Background and Purpose-Patients undergoing intra-arterial therapy (IAT) for acute ischemic stroke receive either general anesthesia (GA) or conscious sedation. GA may delay time to treatment, whereas conscious sedation may result in patient movement and compromise the safety of the procedure. We sought to determine whether there were differences in safety and outcomes in GA patients before initiation of IAT. Methods-A cohort of 980 patients at 12 stroke centers underwent IAT for acute stroke between 2005 and 2009. Only patients with anterior circulation strokes due to large-vessel occlusion were included in the study. A binary logistic-regression model was used to determine independent predictors of good outcome and death. Results-The mean age was 66Ϯ15 years and median National Institutes of Health Stroke Scale score was 17 (interquartile range, 13-20). The overall recanalization rate was 68% and the symptomatic hemorrhage rate was 9.2%. GA was used in 44% of patients with no differences in intracranial hemorrhage rates when compared with the conscious sedation group. The use of GA was associated with poorer neurologic outcome at 90 days (odds ratioϭ2.33; 95% CI, 1.63-3.44; PϽ0.0001) and higher mortality (odds ratioϭ1.68; 95% CI, 1.23-2.30; PϽ0.0001) compared with conscious sedation. Conclusions-Patients placed under GA during IAT for anterior circulation stroke appear to have a higher chance of poor neurologic outcome and mortality. There do not appear to be differences in hemorrhagic complications between the 2 groups. Future clinical trials with IAT can help elucidate the etiology of the differences in outcomes. (Stroke. 2010; 41:1175-1179.)
Dopaminergic transmission within limbic regions of the brain is highly dependent on the regulation of D2 receptor activity. Here we show that the neuronal calcium sensor-1 (NCS-1) can mediate desensitization of D2 dopamine receptors. Analysis of D2 receptors expressed in human embryonic kidney 293 cells indicates that NCS-1 attenuates agonist-induced receptor internalization via a mechanism that involves a reduction in D2 receptor phosphorylation. This effect of NCS-1 was accompanied by an increase in D2 receptor-mediated cAMP inhibition after dopamine stimulation. The ability of NCS-1 to modulate D2 receptor signaling was abolished after a single amino acid mutation in NCS-1 that has been shown to impair the calcium-binding properties of NCS-1. Coimmunoprecipitation experiments from striatal neurons reveal that NCS-1 is found in association with both the D2 receptor and G-protein-coupled receptor kinase 2, a regulator of D2 receptor desensitization. Colocalization of NCS-1 and D2 receptors was examined in both primate and rodent brain. In striatum, NCS-1 and D2 receptors were found to colocalize within sites of synaptic transmission and in close proximity to intracellular calcium stores. NCS-1-D2 receptor interaction may serve to couple dopamine and calcium signaling pathways, thereby providing a critical component in the regulation of dopaminergic signaling in normal and diseased brain.
Background and Purpose-There is considerable heterogeneity in practice patterns between sedation in the intubated state vs nonintubated state during endovascular acute stroke therapy. We sought to compare clinical and radiographic outcomes between these 2 sedation modalities. Methods-Consecutive patients with acute stroke due to middle cerebral artery-M1 segment occlusion treated with endovascular therapy between January 2006 and July 2009 were identified in our interventional acute stroke database.
Background and purpose Endovascular techniques are frequently employed to treat large artery occlusion in acute ischemic stroke (AIS). We sought to determine the predictors and clinical impact of intracranial hemorrhage (ICH) after endovascular therapy. Methods Retrospective analysis of consecutive patients presenting to 13 high volume stroke centers with AIS due to proximal occlusion in the anterior circulation who underwent endovascular treatment within 8 h from symptom onset. Logistic regression was performed to determine the variables associated with ICH, hemorrhagic infarction (HI), and parenchymal hematomas (PHs), as well as 90 day poor outcome (modified Rankin Scale score ≥3) and mortality. Results There were a total of 363 ICHs (overall rate 32.3%; HI=267, 24%; PH=96, 8.5%) among the 1122 study patients (mean age 67±15 years; median National Institutes of Health Stroke Scale score 17 (IQR 13–20)). Independent predictors for HI included diabetes mellitus (OR 2.27, 95% CI (1.58 to 3.26), p<0.0001), preprocedure IV tissue plasminogen activator (tPA) (1.43 (1.03 to 2.08), p<0.037), Merci thrombectomy (1.47 (1.02 to 2.12), p<0.032), and longer time to puncture (1.001 (1.00 to 1.002), p<0.026). Patients with atrial fibrillation (1.61 (1.01 to 2.55), p<0.045) had a higher risk of PH while the use of IA tPA (0.57 (0.35 to 0.90), p<0.008) was associated with lower chances of PH. Both the presence of HI (2.23 (1.53 to 3.25), p<0.0001) and PH (6.24 (3.06 to 12.75), p<0.0001) were associated with poor functional outcomes; however, only PH was associated with higher mortality (3.53 (2.19 to 5.68), p<0.0001). Conclusions Greater understanding about the predictors and consequences of ICH post endovascular stroke therapy is essential to improve risk assessment, patient selection/clinical outcomes, and early prognostication. Our data suggest that patients with atrial fibrillation are particularly prone to severe ICH and question the ‘benign’ nature of HI suggested by earlier studies.
We have used a yeast two-hybrid approach to uncover protein interactions involving the D2-like subfamily of dopamine receptors. Using the third intracellular loop of the D2S and D3 dopamine receptors as bait to screen a human brain cDNA library, we identified filamin A (FLN-A) as a protein that interacts with both the D2 and D3 subtypes. The interaction with FLN-A was specific for the D2 and D3 receptors and was independently confirmed in pulldown and coimmunoprecipitation experiments. Deletion mapping localized the dopamine receptor-FLN-A interaction to the N-terminal segment of the D2 and D3 dopamine receptors and to repeat 19 of FLN-A. In cultures of dissociated rat striatum, FLN-A and D2 receptors colocalized throughout neuronal somata and processes as well as in astrocytes. Expression of D2 dopamine receptors in FLN-A-deficient M2 melanoma cells resulted in predominant intracellular localization of the D2 receptors, whereas in FLN-A-reconstituted cells, the D2 receptor was predominantly localized at the plasma membrane. These results suggest that FLN-A may be required for proper cell surface expression of the D2 dopamine receptors. Association of D2 and D3 dopamine receptors with FLN-A provides a mechanism whereby specific dopamine receptor subtypes may be functionally linked to downstream signaling components via the actin cytoskeleton. I mbalances in dopaminergic signaling are implicated in many neuropsychiatric and motor disorders, including schizophrenia and Parkinson's disease (1). In mammalian brain, dopaminergic signaling is mediated via a cohort of dopamine receptors. Among the cloned dopamine receptor subtypes, the D2-like receptors (D2, D3, and D4) are the major target of antipsychotics, both typical and atypical, as well as anti-Parkinson's drugs (1). These receptors mediate intracellular signaling cascades by coupling to inhibitory subsets of heterotrimeric GTP-binding (G) proteins. In a variety of cell types, D2-like receptor signaling modulates calcium, potassium, and sodium currents through specific regulation of ion channel activities (2, 3). The activation of D2-like receptors also has been implicated in the regulation of cellular morphogenesis (4) and in the maintenance of neuronal structure in adult brain (5-7). Although the D2-like receptors appear to activate discrete signal transduction pathways, the question of whether individual D2-like receptors subserve distinct functional roles is an issue that has not yet been satisfactorily addressed.To better understand the regulation of dopamine receptor signaling, we are interested in identifying dopamine receptor-interacting proteins. Identification of dopamine receptor-interacting proteins unique to specific receptor subtypes may provide important clues to how functional differences between dopamine receptor subtypes are manifested. We conducted yeast two-hybrid screens of a human brain cDNA library, with the third intracellular loop of the D2S and D3 receptors as bait. Using this approach, we identified filamin A (FLN-A) as a dopamine rece...
Traditionally, the interaction of G protein-coupled receptors has been described by models that assume that the receptor exists as a monomer coupled to G protein in a 1:1 stoichiometry. However, these classical models of receptor/G protein coupling may be oversimplified. It has now been shown that many G protein-coupled receptors can form dimers or higher order oligomers and that this phenomenon has relevance to receptor function (for a review, see Ref. 6). Dopamine receptors have also been shown to form dimers and higher order oligomers. Evidence has been provided for D 1 , D 2 , and D 3 homodimers in transfected cell lines (7-9), and D 2 receptors have been shown to exist as dimers in human and rat brain tissues (10). Moreover, Rocheville et al. (11) have recently shown that the dopamine D 2 receptors not only form homodimers but also form heterodimers with somatostatin SSTR 5 receptors. In addition, Gines et al. (12) have shown that the dopamine D 1 receptor forms hetero-oligomers with the adenosine A 1 receptor.As the issue of G protein-coupled receptor homo-and heterodimerization is becoming more and more important, it is crucial to define the mechanism(s) of receptor-receptor interactions in order to predict which receptors can interact with one another. The results obtained until now suggest that more than one mechanism exists and that one receptor can interact with another in more than one way.One of the mechanisms that have been proposed to explain receptor dimerization is the phenomenon of domain swapping
Background and Purpose-Acute ischemic stroke due to tandem occlusions of the extracranial internal carotid artery and intracranial arteries has a poor natural history. We aimed to evaluate our single-center experience with endovascular treatment of this unique stroke population. Methods-Consecutive patients with tandem occlusions of the internal carotid artery origin and an intracranial artery (ie, internal carotid artery terminus, M1 middle cerebral artery, or M2 middle cerebral artery) were studied retrospectively. Treatment consisted of proximal revascularization with angioplasty and stenting followed by intracranial intervention. Endpoints were recanalization of both extracranial and intracranial vessels (Thrombolysis In Myocardial Ischemia Ն2), parenchymal hematoma, and good clinical outcome (modified Rankin Scale Յ2) at 3 months. Results-We identified 77 patients with tandem occlusions. Recanalization occurred in 58 cases (75.3%) and parenchymal hematoma occurred in 8 cases (10.4%). Distal embolization occurred in 3 cases (3.9%). In 18 of 77 patients (23.4%), distal (ie, intracranial) recanalization was observed after proximal recanalization, obviating the need for distal intervention. Good clinical outcomes were achieved in 32 patients (41.6%). In multivariate analysis, Thrombolysis In Myocardial Ischemia Ն2 recanalization, baseline National Institutes of Health Stroke Scale score, baseline Alberta Stroke Programme Early CT score, and age were significantly associated with good outcome. Conclusions-Endovascular therapy of tandem occlusions using extracranial internal carotid artery revascularization as the first step is technically feasible, has a high recanalization rate, and results in an acceptable rate of good clinical outcome.Future randomized, prospective studies should clarify the role of this approach.
We have generated a stable cell line expressing FLAG epitopetagged D3 dopamine receptors and used this cell line to study D3 receptor-protein interactions. To analyze protein interactions, we separately introduced into the stable cell line either D3 receptors carrying an hemagglutinin (HA) epitope tag, or an HA-tagged version of the D3 receptor splice variant D3nf. A combination of confocal laser microscopy and coimmunoprecipitation was used to assay the formation and expression pattern of D3-D3 homodimers or D3-D3nf heterodimers. When coexpressed in HEK 293 cells, FLAG-and HA-tagged D3 receptors exhibited a similar plasma membrane distribution. Using an HA epitope tag-specific antibody, we coimmunoprecipitated HA-and FLAG-tagged D3 receptors, suggesting that D3 receptors are capable of forming homodimers. Epitope-tagged D3nf polypeptides exhibited a markedly different cellular distribution than D3 receptors. When expressed in HEK 293 cells, either alone or in combination with FLAG-tagged D3 receptors, D3nf exhibited a punctate perinuclear distribution. When D3nf was introduced into the stable D3-expressing cell line, D3 receptors were no longer visualized at the plasma membrane. Instead, D3 and D3nf showed a similar, predominantly cytosolic, localization. Using the HA-specific antibody, we were able to coimmunoprecipitate D3 and D3nf polypeptides from transfected cells. These data suggest the existence of physical interaction between D3 and D3nf. This interaction appears to result in the mislocalization of D3 receptors from the plasma membrane to an intracellular compartment, a finding that could be of significance in the etiology of schizophrenia.Dopamine neurotransmission in mammalian brain is mediated by a cohort of receptors that are members of the superfamily of G protein-coupled receptors (GPCRs). In humans, five dopamine receptor subtypes (D1-D5) have been identified by molecular cloning (reviewed in Missale et al., 1998). The five dopamine receptors have been grouped into two subfamilies based upon sequence homologies and pharmacologic profiles. The D1 class of dopamine receptors is comprised of the D1 and D5 receptor subtypes. These receptors are expressed at high levels in cerebral cortex and are coupled to stimulatory subsets of heterotrimeric G proteins. The D2 class of dopamine receptors, consisting of the D2, D3, and D4 subtypes, is coupled to inhibitory subsets of G proteins and is a major target of antipsychotic drugs.Among the D2 class of dopamine receptors, the D3 receptor is distinctive in that it is distributed preferentially in limbic areas of the brain (nucleus accumbens, olfactory tubercle, islands of Calleja, and hippocampus) thought to control cognitive and emotional aspects of behavior (Bouthenet et al., 1991). The D3 receptor has also been shown to bind most antipsychotic drugs, both typical and atypical, with high affinity (Levant, 1997). Because of its anatomic distribution and interaction with antipsychotic drugs, the D3 dopamine receptor has been suggested to play a role i...
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