BACKGROUND:Angioscopy - or endovascular endoscopy - is a catheter-based technique employing a flexible fiberoptic angioscope to directly visualize arterial lumen. Poor resolution and excessive stiffness of pre-existent angioscopes limited their use clinically. Recent advances resulted in novel fused optical fiber bundle angioscopes with improved flexibility and imaging resolution. Use of these devices in endovascular neurosurgery is still largely unexplored. OBJECTIVE:To evaluate image quality and feasibility of optical angioscopes for diagnostic and interventional neuro-angioscopy in carotid arteries of human cadavers. METHODS:A 5-F optical angioscope was used in human cadaveric carotid arteries to inspect integrity of arterial walls, identify atherosclerotic plaques and associated lesions prone to thrombogenicity, place intravascular occlusion coils, and deploy endovascular stents with real-time visualization. RESULTS:Angioscopy provided key information about endoluminal anatomy such as presence and characteristics of atherosclerotic plaques and thrombogenic lesions not detected by conventional diagnostic methods. Direct real-time visualization of vascular lumen during endovascular interventions provided information on spatial distribution of coils, coil loop herniation, and apposition of stent cells against carotid artery wall complementary to angiography. CONCLUSIONS:Fused optical fiber bundle angioscopes provide good-quality endoluminal images in human carotid arteries. Their use can feasibly assist in navigation of extracranial carotid arteries to inspect integrity of the arterial wall and identify atherosclerotic plaques and associated lesions vulnerable to thrombogenicity, allow placement of intravascular occlusion coils, and assess apposition of stents to vessel wall. Further in Vivo validation needs to be conducted along with additional research to improve image quality, flexibility, and size of angioscopes.

Despite decades of research, a countless number of “neuroprotective” drugs that proved effective in animal models of stroke have failed in translational clinical trials for multiple reasons [1]. Yet, the search for the seemingly elusive neuroprotective strategy continued. Ischemic stroke is a leading cause of adult disability, and there is an unmet need to find effective neuroprotective strategies. One such strategy that has been gaining attention is ischemic tolerance and ischemic preconditioning. The phenomenon of ischemic tolerance, where brief periods of cerebral ischemia confer tolerance to subsequent ischemic challenges in the brain, has been confirmed in various animal models of cerebral ischemia. However, induction of direct brain ischemia as an effort to protect the brain presents significant challenges in the clinical setting. Thus, significant recent focus has turned to a specific form of tolerance: remote ischemic preconditioning (rIPC). In rIPC, repeated cycles of temporary ischemia in a remote organ can activate protective pathways in other organs, including the brain. This strategy presents numerous advantages over direct ischemic preconditioning, as it can be accomplished through noninvasive means without specialized equipment—typically via repeated brief periods of arm or leg ischemia using a blood pressure cuff. The cellular signaling pathways that are activated following ischemic preconditioning include: 1) adenosine release and activation of adenosine A1 receptors; 2) inhibition of glutamate release and enhancement of gamma-aminobutyric acid release thus making neurons more resistant to the excitotoxic insult; 3) amelioration of oxidative damage following cerebral ischemia through increased antioxidant production and DNA repair capacity; 4) suppression of inflammation through stimulation of Toll-like receptors, which activate many proinflammatory pathways; and 5) prevention of mitochondria-dependent cell death pathways [2, 3]. Spurred by the relatively straightforward protocols for rIPC, efforts to translate this accumulating body of knowledge and evidence supporting rIPC as a neuroprotective strategy into the clinical setting are slowly rising. Small clinical studies are ongoing to test the role of rIPC in protecting the brain against delayed ischemic injury after subarachnoid hemorrhage [4]. Recently, the value of rIPC as an adjunct therapy to thrombolysis in patients with ischemic stroke was investigated in an open-label, blinded-outcome, proof-of-concept study. The paramedics administered rIPC in the prehospital setting to 443 Danish patients with suspected acute stroke. Transient ischemic attack was more frequent, and National Institutes of Health Stroke Scale score on admission was lower in the rIPC group compared with controls. The risk of tissue infarction as assessed by diffusion–perfusion magnetic resonance imaging was also reduced in the rIPC group [5]. Another proof-of-concept study by Meng et al. [6] evaluated the protective effects of rIPC in 88 Chinese patients younger than 80 years of age with symptomatic intracranial atherosclerosis. Cerebral perfusion status, measured by single-photon emission computed tomography and transcranial Doppler, improved remarkably in patients with rIPC than in controls. In addition, the incidence of recurrent stroke at 300 days was lower and the average time to recovery (defined as modified Rankin Scale Score < 1) was shorter in the rIPC group than in controls. In this issue, Meng et al. [7] expand on their earlier study by investigating the safety and potential effectiveness of rIPC in 59 octo- and nonagenarian patients with symptomatic intracranial atherosclerosis. They conclude that rIPC safely ameliorates plasma biomarkers of inflammation and reduces stroke recurrence in these patients. Although this study is largely limited by its small sample size, it does suggest that rIPC is feasible and likely safe in older stroke patients. The studies of Meng et al. and others [5–7] indicate that rIPC holds promise as a simple and easy neuroprotective strategy for a large number of stroke patients. It is suited for 1) primary and secondary stroke prevention in multiple settings, including symptomatic and asymptomatic intra- and perhaps extracranial arterial occlusive lesions; 2) as an adjunctive strategy with or without reperfusion therapy for acute ischemic stroke; and 3) as a prophylactic strategy against delayed ischemic injury in subarachnoid hemorrhage. However, rIPC is yet to be ready for prime time. More study is needed. Although the overall findings of Meng et al. [7] and others are consistent with data from animal models and are promising, the translation into a possible clinical benefit remains to be shown in large phase III trials. In addition, the optimal timing, frequency, and duration of rIPC need to be better defined. While preclinical and early clinical studies of rIPC are promising, the potential utility of rIPC as a successful neuroprotective strategy should be viewed with cautious optimism. Have we not learned our lessons from the failure of an endless number of stroke neuroprotection studies in the past?

The proteasome has emerged as an important target for therapeutic intervention. In preclinical studies, proteasome inhibitors (PIs) induced apoptosis and inhibited tumor growth, supporting their potential role in the treatment of various tumor types, especially hematologic malignancies. Bortezomib (Velcade), the first clinically validated PI, reversibly binds to the chymotrypsin-like (ChT-L) active sites in the 20S proteasome and potently inhibits cell growth and proliferation in human tumor cell lines and in multiple myeloma (MM) and mantle cell lymphoma. However, the adverse event profile and intravenous administration of bortezomib have underscored the need for the development of PIs with selective actions on different proteasome subunits, which would have different binding kinetics and routes of administration. The most advanced next-generation PI is carfilzomib, an epoxyketone that differs structurally and mechanistically from bortezomib. In preclinical studies, carfilzomib demonstrates sustained inhibition of proteasomal ChT-L activity and greater selectivity than bortezomib. It is thought that the selectivity of carfilzomib for the β5 subunit contributes to its greater cytotoxic response and improved tolerability profile relative to bortezomib. Furthermore, in preclinical studies, carfilzomib did not exhibit the same magnitude of off-target activity against non-proteasomal proteases that is observed with bortezomib. Variations in the binding profiles of some of the next-generation PIs may translate into key differences in pharmacokinetic and toxicity profiles, and thus may be clinically relevant in the treatment of MM.

Ischemic stroke has long been thought to have a genetic component that is independent of conventional vascular risk factors. It has been estimated that over one half of stroke risk is determined by inherited genes. However, until recently, strong evidence of genetic influence on ischemic stroke has been subject to criticism because the risk factors for stroke are also inherited and because previous studies suffered from limitations imposed by this highly heterogeneous neurological disorder. Recent advances in molecular genetics have led to the identification of specific genetic loci that impart susceptibility to ischemic stroke. We review the studies of these genes and discuss the future potential applications of genetic markers on the management of ischemic stroke patients.

Endothelial progenitor cells (EPCs) play an important role in repair of injured vascular endothelium and angiogenesis. Erythropoietin (EPO) is a pleiotropic cytokine with tissue protective functions including ability to protect neurons and vascular endothelial cells from ischemic damage and oxidative stress. More recently, it has been shown that EPO enhances proliferation, differentiation, and mobilization of EPCs. We hypothesized that the beneficial effect of EPO is mediated in part by up-regulation of EPCs antioxidant capacity. The human EPCs, outgrown from circulating mononuclear cells, demonstrated cobble stone morphology and expressed endothelial cell markers. Treatment of EPCs with EPO (0, 0.5, 1, and 10 IU/ml) for 24 h caused a concentration-dependent increase in expression of CuZnSOD protein (36.80 2.97, 52.94 13.06, 66.55 8.66, and 79.71 20.82 relative densitometric unit, respectively). In contrast, the protein levels of manganese superoxide dismutase (MnSOD) and catalase were not affected by EPO. In the spleen (an important source of EPCs) of EPO overexpressing mice (tg6) CuZnSOD protein levels were significantly increased compared to wild type controls (108.79 9.85, and 67.24 31.75 relative densitometric unit, respectively, n 5, P 0.05). MnSOD and catalase protein expressions in the spleen of transgenic mice were not different from those in control animals. Our results suggest that up-regulation of CuZnSOD is an important molecular mechanism underlying vasoprotective effect of EPO.

Female patients experience substantial neuroprotection after experimental stroke compared with male patients, a finding attributed to the protective effects of gonadal hormones. This study examined the response of male- and female-derived organotypic hippocampal slices to oxidative and excitotoxic injury. Both oxygen and glucose deprivation and N-methyl-D-aspartic acid exposure led to neuronal death; however, female-derived cultures sustained less injury than male-derived cultures. Cell death after oxygen and glucose deprivation was ameliorated in male cultures, but not female cultures, by the addition of 7-nitroindazole, a neuronal nitric oxide synthase inhibitor. These studies have relevance to researchers investigating neuroprotective agents in mixed sex experiments.

Background and Purpose— Female, compared with male, animals are protected from cerebral ischemic injury. Physiological concentrations of 17β-estradiol (E2) reduce damage in experimental stroke. E2 augments angiogenesis in reproductive organs and noncerebral vascular beds. We hypothesized that E2 protects brain in stroke through modulation of angiogenesis. We quantified molecular markers of angiogenesis and capillary density before and after unilateral middle cerebral artery occlusion (MCAO). Methods— Female animals were ovariectomized, treated with 25 μg E2 or placebo implants, and subjected to 2-hour MCAO and 22 hours of reperfusion. Brain angiopoietin-1 (Ang-1), Ang-2, Tie-1, Tie-2, vascular endothelial growth factor (VEGF), VEGF R1, and VEGF R2 mRNA levels were determined by RNAse protection assays, and CD31-positive vessels were counted. Results— E2, but not ischemia, upregulated cerebral Ang-1 mRNA by 49%. Capillary density was higher in the brains of E2-treated animals. In estrogen receptor-α knockout (ERKO) mice, E2-mediated induction of Ang-1 mRNA was absent relative to wild-type littermates. Conclusions— These results suggest that E2 increases Ang-1 and enhances capillary density in brain under basal conditions, priming the MCA territory for survival after experimental focal ischemia.

Classically, estrogen acts on cells by directly activating gene transcription driven by ligand-bound nuclear estrogen receptors (ER). Accumulating evidence demonstrates that estrogen acts on neurons by utilizing diverse molecular mechanisms, including rapid signaling by proteins localized to the plasma membrane. Recent studies showing that ERalpha localizes to axons and dendrites of hippocampal neurons suggest that nonnuclear stores of the receptor may transduce estrogen signaling. Here, we have studied the subcellular localization, dynamic regulation, and function of ERalpha in mouse cortical neurons. Estrogen-stimulated mouse cortical neurons activate both estrogen response element (ERE) stimulated transcription and rapid activation of p44/42 mitogen-activated protein kinases (MAPK). We demonstrate that green fluorescent protein (GFP)-tagged ERalpha localizes to neurites in cultured cortical neurons and that the expression within neurites can be down-regulated by estrogen or up-regulated by antiestrogen administered during synthesis. Neurite ERalpha appears to be directed to neurites directly from its site of translation and not from nuclear stores. By using confocal microscopy, we show that ERalpha within neurites stimulates local activation of p44/42 MAP kinases in response to estrogen. We conclude that hormonal status alters subcellular ERalpha targeting in cortical neurons and that neurite-expressed ERalpha is important in the activation of local MAPK signaling.

Spontaneously hypertensive stroke-prone rats (SHRSP), a model for genetic stroke susceptibility, suffer spontaneous stroke and enhanced injury after experimental stroke, in part due to abnormal cerebrovascular development. We hypothesized that angiopoietin system genes in SHRSP may follow unique patterns of expression after experimentally induced stroke. SHRSP, hypertensive control rats (SHR), and normotensive controls (WKY) were subjected to experimental middle cerebral artery occlusion, and brain RNA was analyzed for expression of angiogenic genes. Expression of angiopoietin-2 increased after stroke in all rat strains and was significantly enhanced in SHRSP compared with control strains. In addition, expression of angiopoietin-1 and the angiopoietin receptor dropped markedly after stroke in SHRSP animals, but was not different after ischemia in SHR and WKY strains. Thus, the SHRSP brain elaborates a unique and specific pattern of angiopoietin system gene expression after stroke which may underlie stroke susceptibility of these rats.

Box‐Jenkins time series analysis for the monthly water quality data in Chung Kang River was conducted. It was found that the autoregressive models with order one could be used, and forecasting with seasonal data seems to perform well when the Box‐Jenkins technique is combined with nonparametric transformation. Further, the three‐model structure selection criteria used in the analysis has very good consistency in selecting the best model.