. Observational data suggest that hybrid repair for aortic arch dissection could potentially be favourable, but conclusions can not be drawn from these studies, which are highly selective, and are based on the clinical status of the patient, the presence of comorbidities and the skills of the operators. However, a conclusion about its definitive benefit over conventional open surgical repair cannot be made from this review without published RCTs or CCTs. Future RCTs or CCTs need to have adequate sample sizes and follow-up, and assess clinically-relevant outcomes, in order to determine the optimal treatment for people with aortic arch dissection. It must be noted that this may not be feasible, due to the reasons mentioned.

Hybrid repair versus conventional open repair for thoracic aortic arch aneurysms.

BACKGROUND: Thoracic aortic arch aneurysms (TAAs) can be a life-threatening condition due to the potential risk of rupture. Treatment is recommended when the risk of rupture is greater than the risk of surgical complications. Depending on the cause, size and growth rate of the TAA, treatment may vary from close observation to emergency surgery. Aneurysms of the thoracic aorta can be managed by a number of surgical techniques. Open surgical repair (OSR) of aneurysms involves either partial or total replacement of the aorta, which is dependent on the extent of the diseased segment of the aorta. During OSR, the aneurysm is replaced with a synthetic graft. Hybrid repair (HR) involves a combination of open surgery with endovascular aortic stent graft placement. Hybrid repair requires varying degrees of invasiveness, depending on the number of supra-aortic branches that require debranching. The hybrid technique that combines supra-aortic vascular debranching with stent grafting of the aortic arch has been introduced as a therapeutic alternative. However, the short- and long-term outcomes of HR remain unclear, due to technical difficulties and complications as a result of the angulation of the aortic arch as well as handling of the arch during surgery. OBJECTIVES: To assess the effectiveness and safety of HR versus conventional OSR for the treatment of TAAs. SEARCH METHODS: The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, Embase, CINAHL and AMED databases and World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov trials registers to 22 March 2021. We also searched references of relevant articles retrieved from the electronic search for additional citations. SELECTION CRITERIA: We considered for inclusion in the review all published and unpublished randomised controlled trials (RCTs) and controlled clinical trials (CCTs) comparing HR to OSR for TAAs. DATA COLLECTION AND ANALYSIS: Two review authors independently screened all titles and abstracts obtained from the literature search to identify those that met the inclusion criteria. We retrieved the full text of studies deemed as potentially relevant by at least one review author. The same review authors screened the full-text articles independently for inclusion or exclusion. MAIN RESULTS: No RCTs or CCTs met the inclusion criteria for this review. AUTHORS' CONCLUSIONS: Due to the lack of RCTs or CCTs, we were unable to determine the safety and effectiveness of HR compared to OSR in people with TAAs, and we are unable to provide high-certainty evidence on the optimal surgical intervention for this cohort of patients. High-quality RCTs or CCTs are necessary, addressing the objective of this review.

Cell Death Related Proteins Beyond Apoptosis in the CNS.

Cell death related (CDR) proteins are a diverse group of proteins whose original function was ascribed to apoptotic cell death signaling. Recently, descriptions of non-apoptotic functions for CDR proteins have increased. In this minireview, we comment on recent studies of CDR proteins outside the field of apoptosis in the CNS, encompassing areas such as the inflammasome and non-apoptotic cell death, cytoskeleton reorganization, synaptic plasticity, mitophagy, neurodegeneration and calcium signaling among others. Furthermore, we discuss the evolution of proteomic techniques used to predict caspase substrates that could potentially explain their non-apoptotic roles. Finally, we address new concepts in the field of non-apoptotic functions of CDR proteins that require further research such the effect of sexual dimorphism on non-apoptotic CDR protein function and the emergence of zymogen-specific caspase functions.

Microglia: Agents of the CNS Pro-Inflammatory Response.

The pro-inflammatory immune response driven by microglia is a key contributor to the pathogenesis of several neurodegenerative diseases. Though the research of microglia spans over a century, the last two decades have increased our understanding exponentially. Here, we discuss the phenotypic transformation from homeostatic microglia towards reactive microglia, initiated by specific ligand binding to pattern recognition receptors including toll-like receptor-4 (TLR4) or triggering receptors expressed on myeloid cells-2 (TREM2), as well as pro-inflammatory signaling pathways triggered such as the caspase-mediated immune response. Additionally, new research disciplines such as epigenetics and immunometabolism have provided us with a more holistic view of how changes in DNA methylation, microRNAs, and the metabolome may influence the pro-inflammatory response. This review aimed to discuss our current knowledge of pro-inflammatory microglia from different angles, including recent research highlights such as the role of exosomes in spreading neuroinflammation and emerging techniques in microglia research including positron emission tomography (PET) scanning and the use of human microglia generated from induced pluripotent stem cells (iPSCs). Finally, we also discuss current thoughts on the impact of pro-inflammatory microglia in neurodegenerative diseases.

Kinetic Elephant Trunk Technique: Early Results in Chronic Symptomatic Aortic Dissection Management.

BACKGROUND: The aim was to expand our understanding of the dynamic evolution of the aorta throughout the dissection time course. We investigated how the disease process can be modulated to equalize lumen pressure, enhance perfusion, and stabilize the aorta along its entire length using the kinetic elephant trunk (kET) technique. METHODS: We performed the kET on 9 patients with chronic symptomatic aortic dissection (CSAD) as a primary or secondary intervention, regardless of the chronicity of the dissection. Endovascular scissoring of the intraluminal septum is performed in the infradiaphragmatic dissected aorta to equalize pressure between true and false lumens and allow all branched vessels to be supplied from one lumen. The Streamliner Multilayer Flow Modulator (SMFM), an uncovered cobalt-alloy aortic device, is deployed from the aortic sinus, covering the supra-aortic branches, distally into the distal aorta (primary intervention). In the case of a previous ascending aorta Dacron graft, the SMFM is deployed (secondary intervention) at the level of the Dacron graft so that it is overlapped with the graft and landed in the distal aorta. RESULTS: In the initial study period, all-cause and aortic-related survival were 100%, respectively; all great vessels and visceral branches were patent; and freedom of stroke, end-organ ischemia, paraplegia, and renal failure were 100%. CONCLUSIONS: The kET is a treatment process for managing CSAD. Its simplicity, consistency, and reproducibility in high-risk patients with low morbidity and mortality add to the armamentarium of the cardiovascular specialist. Further assessment of the medium- and long-term outcomes is needed to fully establish the benefits of kET.

Outcome following open and endovascular intervention for carotid stump syndrome.

Carotid stump syndrome is defined as the persistence of retinal or cerebral ischaemic events with complete occlusion of the ipsilateral internal carotid artery. The aim of this retrospective cases series was to assess the outcomes for patients with carotid stump syndrome managed with surgical intervention. A series of 11 cases of carotid stump syndrome in nine patients presented to our tertiary vascular centre from October 2004 to February 2016. Indications for intervention were amaurosis fugax, transient ischaemic attacks and stroke. In total, 11 procedures were performed on nine patients including carotid angioplasty and stenting or carotid endarterectomy with patching. The mean follow-up period was 56.6 months. One patient suffered a myocardial infarction 30 days, post-operatively, and one patient was lost to follow-up. In the remaining seven patients, there was a complete resolution of symptoms. There were no incidents of death, stroke, cranial nerve injury, wound haematoma or procedural bleeding. Surgical exclusion of carotid stumps combined with dual antiplatelet agents was found to be a safe and effective treatment method for carotid stump syndrome.

Minimising failure in critical lower limb ischaemia intervention: Adjuvant capillary bed recruitment is the missed opportunity.

Critical limb ischaemia is the end stage of peripheral arterial disease before limb loss. Contemporary interventions to restore blood flow have high morbidity and mortality and fail to provide sustained restoration of peripheral circulation. Cell-based therapies designed to promote neovascularisation or angiogenesis have been shown in trials to be safe but clinically ineffective. Notwithstanding endless research in the area, no headway has been made in identifying a successful therapy designed specifically to target muscle disease in critical lower limb ischaemia. Thus, the quest to find an effective, lasting solution for critical lower limb ischaemia continues and requires more innovative therapeutic tactics. Our aim is to highlight the crucially interlinked role of the capillary bed, skeletal muscle mass and mitochondria in critical lower limb ischaemia patients and to identify novel therapeutic mechanisms that the vascular interventionalist can add to their armamentarium.

A clinical review of early outcomes from contemporary flow modulation versus open, fenestrated and branch technologies in the management of thoracoabdominal aortic aneurysm.

Traditional therapeutic options for complex thoracoabdominal aneurysm include open repair, hybrid repair or endovascular repair (involving fenestrated or branched endografts). The Streamliner Multilayer Flow Modulator has been available for treatment of thoracoabdominal aneurysms since 2010. Its design permits blood flow to perfuse through the mesh in a modus that preserves collateral branch patency, while modulating turbulent to laminar flow within the device. The flow then stagnates over time within the surrounding aneurysm sac. Significant complications, including paraplegia, renal failure and cerebrovascular accident, are much lower with Streamliner Multilayer Flow Modulator treatment. Application of the Streamliner Multilayer Flow Modulator to complex aortic pathologies presents a novel solution to an, as of yet, unmet clinical need, and has resulted in promising clinical outcomes when compared to existing solutions. The Streamliner Multilayer Flow Modulator offers potential for treatment of thoracoabdominal aortic pathologies in patients and is not just confined to those with complexity that dictates no other management options. While current literature illustrates that there is a decreased risk of mortality and associated complications when this new disruptive technology is utilised, there is still a need for prospective, long-term clinical trials, as well as comparative trials to accurately assess outcomes of Streamliner Multilayer Flow Modulator treatment that are both precise and reproducible. This article is a review of current clinical literature regarding contemporary flow modulating technology compared with open, branched and fenestrated managements, presenting early outcomes.

Stem Cell Smart Technology, where are we now and how far we have to go?

Approximately eight million people in the United States have peripheral arterial disease, which increases exponentially with age. There have been a plethora of available treatments including surgery, angioplasty, atherectomy, laser technology, and cell-based therapies. Cell-based therapies were developed in the hope of translating laboratory-based technology into clinical successes. However, clinical results have been disappointing. Infusion or injection for stem cell therapy is still considered experimental and investigational, and major questions on safety and durability have arisen. In no option patients, how can they be treated safely and successfully? In this article, we review contemporary practice for cell therapy, its pitfalls and breakthroughs, and look at the future ahead. We introduce a novel smart system for minimally invasive delivery of cell therapies, which exemplifies the next generation of endovascular solutions to stem cell technology and promises safety, efficacy, and reliability.

Bioengineered 3D Glial Cell Culture Systems and Applications for Neurodegeneration and Neuroinflammation.

Neurodegeneration and neuroinflammation are key features in a range of chronic central nervous system (CNS) diseases such as Alzheimer's and Parkinson's disease, as well as acute conditions like stroke and traumatic brain injury, for which there remains significant unmet clinical need. It is now well recognized that current cell culture methodologies are limited in their ability to recapitulate the cellular environment that is present in vivo, and there is a growing body of evidence to show that three-dimensional (3D) culture systems represent a more physiologically accurate model than traditional two-dimensional (2D) cultures. Given the complexity of the environment from which cells originate, and their various cell-cell and cell-matrix interactions, it is important to develop models that can be controlled and reproducible for drug discovery. 3D cell models have now been developed for almost all CNS cell types, including neurons, astrocytes, microglia, and oligodendrocyte cells. This review will highlight a number of current and emerging techniques for the culture of astrocytes and microglia, glial cell types with a critical role in neurodegenerative and neuroinflammatory conditions. We describe recent advances in glial cell culture using electrospun polymers and hydrogel macromolecules, and highlight how these novel culture environments influence astrocyte and microglial phenotypes in vitro, as compared to traditional 2D systems. These models will be explored to illuminate current trends in the techniques used to create 3D environments for application in research and drug discovery focused on astrocytes and microglial cells.

Endovascular management of chronic symptomatic aortic dissection with the Streamliner Multilayer Flow Modulator: Twelve-month outcomes from the global registry.

OBJECTIVE: Reported are initial 12-month outcomes of patients with chronic symptomatic aortic dissection managed by the Streamliner Multilayer Flow Modulator (SMFM; Cardiatis, Isnes, Belgium). Primary end points were freedom from rupture- and aortic-related death, and reduction in false lumen index. Secondary end points were patency of great vessels and visceral branches, and freedom of stroke, paraplegia, and renal failure. METHODS: Out of 876 SMFM implanted globally, we have knowledge of 542. To date, 312 patients are maintained in the global registry, of which 38 patients were identified as having an aortic dissection (12.2%). Indications included 35 Stanford type B dissections, two Stanford type A and B dissections, and one mycotic Stanford type B dissection. RESULTS: There were no reported ruptures or aortic-related deaths. All cause survival was 85.3% Twelve-month freedom from neurologic events was 100%, and there were no incidences of end-organ ischemia, paraplegia or renal insult. Morphologic analysis exhibited dissection remodeling by a reduction in longitudinal length of the dissected aorta, and false lumen volume. A statistically significant reduction in false lumen index (P = .016) at 12 months, and a borderline significant increase in true lumen volume (P = .053) confirmed dissection remodeling. CONCLUSIONS: The SMFM is an option in management of complex pan-aortic dissection. Results highlight SMFM implantation leads to dissection stabilization with no further aneurysm progression, and no retrograde type A dissection. Thoracic endovascular aneurysm repair by SMFM ensued in freedom from aortic rupture, neurologic stroke, paraplegia and renal failure. Further analysis of the global registry data will inform long-term outcomes.

Computational fluid analysis of symptomatic chronic type B aortic dissections managed with the Streamliner Multilayer Flow Modulator.

OBJECTIVE: Managing symptomatic chronic type B aortic dissection (SCTBAD) by the Streamliner Multilayer Flow Modulator (SMFM) stent (Cardiatis, Isnes, Belgium) is akin to provisional structural support to induce complete attachment of the dissection flap, but with the ability of aortic remolding. This study investigated the SMFM's capability to enact healing of SCTBAD. METHODS: Clinical data for 12 cases comprising preoperative and postoperative treatment of SCTBAD were obtained from a multicenter database hosted by the Multilayer Flow Modulator Global Registry, Ireland. A biomechanical analysis, by means of computational fluid dynamics modeling, of the hemodynamic effects and branch patency associated with the use of the SMFM was performed for all cases. The mean length of the dissections was 30.23 ± 13.3 cm. There were 30 SMFMs used, which covered 69 aortic branches. RESULTS: At 1-year follow-up, the true lumen volume increased from 175.74 ± 98.83 cm3 to 209.87 ± 128.79 cm3; the false lumen decreased from 135.2 ± 92.03 cm3 to 123.19 ± 110.11 cm3. The false lumen index decreased from 0.29 ± 0.13 (preoperatively) to 0.21 ± 0.15 (postoperatively). The primary SMFM treatment of SCTBAD increased carotid perfusion by 35% ± 21% (P = .0216) and suprarenal perfusion by 78% ± 32% (P = .001). The wall pressure distribution blended along the newly enlarged true lumen, whereas the false lumen wall pressure decreased by 6.23% ± 4.81% for the primary group (cases 1-7) and by 3.84% ± 2.59% for the secondary group (cases 8-12). CONCLUSIONS: SMFM reduces the false lumen wall pressure through flow modulation. It preserves patency of all branches, minimizing the incidence of short-term complications. The SMFM is a valuable option in managing primary SCTBAD, without midterm complications.

Glioma-induced inhibition of caspase-3 in microglia promotes a tumor-supportive phenotype.

Glioma cells recruit and exploit microglia (the resident immune cells of the brain) for their proliferation and invasion ability. The underlying molecular mechanism used by glioma cells to transform microglia into a tumor-supporting phenotype has remained elusive. We found that glioma-induced microglia conversion was coupled to a reduction in the basal activity of microglial caspase-3 and increased S-nitrosylation of mitochondria-associated caspase-3 through inhibition of thioredoxin-2 activity, and that inhibition of caspase-3 regulated microglial tumor-supporting function. Furthermore, we identified the activity of nitric oxide synthase 2 (NOS2, also known as iNOS) originating from the glioma cells as a driving stimulus in the control of microglial caspase-3 activity. Repression of glioma NOS2 expression in vivo led to a reduction in both microglia recruitment and tumor expansion, whereas depletion of microglial caspase-3 gene promoted tumor growth. Our results provide evidence that inhibition of the denitrosylation of S-nitrosylated procaspase-3 mediated by the redox protein Trx2 is a part of the microglial pro-tumoral activation pathway initiated by glioma cancer cells.

Spatio-temporal activation of caspase-8 in myeloid cells upon ischemic stroke.

Ischemic stroke (caused by thrombosis, embolism or vasoconstriction) lead to the recruitment and activation of immune cells including resident microglia and infiltrating peripheral macrophages, which contribute to an inflammatory response involved in regulation of the neuronal damage. We showed earlier that upon pro-inflammatory stimuli, the orderly activation of caspase-8 and caspase-3/7 regulates microglia activation through a protein kinase C-δ dependent pathway. Here, we present in vivo evidence for the activation of caspase-8 and caspase-3 in microglia/macrophages in post-mortem tissue from human ischemic stroke subjects. Indeed, CD68-positive microglia/macrophages in the ischemic peri-infarct area exhibited significant expression of the cleaved and active form of caspase-8 and caspase-3. The temporal and spatial activation of caspase-8 was further investigated in a permanent middle cerebral artery occlusion mouse model of ischemic stroke. Increasing levels of active caspase-8 was found in Iba1-positive cells over time in the peri-infarct area, at 6, 24 and 48 h after artery occlusion. Analysis of post-mortem brain tissue from human subject who suffered two stroke events, referred as recent and old stroke, revealed that expression of cleaved caspase-8 and -3 in CD68-positive cells could only be found in the recent stroke area. Analysis of cleaved caspase-8 and -3 expressions in a panel of human stroke cases arranged upon days-after stroke and age-matched controls suggested that the expression of these caspases correlated with the time of onset of stroke. Collectively, these data illustrate the temporal and spatial activation of caspase-8 and -3 in microglia/macrophages occurring upon ischemic stroke and suggest that the expression of these caspases could be used in neuropathological diagnostic work.

Insights from complex aortic surgery with a Streamliner device for aortic arch repair (STAR).

OBJECTIVE: Aortic arch aneurysms and thoracoabdominal aortic arch aneurysms are technically challenging to manage by established surgical and endovascular methods. The Streamliner Multilayer Flow Modulator device (Cardiatis, Isnes, Brussels, Belgium) offers an unorthodox option for these high-risk cases. The Streamliner device for aortic arch repair (STAR) study investigated complex aneurysm cases managed by the Streamliner Multilayer Flow Modulator device and offers an analytic solution for a clinical dilemma. METHODS: Six cases were included, with a 1-year follow-up, comprising 4 pure arch aneurysms and 2 thoracoabdominal aortic arch aneurysms Crawford type I, from a multicenter database hosted by the Streamliner Multilayer Flow Modulator Global Registry. A total of 50% of cases were performed under instructions for use. All were American Society of Anesthesiology IV and originated from zone 0. All cases were computationally analyzed, which consisted of (1) simulating the treatment on the basis of the postoperative data, (2) repositioning the stents for the failed technical cases, and (3) assessing the effects of overlapping devices on branch patency. RESULTS: Correct device placement induced aneurysm flow streamlining, which reduced the dynamic pressure by 23% to 66%, whereas incorrect placements promoted Failure Mode I with 58% and 16% dynamic pressure increases and aneurysm volume expansion up to 23%. Overlapped devices improved distal perfusion by increasing arch branch outflows from 5% to 24%. The Streamliner Multilayer Flow Modulator device does not benefit a sac volume greater than 400 cm3. CONCLUSIONS: The Streamliner Multilayer Flow Modulator device is a new technology that can manage complex aortic arch aneurysms and thoracoabdominal aortic arch aneurysms with favorable clinical outcomes if it is performed under instructions for use. Careful procedure planning and perioperative virtual stent placement will avoid foreshortening, prevent inadequate stent overlap lengths, and provide insight into the sufficient numbers of required implanted devices.