Copeptin is a novel, independent prognostic marker improving currently used risk stratification of stroke patients. Ann Neurol 2009;66:799-808.

No abstract

Individuals with acute myeloid leukemia (AML) harboring an internal tandem duplication (ITD) in the gene encoding Fms-related tyrosine kinase 3 (FLT3) who relapse after allogeneic hematopoietic cell transplantation (allo-HCT) have a 1-year survival rate below 20%. We observed that sorafenib, a multitargeted tyrosine kinase inhibitor, increased IL-15 production by FLT3-ITD leukemia cells. This synergized with the allogeneic CD8 T cell response, leading to long-term survival in six mouse models of FLT3-ITD AML. Sorafenib-related IL-15 production caused an increase in CD8CD107aIFN-γ T cells with features of longevity (high levels of Bcl-2 and reduced PD-1 levels), which eradicated leukemia in secondary recipients. Mechanistically, sorafenib reduced expression of the transcription factor ATF4, thereby blocking negative regulation of interferon regulatory factor 7 (IRF7) activation, which enhanced IL-15 transcription. Both IRF7 knockdown and ATF4 overexpression in leukemia cells antagonized sorafenib-induced IL-15 production in vitro. Human FLT3-ITD AML cells obtained from sorafenib responders following sorafenib therapy showed increased levels of IL-15, phosphorylated IRF7, and a transcriptionally active IRF7 chromatin state. The mitochondrial spare respiratory capacity and glycolytic capacity of CD8 T cells increased upon sorafenib treatment in sorafenib responders but not in nonresponders. Our findings indicate that the synergism of T cells and sorafenib is mediated via reduced ATF4 expression, causing activation of the IRF7-IL-15 axis in leukemia cells and thereby leading to metabolic reprogramming of leukemia-reactive T cells in humans. Therefore, sorafenib treatment has the potential to contribute to an immune-mediated cure of FLT3-ITD-mutant AML relapse, an otherwise fatal complication after allo-HCT.

Microglia, the brain-resident immune cells, are critically involved in many physiological and pathological brain processes, including neurodegeneration. Here we characterize microglia morphology and transcriptional programs across ten species spanning more than 450 million years of evolution. We find that microglia express a conserved core gene program of orthologous genes from rodents to humans, including ligands and receptors associated with interactions between glia and neurons. In most species, microglia show a single dominant transcriptional state, whereas human microglia display significant heterogeneity. In addition, we observed notable differences in several gene modules of rodents compared with primate microglia, including complement, phagocytic, and susceptibility genes to neurodegeneration, such as Alzheimer's and Parkinson's disease. Our study provides an essential resource of conserved and divergent microglia pathways across evolution, with important implications for future development of microglia-based therapies in humans.

BACKGROUND AND PURPOSE:The published results of treating internal carotid artery aneurysms with the PED do not necessarily apply to its use in the posterior circulation because disabling brain stem infarcts can be caused by occlusion of a single perforator. In this multicenter study, we assessed the safety of PED placement in the posterior circulation.

Dural arteriovenous fistulas (DAVFs) of the hypoglossal canal (HCDAVFs) are rare and display a complex angiographic anatomy. Hitherto, they have been referred to as various entities (for example, "marginal sinus DAVFs") solely described in case reports or small series. In this in-depth review of HCDAVF, the authors describe clinical and imaging findings, as well as treatment strategies and subsequent outcomes, based on a systematic literature review supplemented by their own cases (120 cases total). Further, the involved craniocervical venous anatomy with variable venous anastomoses is summarized. Hypoglossal canal DAVFs consist of a fistulous pouch involving the anterior condylar confluence and/or anterior condylar vein with a variable intraosseous component. Three major types of venous drainage are associated with distinct clinical patterns: Type 1, with anterograde drainage (62.5%), mostly presents with pulsatile tinnitus; Type 2, with retrograde drainage to the cavernous sinus and/or orbital veins (23.3%), is associated with ocular symptoms and may mimic cavernous sinus DAVF; and Type 3, with cortical and/or perimedullary drainage (14.2%), presents with either hemorrhage or cervical myelopathy. For Types 1 and 2 HCDAVF, transvenous embolization demonstrates high safety and efficacy (2.9% morbidity, 92.7% total occlusion). Understanding the complex venous anatomy is crucial for planning alternative approaches if standard transjugular access is impossible. Transarterial embolization or surgical disconnection (morbidity 13.3%-16.7%) should be reserved for Type 3 HCDAVFs or lesions with poor venous access. A conservative strategy could be appropriate in Type 1 HCDAVF for which spontaneous regression (5.8%) may be observed.

BACKGROUND AND PURPOSE: BBA is a rare type of intracranial aneurysm that is difficult to treat both surgically and endovascularly and is often associated with a high degree of morbidity/mortality. The aim of this study was to present clinical and angiographic results, as well as antiplatelet/anticoagulation regimens, of endovascular BBA treatment by using predominantly stent-assisted coil embolization.

The persistent trigeminal artery (PTA) is the most common and most cephalad-located embryological anastomosis between the developing carotid artery and vertebrobasilar system to persist into adulthood. As such, it is frequently reported as an incidental finding in computed tomography angiography and magnetic resonance angiography studies. Here, we review the embryology, anatomy, and angiographic imaging findings, including important variants of this commonly encountered cerebrovascular anomaly (reported incidence of PTA/PTA variants ranges from 0.1% to 0.76%). Further, the aim is to present the range of associated arterial anomalies or syndromes, as well as pathologies that are associated with a PTA: aneurysms, trigeminal cavernous fistulas, and trigeminal nerve compression. Besides summarizing the risks and clinical presentation of such pathologies, their management is discussed with endovascular strategies mostly being the primary choice for aneurysms and trigeminal cavernous fistulas. Symptomatic trigeminal nerve compression can be treated with microvascular decompression surgery. As an illustrative example, a case of a trigeminal cavernous fistula on a PTA variant is included, mainly to emphasize the importance of understanding the variant anatomy for treatment planning in such pathologies. Finally, recommendations on how to manage patients with PTA-associated vascular pathologies are advanced.