Patients who were successfully revascularized by the Penumbra system had significantly better outcomes than those who were not. Initial post-market experience of the Penumbra system revealed that the revascularization rate and safety profile of the device are comparable to those reported in the Pivotal trial.
However, the proportion of patients who had good functional outcome was higher than expected. The utility of computed tomographic perfusion CTP -based patient selection for intra-arterial treatment of acute ischemic stroke has not been proven in randomized trials and requires further study in a cohort that was not selected based on CTP.
Our objective was to study the relationship between CTP-derived parameters and outcome and treatment effect in patients with acute ischemic stroke because of a proximal intracranial arterial occlusion. Association of CTP-derived parameters ischemic -core volume, penumbra volume, and percentage ischemic core with outcome was estimated with multivariable ordinal logistic regression as an adjusted odds ratio for a shift in the direction of a better outcome on the modified Rankin Scale.
Interaction between CTP-derived parameters and treatment effect was determined using multivariable ordinal logistic regression. The adjusted odds ratio for improved functional outcome for ischemic core, percentage ischemic core, and penumbra were 0. Our group has been systematically investigating the effects of the neuropeptide pituitary adenylate-cyclase activating polypeptide PACAP on the ischemic brain.
To do so, we have established and utilized the permanent middle cerebral artery occlusion PMCAO mouse model, in which PACAP38 1 pmol injection is given intracerebroventrically and compared to a control saline 0. In our previous studies, we have accumulated a large volume of data gene inventory from the whole brain ipsilateral and contralateral hemispheres after both PMCAO and post-PACAP38 injection.
In our latest research, we have targeted specifically infarct or ischemic core hereafter abbreviated IC and penumbra hereafter abbreviated P post-PACAP38 injections in order to re-examine the transcriptome at 6 and 24 h post injection. The current study aims to delineate the specificity of expression and localization of differentially expressed molecular factors influenced by PACAP38 in the IC and P regions. Among the gene inventories obtained here, two genes, brain-derived neurotrophic factor Bdnf and transthyretin Ttr were found to be induced by PACAP38 treatment, which we had not been able to identify previously using the whole hemisphere transcriptome analysis.
Using bioinformatics analysis by pathway- or specific-disease-state focused gene classifications and Ingenuity Pathway Analysis IPA the differentially expressed genes are functionally classified and discussed. Among these, we specifically discuss some novel and previously. Expression of neuronal and signaling proteins in penumbra around a photothrombotic infarction core in rat cerebral cortex. Photodynamic impact on animal cerebral cortex using water-soluble Bengal Rose as a photosensitizer, which does not cross the blood-brain barrier and remains in blood vessels, induces platelet aggregation, vessel occlusion, and brain tissue infarction.
This reproduces ischemic stroke. Irreversible cell damage within the infarction core propagates to adjacent tissue and forms a transition zone - the penumbra. Tissue necrosis in the infarction core is too fast minutes to be prevented, but much slower penumbral injury hours can be limited.
We studied the changes in morphology and protein expression profile in penumbra 1 h after local photothrombotic infarction induced by laser irradiation of the cerebral cortex after Bengal Rose administration. Morphological changes in the penumbra were lesser and decreased towards its periphery. Antibody microarrays against neuronal and signaling proteins were used for proteomic study.
These changes in expression of some neuronal proteins were directed mainly to protection and tissue recovery in the penumbra. Some upregulated proteins might serve as markers of protection processes in a penumbra. Endovascular thrombectomy ET is standard-of-care for ischemic stroke patients with large vessel occlusion, but estimates of potentially eligible patients from population-based studies have not been published.
Such data are urgently needed to rationally plan hyperacute services. Retrospective analysis determined the incidence of ET-eligible ischemic strokes in a comprehensive population-based stroke study Adelaide, Australia Stroke patients were stratified via a prespecified eligibility algorithm derived from recent ET trials comprising stroke subtype, pathogenesis, severity, premorbid modified Rankin Score, presentation delay, large vessel occlusion, and target mismatch penumbra.
Apoptosis may contribute to a significant proportion of neuron death following acute brain ischemia ABI , but the underlying mechanisms are still not fully understood. Brain ischemia may lead to stroke, which is one of the main causes of long-term morbidity and mortality in both developed and developing countries. Therefore, stroke prevention and treatment is clinically important. There are two important separate areas of the brain during ABI: the ischemic core and the ischemic penumbra.
The ischemic core of the brain experiences a sudden reduction of blood flow, just minutes after ischemic attack with irreversible injury and subsequent cell death. On the other hand, apoptosis within the ischemic penumbra may occur after several hours or days, while necrosis starts in the first hours after the onset of ABI in the ischemic core.
These changes in cellular homeostasis may trigger either necrosis or apoptosis, which often depends on cell type, cell age, and location in the brain. Apoptosis results in DNA fragmentation, degradation of cytoskeletal and nuclear proteins, cross-linking of proteins, formation of apoptotic bodies, expression of ligands for phagocytic cell receptors and finally uptake by phagocytic cells.
This review focuses on recent findings based on animal and human studies regarding the apoptotic mechanisms of neuronal death following ABI and the development of potential neuroprotective agents that reduce morbidity. The effects of statins on stroke prevention and treatment as well as on apoptotic mediators are also considered.
Magnetic resonance diffusion-perfusion mismatch in acute ischemic stroke: An update. The concept of magnetic resonance perfusion-diffusion mismatch PDM provides a practical and approximate measure of the tissue at risk and has been increasingly applied for the evaluation of hyperacute and acute stroke in animals and patients.
Recent studies demonstrated that PDM does not optimally define the ischemic penumbra ; because early abnormality on diffusion-weighted imaging overestimates the infarct core by including part of the penumbra , and the abnormality on perfusion weighted imaging overestimates the penumbra by including regions of benign oligemia. To overcome these limitations, many efforts have been made to optimize conventional PDM. Various alternatives beyond the PDM concept are under investigation in order to better define the penumbra.
The PDM theory has been applied in ischemic stroke for at least three purposes: to be used as a practical selection tool for stroke treatment; to test the hypothesis that patients with PDM pattern will benefit from treatment, while those without mismatch pattern will not; to be a surrogate measure for stroke outcome. The main patterns of PDM and its relation with clinical outcomes were also briefly reviewed. The conclusion was that patients with PDM documented more reperfusion, reduced infarct growth and better clinical outcomes compared to patients without PDM, but it was not yet clear that thrombolytic therapy is beneficial when patients were selected on PDM.
Studies based on a larger cohort are currently under investigation to further validate the PDM hypothesis. Targeted delivery of growth factors in ischemic stroke animal models. Ischemic stroke is caused by reduced blood supply and leads to loss of brain function.
The reduced oxygen and nutrient supply stimulates various physiological responses, including induction of growth factors. Growth factors prevent neuronal cell death, promote neovascularization, and induce cell growth.
However, the concentration of growth factors is not sufficient to recover brain function after the ischemic damage, suggesting that delivery of growth factors into the ischemic brain may be a useful treatment for ischemic stroke. In this review, various approaches for the delivery of growth factors to ischemic brain tissue are discussed, including local and targeting delivery systems.
To develop growth factor therapy for ischemic stroke, important considerations should be taken into account. First, growth factors may have possible side effects. Thus, concentration of growth factors should be restricted to the ischemic tissues by local administration or targeted delivery.
Second, the duration of growth factor therapy should be optimized. Growth factor proteins may be degraded too fast to have a high enough therapeutic effect. Therefore, delivery systems for controlled release or gene delivery may be useful. Third, the delivery systems to the brain should be optimized according to the delivery route. Temporal activation of Nrf2 in the penumbra and Nrf2 activator-mediated neuroprotection in ischemia-reperfusion injury.
Oxidative stress plays a critical role in mediating tissue injury and neuron death during ischemia-reperfusion injury IRI. The Keap1-Nrf2 defense pathway serves as a master regulator of endogenous antioxidant defense, and Nrf2 has been attracting attention as a target for the treatment of IRI.
In this study, we evaluated Nrf2 expression in IRI using OKD Keap1-dependent oxidative stress detector mice and investigated the neuroprotective ability of an Nrf2 activator.
We demonstrated temporal changes in Nrf2 expression in the same mice with luciferase assays and an Nrf2 activity time course using Western blotting. We also visualized Nrf2 expression in the ischemic penumbra and investigated Nrf2 expression in mice and humans using immunohistochemistry.
Endogenous Nrf2 upregulation was not detected early in IRI, but expression peaked 24h after ischemia. Nrf2 expression was mainly detected in the penumbra , and it was found in neurons and astrocytes in both mice and humans. Intravenous administration of the Nrf2 activator bardoxolone methyl BARD resulted in earlier upregulation of Nrf2 and heme oxygenase These findings indicate that earlier Nrf2 activation protects neurons, possibly via effects on astrocytes.
Cortical spreading depression CSD , based on its similarities with peri-infarct depolarization, is an ideal model for investigating transformation from the ischemic penumbra to infarct core. However, the underlying mechanisms remain unclear. The results demonstrated that CSD preconditioning significantly decreased the infarct volume, neurological deficits and neuronal apoptosis in the cortical penumbra of middle cerebral artery occlusion rats, which was inhibited by the autophagy inhibitor 3-methyladenine 3-MA, nmol.
The neuroprotection of CSD is likely a result of AMPK-mediated autophagy activity and autophagy-induced neuronal cells apoptosis inhibition. AMPK-mediated autophagy may represent a new target for stroke.
Modelling the penumbra in Computed Tomography1. Kueh, Audrey; Warnett, Jason M. Since X-rays do not arise from a point source, artefacts are produced.
In particular there is a penumbra effect, leading to poorly defined edges within a reconstructed volume. Penumbra models can be simulated given a fixed spot geometry and the known experimental setup.
METHODS: Two models for the spot geometry are considered; one consists of a single Gaussian spot, the other is a mixture model consisting of a Gaussian spot together with a larger uniform spot.
The mixture model which adds a larger uniform spot exhibits a much improved fit. The parameters corresponding to the uniform spot are similar across all powers, and further experiments suggest that the uniform spot produces only soft X-rays of relatively low-energy.
The use of a thin copper filter reduces the size of the effective penumbra. Long-term survival and regeneration of neuronal and vasculature cells inside the core region after ischemic stroke in adult mice. Focal cerebral ischemia results in an ischemic core surrounded by the peri-infarct region penumbra. Most research attention has been focused on penumbra while the pattern of cell fates inside the ischemic core is poorly defined.
In the present investigation, we tested the hypothesis that, inside the ischemic core, some neuronal and vascular cells could survive the initial ischemic insult while regenerative niches might exist many days after stroke in the adult brain. Adult mice were subjected to focal cerebral ischemia induced by permanent occlusion of distal branches of the middle cerebral artery MCA plus transient ligations of bilateral common carotid artery CCA.
Massive cell death occurred due to multiple mechanisms and a significant infarction was cultivated in the ischemic cortex 24 h later.
BrdU-positive but TUNEL-negative neuronal and endothelial cells were detected in the core where extensive extracellular matrix infrastructure developed.
The long term survival of neuronal and vascular cells inside the ischemic core was also seen after a severe ischemic stroke induced by permanent embolic occlusion of the MCA. These data suggest that the ischemic core is an actively regulated brain region with residual and newly formed viable neuronal and vascular cells acutely and chronically after at.
We present a particular case of the formation of a penumbra sector around a developing sunspot in the active region NOAA on August 11 by using the high-resolution data observed by the New Solar Telescope at the Big Bear Solar Observatory and the data acquired by the Helioseismic and Magnetic Imager and the Atmospheric Imaging Assembly on board the Solar Dynamics Observatory satellite.
Before the new penumbra sector formed, the developing sunspot already had two umbrae with some penumbral filaments. The penumbra sector gradually formed at the junction of two umbrae. We found that the formation of the penumbra sector can be divided into two stages.
First, during the initial stage of penumbral formation, the region where the penumbra sector formed always appeared blueshifted in a Dopplergram. The area, mean transverse magnetic field strength, and total magnetic flux of the umbra and penumbra sector all increased with time. The initial penumbral formation was associated with magnetic emergence. These results indicate that the umbra provided magnetic flux for penumbral development after the penumbra sector appeared.
We also found that the newly formed penumbra sector was associated with sunspot rotation. Based on these findings, we suggest that the penumbra sector was the result of the emerging flux that was trapped in the photosphere at the initial stage of penumbral formation, and when the rudimentary penumbra formed, the penumbra sector developed at the cost of the umbra.
Targeting neutrophils in ischemic stroke: translational insights from experimental studies. Neutrophils have key roles in ischemic brain injury, thrombosis, and atherosclerosis. As such, neutrophils are of great interest as targets to treat and prevent ischemic stroke.
After stroke, neutrophils respond rapidly promoting blood—brain barrier disruption, cerebral edema, and brain injury. A surge of neutrophil-derived reactive oxygen species, proteases, and cytokines are released as neutrophils interact with cerebral endothelium. Neutrophils also are linked to the major processes that cause ischemic stroke, thrombosis, and atherosclerosis. Thrombosis is promoted through interactions with platelets, clotting factors, and release of prothrombotic molecules.
In atherosclerosis, neutrophils promote plaque formation and rupture by generating oxidized-low density lipoprotein, enhancing monocyte infiltration, and degrading the fibrous cap. In experimental studies targeting neutrophils can improve stroke. However, early human studies have been met with challenges, and suggest that selective targeting of neutrophils may be required.
Several properties of neutrophil are beneficial and thus may important to preserve in patients with stroke including antimicrobial, antiinflammatory, and neuroprotective functions. Improvement of radiological penumbra using intermediate energy photons IEP for stereotactic radiosurgery. Using efficient immobilization and dedicated beam collimation devices, stereotactic radiosurgery ensures highly conformal treatment of small tumours with limited microscopic extension.
One contribution to normal tissue irradiation remains the radiological penumbra. This work aims at demonstrating that intermediate energy photons IEP , above orthovoltage but below megavoltage, improve dose distribution for stereotactic radiosurgery for small irradiation field sizes due to a dramatic reduction of radiological penumbra. Two different simulation systems were used: i Monte Carlo simulation to investigate the dose distribution of monoenergetic IEP between keV and 1 MeV in water phantom; ii the Pinnacle3 TPS including a virtual IEP unit to investigate the dosimetry benefit of treating with 11 non-coplanar beams a 2 cm tumour in the middle of a brain adjacent to a 1 mm critical structure.
Radiological penumbrae below microm are generated for field size below 2 x 2 cm2 using monoenergetic IEP beams between and keV. An kV beam generated in a 0. Pinnacle3 confirms the dramatic reduction in penumbra size.
DVHs show for a constant dose distribution conformality, improved dose distribution homogeneity and better sparing of critical structures using a kV beam compared to a 6 MV beam. Improving neurovascular outcomes with bilateral forepaw stimulation in a rat photothrombotic ischemic stroke model. Restoring perfusion to the penumbra during the hyperacute phase of ischemic stroke is a key goal of neuroprotection. Thrombolysis is currently the only approved treatment for ischemic stroke.
However, its use is limited by the narrow therapeutic window and side effect of bleeding. Therefore, other interventions are desired that could potentially increase the perfusion of the penumbra. Here, we hypothesized that bilateral peripheral electrical stimulation will improve cerebral perfusion and restore cortical neurovascular response.
We assess the outcomes of bilateral forepaw electrical stimulation at intensities of 2 and 4 mA, administered either unilaterally or bilaterally. We developed a combined electrocorticogram ECoG -functional photoacoustic microscopy fPAM system to evaluate the relative changes in cerebral hemodynamic function and electrophysiologic response to acute, focal stroke. This experimental model can be used to study other potential interventions such as therapeutic hypertension and hypercarbia.
Fine Structure and Dynamics of Sunspot Penumbra. A mature sunspot is usually surrounded by a penumbra : strong vertical magnetic field in the umbra, the dark central region of sunspot, becomes more and more horizontal toward the periphery forming an ensemble of a thin magnetic filaments of varying inclinations.
Recent high resolution observations with the 1-meter Swedish Solar Telescope SST on La Palma revealed a fine substructure of penumbral filaments and new regularities in their dynamics. We present results of recent observations obtained with the SST. We find e. We propose a mechanism that may explain the fine structure of penumbral filaments, the observed regularities, and their togetherness with sunspot formation.
The mechanism is based on the anatomy of sunspots in which not only penumbra has a filamentary structure but umbra itself is a dense conglomerate of twisted interlaced flux tubes. Hypoperfusion induces overexpression of beta-amyloid precursor protein mRNA in a focal ischemic rodent model.
Silent stroke is one of the risk factors of dementia. In the present study, we used a novel focal ischemic animal model to investigate the effects of comparatively small changes of cerebral blood flow CBF on the expression of beta-amyloid precursor protein APP mRNA. Focal ischemia was achieved by introducing a monofilament to the bifurcation of anterior and middle cerebral arteries. Brain samples were harvested from ischemic core and penumbra of cortices at 1, 4 and 7 days following ischemia.
This study suggests brain hypoperfusion enhances APP mRNA expression and may contribute to the progression of cognitive impairment after silent stroke. We studied the variations of line of sight photospheric plasma flows during the formation phase of the penumbra around a pore in active region NOAA Before the penumbra formed we observed a redshift of the spectral line in the inner part of the annular zone surrounding the pore as well as a blueshift of materialmore » associated with opposite magnetic polarity farther away from the pore.
We found that the onset of the classical Evershed flow occurs on a very short timescale 1 to 3 hr while the penumbra is forming. During the same time interval we found changes in the magnetic field inclination in the penumbra , with the vertical field actually changing sign near the penumbral edge, while the total magnetic field showed a significant increase, about G. To explain these and other observations related to the formation of the penumbra and the onset of the Evershed flow we propose a scenario in which the penumbra is formed by magnetic flux dragged down from the canopy surrounding the initial pore.
The Evershed flow starts when the sinking magnetic field dips below the solar surface and magnetoconvection sets in. The magnetic nature of umbra- penumbra boundary in sunspots.
Sunspots are the longest-known manifestation of solar activity, and their magnetic nature has been known for more than a century. Despite this, the boundary between umbrae and penumbrae , the two fundamental sunspot regions, has hitherto been solely defined by an intensity threshold.
Here, we aim at studying the magnetic nature of umbra- penumbra boundaries in sunspots of different sizes, morphologies, evolutionary stages, and phases of the solar cycle. We defined these umbra- penumbra boundaries by an intensity threshold and performed a statistical analysis of the magnetic field properties on these boundaries.
Results: We statistically prove that the umbra- penumbra boundary in stable sunspots is characterised by an invariant value of the vertical magnetic field component: the vertical component of the magnetic field strength does not depend on the umbra size, its morphology, and phase of the solar cycle.
In contrast, the magnetic field strength and inclination averaged along individual boundaries are found to be dependent on the umbral size: the larger the umbra, the stronger and more horizontal the magnetic field at its boundary. Conclusions: The umbra and penumbra of sunspots are separated by a boundary that has hitherto been defined by an intensity threshold. We now unveil the empirical law of the magnetic nature of the umbra- penumbra boundary in stable sunspots: it is an invariant vertical component of the magnetic field.
Photodynamic impact induces ischemic tolerance in models in vivo and in vitro. Ischemic tolerance determines resistance to lethal ischemia gained by a prior sublethal stimulus i.
We reproduced this effect in two variants. It is a model of ischemic stroke. Cerebral tissue edema and global necrosis of neurons and glial cells occurred in the infarction core, which was surrounded by a 1. The maximal pericellular edema, hypo- and hyperchromia of neurons were observed in penumbra 24 h after PTI.
The repeated laser irradiation of the contralateral cerebral cortex also caused PTI but lesser as compared with single PDT. Sensorimotor deficits in PDT-treated rats was registered using the behavioral tests. The preliminary PTI caused the preconditioning effect. Structural magnetic elements observed in sunspot penumbrae are employed as indicators of motions occurring in and around penumbrae.
In a first approximation, the penumbral magnetic fields can be considered alternating spines and interspine filaments. In the plane of the sky, spines are thin radial elements with higher field strengths and lower magnetic-field inclinations compared with those in surrounding areas. It is confirmed that spines first appear as protrusions of the umbra magnetic fields visible in magnetograms, and then develop simultaneously with the growth of the penumbra.
The departure of magnetic elements from penumbrae as a result of the detachment of the ends of spines begin Inmature penumbrae , magnetic elements emerge fairly often, and the departure of groups of field elements sometimes generates structures resembling moving ribbons. The velocities of magnetic elements that have separated from spines are a factor of two to three lower than those of elements that have separated from inter-spine filaments.
The results obtained agree well with an "uncombed" model for the penumbral magnetic fields. Cerebral collaterals and collateral therapeutics for acute ischemic stroke. Cerebral collaterals are vascular redundancies in the cerebral circulation that can partially maintain blood flow to ischemic tissue when primary conduits are blocked. After occlusion of a cerebral artery, anastomoses connecting the distal segments of the MCA with distal branches of the ACA and PCA known as leptomeningeal or pial collaterals allow for partially maintained blood flow in the ischemic penumbra and delay or prevent cell death.
However, collateral circulation varies dramatically between individuals, and collateral extent is significant predictor of stroke severity and recanalization rate.
Collateral therapeutics attempt to harness these vascular redundancies by enhancing blood flow through pial collaterals to reduce ischemia and brain damage after cerebral arterial occlusion. While therapies to enhance collateral flow remain relatively nascent neuroprotective strategies, experimental therapies including inhaled NO, transient suprarenal aortic occlusion, and electrical stimulation of the parasympathetic sphenopalatine ganglion show promise as collateral therapeutics with the potential to improve treatment of acute ischemic stroke.
Ischemic stroke is a complex disease with multiple etiologies and clinical manifestations. Paired immunoglobulin-like receptor B PirB , which is originally thought to function exclusively in the immune system, is now also known to be expressed by neurons.
A growing number of studies indicate that PirB can inhibit neurite outgrowth and restrict neuronal plasticity. The aim of the study is to investigate whether PirB can be an attractive theranostic target for ischemic stroke. First, we investigated the spatial-temporal expression of PirB in multiple ischemic stroke models, including transient middle cerebral artery occlusion, photothrombotic cerebral cortex ischemia, and the neuronal oxygen glucose deprivation model.
Then, anti-PirB immunoliposome nanoprobe was developed by thin-film hydration method and investigated its specific targeting in vitro and in vivo. Finally, soluble PirB ectodomain sPirB protein delivered by polyethylene glycol-modified nanoliposome was used as a therapeutic reagent for ischemic stroke by blocking PirB binding to its endogenous ligands.
These results showed that PirB was significantly upregulated after cerebral ischemic injury in ischemic stroke models. Anti-PirB immunoliposome nanoprobe was successfully developed and specifically bound to PirB in vitro. There was accumulation of anti-PirB immunoliposome nanoprobe in the ischemic hemisphere in vivo. Soluble PirB ectodomains remarkably improved ischemic stroke model recovery by liposomal delivery system. These data indicated that PirB was a significant element in the pathological process of cerebral ischemia.
Therefore, PirB may act as a novel theranostic target for ischemic stroke. Published on behalf of the American Heart Association, Inc. Recently, high-resolution observations improved our understanding of the penumbra formation process around sunspots. In particular, two aspects have been carefully investigated: whether the settlement of the penumbra can occur between the main opposite magnetic polarities where new magnetic flux is still emerging, and the establishment of the Evershed flow.
In this paper, we present the analysis of twelve active regions ARs where both the penumbra formation and the onset of the Evershed flow were observed. The results obtained in our sample provided the following information about the stable settlement of the penumbra : eight spots formed the first stable penumbral sector in the region between the two opposite polarities, and nine spots formed on the opposite side.
Moreover, eleven sunpots showed an inverse Evershed flow i. Comparing our results with recent observations, we are able to discriminate between the different ways of penumbra formation.
Moreover, we suggest that the change from inverse Evershed flow, visible before the penumbra appears, into the classical Evershed flow may be a signature of the formation of penumbral filaments. Extravasation into brain and subsequent spread beyond the ischemic core of a magnetic resonance contrast agent following a step-down infusion protocol in acute cerebral ischemia. Limiting expansion of the ischemic core lesion by reinstating blood flow and protecting the penumbral cells is a priority in acute stroke treatment.
However, at present, methods are not available for effective drug delivery to the ischemic penumbra. To address these issues this study compared the extravasation and subsequent interstitial spread of a magnetic resonance contrast agent MRCA beyond the ischemic core into the surrounding brain in a rat model of ischemia-reperfusion for bolus injection and step-down infusion SDI protocols. Male Wistar rats underwent middle cerebral artery MCA occlusion for 3 h followed by reperfusion.
Perfusion-diffusion mismatched regions indicating the extent of spread were identified by measuring cerebral blood flow CBF deficits by arterial spin-labeled magnetic resonance imaging and the extent of the ischemic core by mapping the apparent diffusion coefficient ADC of water with diffusion-weighted imaging.
Spatial and temporal expansion of the MRCA front during a 25 min imaging period was measured from images obtained at 2. The bolus injection led to MRCA enhancement with an area that initially spread into the ischemic core and then diminished over time. The SDI produced a gradual increase in the area of MRCA enhancement that slowly enlarged to occupy the core, eventually expanded beyond it into the surrounding tissue and then plateaued.
The total number of pixels covered by the SDI at its maximum was. Abstract: Tissue plasminogen activator t-PA is the only FDA-approved drug for acute ischemic stroke treatment, but its clinical use is limited due to the narrow therapeutic time window and severe adverse effects, including hemorrhagic transformation HT and neurotoxicity.
One of the potential resolutions is to use adjunct therapies to reduce the side effects and extend t-PA's therapeutic time window.
However, therapies modulating single target seem not to be satisfied, and a multi- target strategy is warranted to resolve such complex disease. Recently, large amount of efforts have been made to explore the active compounds from herbal supplements to treat ischemic stroke. Some natural compounds revealed both neuro- and blood-brain-barrier BBB -protective effects by concurrently targeting multiple cellular signaling pathways in cerebral ischemia-reperfusion injury.
Thus, those compounds are potential to be one-drug-multi- target agents as combined therapy with t-PA for ischemic stroke. In this review article, we summarize current progress about molecular targets involving in t-PA-mediated HT and neurotoxicity in ischemic brain injury.
Based on these targets , we select 23 promising compounds from currently available literature with the bioactivities simultaneously targeting several important molecular targets. We propose that those compounds merit further investigation as combined therapy with t-PA. Finally, we discuss the potential drawbacks of the natural compounds' studies and raise several important issues to be addressed in the future for the development of natural compound as an adjunct therapy.
Lateral penumbra of multileaf collimator plays an important role in radiotherapy treatment planning. Growing evidence has revealed that, for a single-focused multileaf collimator, lateral penumbra width is leaf position dependent and largely attributed to the leaf end shape. In our study, an analytical method for leaf end induced lateral penumbra modelling is formulated using Tangent Secant Theory.
Compared with Monte Carlo simulation and ray tracing algorithm, our model serves well the purpose of cost-efficient penumbra evaluation. With biobjective function of penumbra mean and variance introduced, genetic algorithm is carried out for approximating the Pareto frontier. Results show that for circular arc leaf end objective function is convex and convergence to optimal solution is guaranteed using gradient based iterative method. For treatment modalities in clinical application, optimized leaf ends are in close agreement with actual shapes.
Taken together, the method that we propose can provide insight into leaf end shape design of multileaf collimator. Imaging ischemic strokes in rodents using visible-light optical coherence tomography Conference Presentation. Monitoring cortical hemodynamic response after ischemic stroke IS is essential for understanding the pathophysiological mechanisms behind IS-induced neuron loss.
Functional optical coherence tomography OCT is an emerging technology that can fulfill the requirement, providing label-free, high-resolution 3D images of cerebral hemodynamics. Unfortunately, strong tissue scattering pose a significant challenge for existing OCT oximetry techniques, as they either ignore the effect or compensate it numerically. Astrup, J. Thresholds in cerebral ischemia — the ischemic penumbra. Stroke, 12 , — PubMed Google Scholar.
Fisher, M. The ischemic penumbra: Identification, evolution and treatment concepts. Cerebrovascular Diseases Review , 17 Suppl. Google Scholar. Kwiatkowski, T. Effects of tissue plasminogen activator for acute ischemic stroke at one year.
As the hypothalamic nuclei provide both the releasing hormones for the anterior hypophysis and the hormones to be liberated from the posterior hypophysis, preserved hypothalamic-hypophyseal function in some patients presumed to be brain dead cannot be explained by a hypothetical collateral blood flow to the anterior hypophysis through the inferior hypophyseal arteries arising extradurally from the internal carotid arteries. A reduced BBF down to Sustained hypophyseal function is therefore indirect evidence for active function, circulation and structural integrity of hypothalamic nuclei.
Gramm and co-workers 8 followed 32 potential organ donors over a period of up to 80 h after the diagnosis of brain death established according to current criteria, determining the serum and plasma concentrations of hypothalamic-pituitary hormones, thyroid hormones, and cortisol.
In addition, none of the circulating hormones of the anterior hypophysis declined progressively according to their plasma half-lives from the onset of the "brain-death syndrome". These results are in agreement with earlier and less extensive studies 9, Direct evidence of sustained hypothalamic secretory activity was provided by Arita and co-workers 11 who measured the serum concentrations of 3 different releasing hormones growth hormone-releasing hormone - GH-RH, adrenocorticotrophic hormone-releasing hormone - ACTH-RH, luteinizing hormone-releasing hormone - LH-RH in 24 cases within 24 h after the diagnosis of brain death.
In general, one or more hypothalamic hormones were detectable in every case. Sustained thermoregulation, paradoxically considered a prerequisite for the diagnosis of brain death 2 , is clear evidence for preserved hypothalamic function and rather suggests GIP in patients with increased ICP and suppressed cephalic reflexes.
Therefore, although eventually depressed as suggested by signs of diabetes insipidus , the blood supply to the hypothalamus seems to be high enough to sustain most of its secretory functions in most patients for the first days after the current criteria for the diagnosis of brain death are fulfilled.
Sustained hypothalamic circulation implying circulation above That situation is illustrated in Figure 1 with hypothetical case examples No. On the other hand, the concept of GIP contradicts the assumption that hypercarbia induced by apnea testing would help to differentiate recoverable from irreversible cases of brain stem injury.
Rather, hypercarbia may further impair the blood supply to the brain stem in these patients. Although vascular responses to changes in CO 2 are diminished, for instance, in victims of severe head trauma, some reactivity persists even in deeply comatose patients. As intracranial compliance is remarkably reduced following severe head trauma, even a minor hypercarbia-induced aggravation of brain swelling may largely worsen the intracranial hypertension and the resulting global ischemic insult Preservation of brain blood flow in these patients requires significantly higher levels of perfusion pressure than in other individuals Accordingly, transient arterial hypotension leads to irreversible collapse of intracranial circulation in cats subjected to severe head trauma, so that even supranormal levels of perfusion pressure cannot restore the brain blood flow in these animals The sudden association of hypercarbia-induced increase in ICP with severe hypotension presumably related to the detrimental effects of acidemia on the myocardium possibly enables the establishment of tension forces between the intraluminal surfaces of brain vessels, and thereby causes irreversible collapse of intracranial circulation.
Therefore, apnea testing may induce rather than diagnose irreversible damage to brain tissue, and the results of all confirmatory tests carried out thereafter may reflect the deleterious effects of induced apnea with or without hypoxia.
Direct measurements of BBF following the diagnosis of brain death support the detrimental effects of apnea testing. Due to such a sudden and permanent efflux of blood volume from intracranial space vascular collapse determined by apnea testing, normal levels of intracranial and perfusion pressures may be subsequently found in paradoxical association with absent or extremely reduced intracranial blood flow less than Accordingly, Obrist and colleagues 16 found this combination of features in all of 9 patients fulfilling the current diagnostic criteria for brain death.
During progression to brain death - solely defined as "loss of cranial nerve reflexes and flat EEG" in deeply comatose patients - these authors found that "ICP increased to and remained at or above the level of mean arterial pressure" in all of 10 patients up to spontaneous cardiac arrest.
The possible detrimental effects of the apnea test on a subset of potentially recoverable hypothetical case examples No. Figure 2 - Evolution of brain blood flow BBF in three hypothetical cases of intracranial hypertension: influence of hypotension induced by apnea testing at h survival.
Whilst BBF is unaffected in case 1, apnea testing hastens and sets the clinical outcome to irreversible brain damage in cases 2 and 3 by inducing collapse of intracranial vessels.
For abbreviations see legend to Figure 1. As in most early studies that followed the emergence of brain death in medical practice, apnea testing was avoided, and the "lack of any observed effort of the patient to override the respirator or by a ventilatory effort or movement other than that induced by the respirator" was chosen to characterize the loss of respiratory reflex Forty-eight hours of cephalic areflexia did not significantly change that percent value Those surprisingly good results were obtained despite the fact that the neurological conditions of the head trauma victims probably further deteriorated from admission up to an average survival of 16 h, when a h treatment with moderate hypothermia was initiated The mechanisms that account for recovery from such a pre-mortal state may include a avoidance of detrimental effects related to apnea testing 26 , b normalization of ICP recirculation from GIP - see Figure 3 during cooling to 33 o C 27 , c regression of brain edema 27 , d inhibition of the detrimental cascade of neurochemical events triggered by a transient ischemic insult 28 , and e prevention of intracranial thermal pooling that increases brain temperature to levels capable of damaging vascular and neuronal proteins Figure 3 - Evolution of brain blood flow in three hypothetical cases of increased intracranial pressure ICP : influence of moderate hypothermia 33 o C induced at h survival.
Simultaneous normalization of intracranial pressure observed during cooling to 33 o C 27 leads to recirculation of cases 2 and 3 whilst case 1 is unaffected. Remarkable absorption of brain edema during the next few hours of hypothermic treatment should prevent recurrence of ICP Brain temperature may reach more than 2 o C above rectal temperature, and antipyresis effectively reduces this difference In addition to reducing acute neuronal damage 31 ,postischemic administration of an antipyretic drug prevented the development of chronic neurodegeneration when associated with the hypothermic treatment in rats Accordingly, Jones and co-workers 33 found hyperthermia to be one of the most important determinants of poor outcome following head trauma.
Prevention of arterial hypotension also impedes intracranial thermal pooling 29 , and may act synergistically with antipyresis to protect the injured brain tissue. Cases of basilar artery occlusion presenting apneic coma seem to evolve invariably to death when recirculation is not induced In contrast, intra-arterial thrombolysis has been reported to induce remarkable functional recovery from basilar artery occlusion in a case of apneic coma and cephalic areflexia for h A subset of these cases may therefore sustain ischemic penumbra of the brain stem for a few hours from the onset of symptoms, and respond to timely intra-arterial thrombolysis, provided that apnea is not allowed for the diagnosis of brain death.
Absence of clinically detectable cephalic reflexes may occur in association with other signs of preserved brain stem function. Cortical somatosensory-evoked potentials were abolished 46 h but not 2. Similarly, the existence of spinal cord cardiovascular centers does not exclude the brain stem as the anatomical site responsible for maintenance of normal blood pressure, or for the hemodynamic responses to surgical incisions for removal of transplantable organs in patients currently diagnosed as brain or brain stem dead Rather, the absence of a recordable period of profound hypotension that follows acute inactivation of vasomotor centers by ischemia due to rising intracranial pressure is not consistent with that diagnosis The diverse cephalic reflexes evaluated for the clinical diagnosis of brain death do not disappear simultaneously as the blood supply to the brain stem decreases 38 , suggesting that some synaptic circuits expend higher amounts of energy than others.
Similarly, both the neuronal control of hemodynamic conditions and the verification of somatosensory-evoked potentials may require lower levels of blood supply than the demonstration of cephalic reflexes upon neurological examination. Accordingly, even the evidence for one single and depressed sign of brain stem activity may imply levels of infratentorial blood flow above the threshold associated with disruption of ionic homeostasis of neuronal cells.
Therefore, these signs may identify patients with a higher likelihood for recovery following resuscitative hypothermia As compared to tests for those synapse-dependent functions, which are expected to be cumulatively suppressed as BBF falls from around Even after fulfillment of clinical diagnostic criteria, the vertebro-basilar artery remained visible on 2 consecutive daily angiograms in a case of infratentorial hemorrhage Other cases of delayed or partial opacification of the intracranial arteries following the diagnosis of brain death have been reported Conversely, angiography may fail to detect intracranial blood flow despite indirect evidence for continuous endocrine activity of hypothalamic nuclei 8,9.
These data contradict the long-held assumption that the absence of angiographic images of brain arteries should be considered an indisputable evidence for intracranial circulatory arrest. Actually, for optimal visualization of vascular images, the contrast media must be infused intra-arterially at specific rates considering a normal range of intracranial blood flow A reduced perfusion pressure may therefore decrease the brain blood flow and affect vascular opacification Angiographic findings as well as the results of other less reliable confirmatory tests therefore are to be correlated with specific levels of intracranial blood flow.
The hypothesis of GIP is supported by both direct and indirect data, and is in agreement with previous criticisms against a the definition of brain death by statute as "irreversibility of cessation of brain function" 49 , and b current misconceptions regarding diagnosis and prognosis of death More effective therapeutic resources based on new pathophysiological concepts may improve the prognosis of patients in critical conditions.
Likewise, the confirmation of the GIP hypothesis may indicate the value of hypothermia and other resources for the treatment of a subset of patients in a coma with cephalic areflexia nowadays conceivably misdiagnosed as neurologically unrecoverable. Address for correspondence: C. E-mail: coimbracg.
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