The glial water channel aquaporin-4 (AQP4) has been hypothesized to modulate water and potassium fluxes associated with neuronal activity. In this study, we examined the seizure phenotype of AQP4 -/- mice using in vivo electrical stimulation and electroencephalographic (EEG) recording. AQP4 -/- mice were found to have dramatically prolonged stimulation-evoked seizures after hippocampal stimulation compared to wild-type controls (33 +/- 2 s vs. 13 +/- 2 s). In addition, AQP4 -/- mice were found to have a higher seizure threshold (167 +/- 17 microA vs. 114 +/- 10 microA). To assess a potential effect of AQP4 on potassium kinetics, we used in vivo recording with potassium-sensitive microelectrodes after direct cortical stimulation. Although there was no significant difference in baseline or peak [K(+)](o), the rise time to peak [K(+)](o) (t(1/2), 2.3 +/- 0.5 s) as well as the recovery to baseline [K(+)](o) (t(1/2), 15.6 +/- 1.5 s) were slowed in AQP4 -/- mice compared to WT mice (t(1/2), 0.5 +/- 0.1 and 6.6 +/- 0.7 s, respectively). These results implicate AQP4 in the expression and termination of seizure activity and support the hypothesis that AQP4 is coupled to potassium homeostasis in vivo.

Cerebral edema plays a central role in the pathophysiology of many diseases of the central nervous system (CNS) including ischemia, trauma, tumors, inflammation, and metabolic disturbances. The formation of cerebral edema results in an increase in tissue water content and brain swelling which, if unchecked, can lead to elevated intracranial pressure (ICP), reduced cerebral blood flow, and ultimately cerebral herniation and death. Despite the clinical significance of cerebral edema, the mechanism of brain water transport and edema formation remain poorly understood. As a result, current therapeutic tools for managing cerebral edema have changed little in the past 90 years. “Malignant ischemic stroke” is characterized by high mortality (~80%) and represents a major clinical problem in cerebrovascular disease. Widespread ischemic injury in these patients causes progressive cerebral edema, increased ICP, and rapid clinical decline. In response to these observations, a series of recent studies have begun to target cerebral edema in the management of large ischemic strokes. During cerebral edema formation, the glial water channel aquaporin-4 (AQP4) has been show to facilitate astrocyte swelling (“cytotoxic swelling”). AQP4 has also been seen to be responsible for the reabsorption of extracellular edema fluid (“vasogenic edema”). In the present review, the role of AQP4 in the development of cerebral edema is discussed with emphasis on its contribution to ischemic edema. We also examine the potential of AQP4 as a therapeutic target in edema associated with stroke.

Research and practice in critical care medicine have long been defined by syndromes, which, despite being clinically recognizable entities, are, in fact, loose amalgams of heterogeneous states that may respond differently to therapy. Mounting translational evidence-supported by research on respiratory failure due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection-suggests that the current syndrome-based framework of critical illness should be reconsidered. Here we discuss recent findings from basic science and clinical research in critical care and explore how these might inform a new conceptual model of critical illness. De-emphasizing syndromes, we focus on the underlying biological changes that underpin critical illness states and that may be amenable to treatment. We hypothesize that such an approach will accelerate critical care research, leading to a richer understanding of the pathobiology of critical illness and of the key determinants of patient outcomes. This, in turn, will support the design of more effective clinical trials and inform a more precise and more effective practice at the bedside.

Aquaporin-4 (AQP4) is a water transport protein expressed in glial cell plasma membranes, including glial cell foot processes lining the blood-brain barrier. AQP4 deletion in mice reduces cytotoxic brain edema produced by different pathologies. To determine whether AQP4 is rate-limiting for brain water accumulation and whether altered AQP4 expression, as occurs in various pathologies, could have functional importance, we generated mice that overexpressed AQP4 in brain glial cells by a transgenic approach using the glial fibrillary acid protein promoter. Overexpression of AQP4 protein in brain by ϳ2.3-fold did not affect mouse survival, appearance, or behavior, nor did it affect brain anatomy or intracranial pressure (ICP). However, following acute water intoxication produced by intraperitoneal water injection, AQP4-overexpressing mice had an accelerated progression of cytotoxic brain swelling, with ICP elevation of 20 ؎ 2 mmHg at 10 min, often producing brain herniation and death. In contrast, ICP elevation was 14 ؎ 2 mmHg at 10 min in control mice and 9.8 ؎ 2 mmHg in AQP4 knockout mice. The deduced increase in brain water content correlated linearly with brain AQP4 protein expression. We conclude that AQP4 expression is rate-limiting for brain water accumulation, and thus, that altered AQP4 expression can be functionally significant. Aquaporin-4 (AQP4)2 is a water-selective membrane transport protein expressed in glial cells in brain, particularly at the borders between brain parenchyma and the major fluid compartments in brain (1, 2). Strong AQP4 expression is found in astroglial cell foot processes at the blood-brain barrier, in glia lining the subarachnoid cerebrospinal fluid space, and in ependyma and subependymal glia lining the ventricular cerebrospinal fluid space. AQP4 expression in glial cells is up-regulated in various brain pathologies, including trauma (3, 4), tumor (5, 6), subarachnoid hemorrhage (7), ischemia (8), and inflammation (9, 10). Whether increased AQP4 expression is functionally significant for water movement between brain and cerebrospinal fluid or blood is not known, as is whether AQP4 is ratelimiting for water movement across the blood-brain barrier. Because water movement from blood to brain parenchyma involves water transport across a tight endothelial cell layer, which does not express AQPs, followed by transport across AQP4-expressing glial cell foot processes surrounding brain microvessels, water movement into the brain may be limited by the endothelial barrier.Evidence from AQP4 knock-out mice indicates slowed water movement both into and out of the brain in AQP4 deficiency, resulting in opposite consequences for cytotoxic versus vasogenic brain edema (reviewed in Ref. 11). AQP4 knock-out mice have reduced brain swelling and improved survival when compared with control, wild-type mice following water intoxication and reduced hemispheric swelling after focal cerebral ischemia (12). AQP4-null mice also have greatly improved survival in a mouse model of bacterial meningitis (9). Ac...

BACKGROUND The treatment of dolichoectatic basilar trunk aneurysms has been ineffectual or morbid due to non-saccular morphology, deep location, and involvement of brainstem perforators. Treatment with bypass surgery has been advocated to eliminate malignant hemodynamics and stabilize aneurysm growth. OBJECTIVE To validate that flow alteration with bypass and parent artery occlusion favorably impacts aneurysm progression. METHODS Surgical management evolved in 3 phases, each with different hemodynamic alterations. RESULTS During a 17-year period, 37 patients with dolichoectatic basilar trunk aneurysms were retrospectively identified, of whom 21 patients were observed, 12 treated immediately, and 4 selected for treatment after clinical progression. In Phase 1, flow reversal was overly thrombogenic, despite heparin (N=5, final mortality, 100%). In Phase 2, flow reduction with IC-IC bypass was safer than flow reversal but did not prevent progressive aneurysm enlargement (N=3, final mortality 67%). In Phase 3, distal clip occlusion of the basilar trunk aneurysm preserved anterograde flow in the aneurysm without rupture, but reduced flow threatened perforator patency, despite treatment with Clopidogrel (Plavix) (N=8, final mortality 62%). CONCLUSION Shifting treatment strategy for dolichoectatic basilar trunk aneurysms improved surgical (80% to 50%) and final mortalities (100% to 62%), with stabilization of aneurysms in the Phase 3 survivors. Good outcomes are determined by perforator preservation and mitigating aneurysm thrombosis. Occlusion techniques with increased distal run-off appear to benefit perforators. The treatment of dolichoectatic basilar trunk aneurysms can advance through concentrated management in dedicated centers, concerted efforts to study morphology/hemodynamics with computational methods, and widespread collection of registry data.

Tumor-associated macrophages (TAMs) constitute up to 50% of tumor bulk in glioblastoma (GBM) and play an important role in tumor maintenance and progression. The recently discovered differences between invading tumour periphery and hypoxic tumor core implies that macrophage biology is also distinct by location. This may provide further insight into the observed treatment resistance to immune modulation. We hypothesize that macrophage activation occurs through processes that are distinct in tumor periphery versus core. We therefore investigated regional differences in TAM recruitment and evolution in GBM by combining open source single cell and bulk gene expression data. We used single cell gene expression data from 4 glioblastomas (total of 3589 cells) and 122 total bulk samples obtained from 10 different patients. Cell identity, ontogeny (bone-marrow derived macrophages-BMDM vs microglia), and macrophage activation state were inferred using verified gene expression signatures. We captured the spectrum of immune states using cell trajectory analysis with pseudotime ordering. In keeping with previous studies, TAMs carrying BMDM identity were more abundant in tumor bulk while microglia-derived TAMs dominated the tumor periphery across all macrophage activation states including pre-activation. We note that core TAMs evolve towards a pro-inflammatory state and identify a subpopulation of cells based on a gene program exhibiting strong, opposing correlation with Programmed cell Death-1 (PD-1) signaling, which may correlate to their response to PD-1 inhibition. By contrast, peripheral TAMs evolve towards anti-inflammatory phenotype and contains a population of cells strongly associated with NFkB signaling. Our preliminary analysis suggests important regional differences in TAMs with regard to recruitment and evolution. We identify regionally distinct and potentially actionable cell subpopulations and advocate the need for a multi-targeted approach to GBM therapeutics.

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