text:
Inflammatory mechanisms in ischemic stroke: therapeutic approaches
- Shaheen E Lakhan1Email author,
- Annette Kirchgessner1 and
- Magdalena Hofer1
© Lakhan et al; licensee BioMed Central Ltd. 2009
Received: 3 August 2009
Accepted: 17 November 2009
Published: 17 November 2009
Acute ischemic stroke is the third leading cause of death in industrialized countries and the most frequent cause of permanent disability in adults worldwide. Despite advances in the understanding of the pathophysiology of cerebral ischemia, therapeutic options remain limited. Only recombinant tissue-plasminogen activator (rt-PA) for thrombolysis is currently approved for use in the treatment of this devastating disease. However, its use is limited by its short therapeutic window (three hours), complications derived essentially from the risk of hemorrhage, and the potential damage from reperfusion/ischemic injury. Two important pathophysiological mechanisms involved during ischemic stroke are oxidative stress and inflammation. Brain tissue is not well equipped with antioxidant defenses, so reactive oxygen species and other free radicals/oxidants, released by inflammatory cells, threaten tissue viability in the vicinity of the ischemic core. This review will discuss the molecular aspects of oxidative stress and inflammation in ischemic stroke and potential therapeutic strategies that target neuroinflammation and the innate immune system. Currently, little is known about endogenous counterregulatory immune mechanisms. However, recent studies showing that regulatory T cells are major cerebroprotective immunomodulators after stroke suggest that targeting the endogenous adaptive immune response may offer novel promising neuroprotectant therapies.
Stroke is the third leading cause of death in industrialized countries [1] and the most frequent cause of permanent disability in adults worldwide [2]. Three months following a stroke, 15-30% of stroke survivors are permanently disabled and 20% require institutional care [3]. Deficits can include partial paralysis, difficulties with memory, thinking, language, and movements. In the Western world, over 70% of individuals experiencing a stroke are over 65 years of age. Since life expectancy continues to grow, the absolute number of individuals with stroke will further increase in the future.
The most common cause of stroke is the sudden occlusion of a blood vessel by a thrombus or embolism, resulting in an almost immediate loss of oxygen and glucose to the cerebral tissue. Although different mechanisms are involved in the pathogenesis of stroke, increasing evidence shows that ischemic injury and inflammation account for its pathogenic progression [4]. Cerebral ischemia triggers the pathological pathways of the ischemic cascade and ultimately causes irreversible neuronal injury in the ischemic core within minutes of the onset [5].
However, a much larger volume of brain tissue surrounding this ischemic core, known as the penumbra, can be salvaged if cerebral blood flow is promptly restored. Thus, the original definition of the ischemic penumbra referred to areas of brain that were damaged but not yet dead, offering the promise that if proper therapies could be found, one could rescue brain tissue after stroke and reduce post-stroke disability.
Despite advances in the understanding of the pathophysiology of cerebral ischemia, therapeutic options for acute ischemic stroke remain very limited [2]. Only one drug is approved for clinical use for the thrombolytic treatment of acute ischemic stroke in the US and that is intravenous recombinant tissue plasminogen activator (rt-PA). When delivered within three hours after symptom onset, rt-PA reduces neurological deficits and improves the functional outcome of stroke patients. However, this improvement in recovery is achieved at the expense of an increased incidence in symptomatic intracranial hemorrhage, which occurs in ~6% of patients. Furthermore, since the large majority of patients with acute ischemic stroke do not go to the hospital within three hours of stroke onset most do not receive rt-PA treatment [6]. Consequently, the successful treatment of acute ischemic stroke remains one of the major challenges in clinical medicine.
This review will provide a brief overview of the current understanding of the inflammatory mechanisms involved in an acute ischemic stroke and the neuroprotective agents that can curtail neuroinflammation and potentially show utility in the treatment of stroke. Neuroprotective treatments are therapies that block the cellular, biochemical, and metabolic elaboration of injury during exposure to ischemia. Of the more than 100 neuroprotective agents that reached randomized clinical trials in focal ischemic stroke, none has proven unequivocally efficacious, despite success seen in preceding animal studies [7]. However, the failed trials of the past have greatly increased our understanding of the fundamental biology of ischemic brain injury and have laid a strong foundation for future advance. New anti-inflammatory targets continue to be identified, which is an important area for translational medicine in acute stroke. Overall, the prospects for safe neuroprotective therapies to improve stroke outcome remain promising [8]
Ischemic cascade
Acute ischemic stroke accounts for about 85% of all cases while hemorrhagic stroke is responsible for almost 15% of all strokes. Ischemic stroke results from the sudden decrease or loss of blood circulation to an area of the brain, resulting in a corresponding loss of neurological function. It is a nonspecific term encompassing a heterogeneous group of etiologies including thrombosis, embolism, and relative hypoperfusion. In most cases, the cause is atherothrombosis of large cervical or intracranial arteries, or embolism from the heart.
As a result of residual perfusion from the collateral blood vessels, regions where blood flow drops to approximately 30 ml/100 g/min ischemic cascade progresses at a slower rate. Neuronal cells may tolerate this level of reduced (20-40% of control values) blood flow for several hours from the stroke onset with full recovery of function following restoration of blood flow [9].
In the center of the ischemic region cells undergo anoxic depolarization and they never repolarize. While in the penumbral region, the cells can repolarize at the expense of further energy consumption and depolarize again in response to elevated levels of extracellular glutamate and potassium ions. Such repetitive depolarizations called "peri-infarct depolarizations" lead to the increased release of the excitatory neurotransmitter glutamate with resulting excitotoxic cell damage [10]. Ultimately, the severity of functional and structural changes in the brain caused by ischemia will depend on its degree and duration.
Hyperbaric (HBO) and normobaric oxygen (NBO) therapies attempt to increase the partial pressure of oxygen to the tissue and thereby limit the damage caused by hypoperfusion. However, three clinical trials of hyperbaric oxygen therapy failed to show efficacy [11]. Normobaric, high-flow oxygen therapy was shown to cause a transient improvement of clinical deficits and MRI abnormalities in a sub-group of patients with acute ischemic stroke. Further studies are needed to investigate the safety and efficacy of hyperoxia as a stroke therapy [12].
Oxidative stress
Oxidative stress contributes to the pathogenesis of a number of neurological conditions including stroke. Oxidative stress is defined as the condition occurring when the physiological balance between oxidants and antioxidants is disrupted in favor of the former with potential damage for the organism. Oxidative stress leading to ischemic cell death involves the formation of ROS/reactive nitrogen species through multiple injury mechanisms, such as mitochondrial inhibition, Ca2+ overload, reperfusion injury, and inflammation [13]. Plenty of ROS are generated during an acute ischemic stroke and there is considerable evidence that oxidative stress is an important mediator of tissue injury in acute ischemic stroke [14]. Brain ischemia generates superoxide (O2-), which is the primary radical from which hydrogen peroxide is formed. Hydrogen peroxide is the source of hydroxyl radical (OH). Nitric oxide is a water- and lipid-soluble free radical that is produced from L-arginine by three types of nitric oxide synthases (NOS). Ischemia causes an increase in NOS type I and III activity in neurons and vascular endothelium, respectively. At a later stage, elevated NOS type II (iNOS) activity occurs in a range of cells including glia and infiltrating neutrophils. Thus, free radicals are regarded as an important therapeutic target for improving the outcome of an ischemic stroke. Several compounds with significant antioxidant properties including ebselen [15], and resveratrol [16], a natural phytoalexin found in some dietary sources such as grapes and red wine, have been demonstrated to reduce stroke-related brain damage in animal models.
The transcription factor Nrf2
Nuclear factor erythroid-related factor 2 (Nrf2) is a transcription factor that regulates an expansive set of antioxidant genes that act in synergy to remove ROS through sequential enzymatic reactions [17].
Several studies have shown that increasing Nrf2 activity is highly neuroprotective in in vitro models that stimulate components of stroke damage, such as oxidative glutamate toxicity, H2O2 exposure, and Ca2+ overload [18]. Administration of the well characterized Nrf2 inducer, tert-butylhydroquinone (tBHQ), a metabolite of the widely used food antioxidant butylated hydroxyanisole, significantly improved sensorimotor and histological outcome in two models of I/R in rats and mice [19]. Within this injury paradigm, Nrf2 activation before stroke was able to salvage the cortical penumbra but not the stroke core. Clear differences in stroke outcome were found as early as 24 hours after reperfusion. Moreover, prophylactic treatment improved functional recovery up to one month after transient MCAO suggesting that previous Nrf2 activation may reduce neuronal cell death during delayed apoptosis and inflammation long after stroke onset.
Conversely, Nrf2-deficient mice are significantly more prone to ischemic brain injury and neurological deficits than WT mice. Deletion of the Nrf2 gene renders animals more susceptible to various stressors mainly because of the failure to induce phase II enzymes. Furthermore, an Nrf2 inducer was able to reverse neuronal cell death induced by the free radical donor tert-butylhydroperoxide (t-BuOOH) [19]. The MCAO and reperfusion model is known to induce a transient focal ischemic cascade that uniquely includes a substantial surge of free radical damage.
Ischemia/reperfusion (I/R) injury
The ischemic cascade usually goes on for hours but can last for days, even after restoration of blood circulation. Although reperfusion of ischemic brain tissue is critical for restoring normal function, it can paradoxically result in secondary damage, called ischemia/reperfusion (I/R) injury.
The definitive pathophysiology regarding I/R injury still remains obscure; however, oxidative stress mediators such as reactive oxygen species (ROS) released by inflammatory cells around the I/R injured areas are suggested to play a critical role [20]. The increase in oxygen free radicals triggers the expression of a number of pro-inflammatory genes by inducing the synthesis of transcription factors, including NF-κB, hypoxia inducible factor 1, interferon regulator factor 1 and STAT3. As a result, cytokines are upregulated in the cerebral tissue and consequently, the expression of adhesion molecules on the endothelial cell surface is induced, including intercellular adhesion molecule 1 (ICAM-1), P-selectin and E-selectin which mediate adhesion of leukocytes to endothelia in the periphery of the infarct [21].
Furthermore, the complement cascade has been shown to play a critical role in I/R injury [22]. In addition to direct cell damage, regional brain I/R induces an inflammatory response involving complement activation and generation of active fragments such as C3a and C5a anaphylatoxins. Expression of C3a and complement 5a receptors was found to be significantly increased after middle cerebral artery occlusion (MCAO) in the mouse indicating an active role of the complement system in cerebral ischemic injury. Complement inhibition resulted in neuroprotection in animal models of stroke [23].
Post-ischemic inflammation
Although for many years the CNS was considered an immune-privileged organ, it is now well accepted that the immune and the nervous system are engaged in bi-directional crosstalk. Moreover, mounting data suggest that in the brain, as in peripheral organs, inflammatory cells participate in tissue remodeling after injury.
Microglial cells are the resident macrophages of the brain and play a critical role as resident immunocompetent and phagocytic cells in the CNS. Ekdahl and colleagues [24] reported an increased number of activated microglial cells up to 16 weeks after two hour MCAO in rats. After activation by ischemia, microglia can transform into phagocytes and they can release a variety of substances many of which are cytotoxic and/or cytoprotective. Microglia may exert neuroprotection by producing neurotrophic molecules such as brain-derived neurotrophic factor (BDNF), insulin-like growth factor I (IGF-I), and several other growth factors. There is substantial evidence that activated microglial cells in response to ischemia have the potential of releasing several pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6, as well as other potential cytotoxic molecules including NO, ROS, and prostanoids [25].
Astrocytes, like microglia, are capable of secreting inflammatory factors such as cytokines, chemokines, and NO [26]. Cytokines upregulate the expression of cell adhesion molecules (CAMs). Within four to six hours after ischemia onset, circulating leukocytes adhere to vessel walls and migrate into the brain with subsequent release of additional pro-inflammatory mediators and secondary injury in the penumbra. Neutrophils are the earliest leukocyte subtype to show substantial upregulation in gene expression studies and to infiltrate areas of brain ischemia (see below). Recently, Shichita et al. [27] demonstrated an infiltration of γdT cells 3 days after the onset of ischemia in a mouse model, along with a production of IL-17 which amplify the inflammatory cascade. IL-23 from infiltrating macrophages appear to produce Il-23 which attracts the infiltrating γdT cells. Blocking a specific γdT cell receptor with an antibody effectively reduced three-day infarct volumes, even when treatment was initiated at 24 hours after onset of cerebral ischemia. Targeting these γdT cells may offer a clinical opportunity with a longer therapeutic window to prevent the secondary inflammatory expansion of cerebral damage after stroke.
Cytokines and brain inflammation
Cytokines are a group of small glycoproteins that are produced in response to an antigen and were originally described as mediators for regulating the innate and adaptive immune systems. Cytokines are thus upregulated in the brain in a variety of diseases, including stroke. In the brain, cytokines are expressed not only in the cells of the immune system, but are also produced by resident brain cells, including neurons and glia [28]. In addition, it has been shown that peripherally derived cytokines are involved in brain inflammation. Thus, peripherally derived mononuclear phagocytes, T lymphocytes, NK cells and polymorphonuclear leukocytes produce and secrete cytokines and might contribute to inflammation of the CNS [29].
The most studied cytokines related to inflammation in acute ischemic stroke are tumor necrosis factor-α (TNF-α), the interleukins (IL), IL-1β, IL-6, IL-20, IL-10 and transforming growth factor (TGF)-β. While IL-1β and TNF-α, appear to exacerbate cerebral injury, TGF-β and IL-10 may be neuroprotective [30, 31]. Increased production of pro-inflammatory cytokines and lower levels of the anti-inflammatory IL-10 are related to larger infarctions and poorer clinical outcome.
Elevated IL-1β mRNA expression occurs within the first 15-30 min after permanent MCAO and elevated IL-1β protein expression occurs a few hours later and remains elevated for up to 4 days [32]. There are studies that correlate an increase in the levels of IL-1β after ischemia with worsening of the infarct severity. For example, Yamasaki et al [33] demonstrated that intraventricular injection of recombinant IL-1β after MCAO increases the formation of brain edema, the volume of the size and the influx of neutrophils. In addition, IL-1β deficient mice presented smaller infarcts in comparison with wild-type mice [34].
High circulating IL-1β elevates circulating IL-6, another well known cytokine that is upregulated following cerebral ischemia [35]. Moreover, the serum level of IL-6 correlates with brain infarct volume [36] and is a powerful predictor of early neurological deterioration [37]. On the other hand, Clark et al [38] demonstrated that infarct size and neurological function were not different in animals deficient in IL-6 after transient CNS ischemia. This suggests that IL-6 does not have a direct influence on acute ischemic injury.
IL-20 is induced when IL-1β modulates p38 MAPK and the NF-κB pathway. IL-20 in turn induces the production of IL-6. Inhibition of IL-20 by a specific mAb significantly ameliorated the brain ischemic infarction in rats following MCAO [39].
Clinical studies of agents targeting inflammatory pathways in acute ischemic stroke.
Neuroprotective Agent
Mode of Action
Recombinant human IL-1RA
Interleukin-1 receptor antagonist
Anti-ICAM-1 monoclonal antibody
Lipid peroxidation inhibitor
Neutrophil inhibitory factor
Cerovive (NXY-059)
Nitrone-based free radical trapping agent
Acetaminophen (Paracetamol)
Anti-pyretic effect
Ca2+ channel antagonist
Edaravone MCI-186
Free radical scavenger
ONO-2506 (Arundic Acid)
Astrocyte modulator
IL-10 is an anti-inflammatory cytokine that acts by inhibiting IL-1 and TNF-α, and by suppressing cytokine receptor expression and receptor activation as well. As a consequence, IL-10 could provide neuroprotection in acute ischemic stroke. Both central and systemic administration of IL-10 to rats subjected to MCAO significantly reduced infarct size 30 min to three hours post MCAO [30]. In acute ischemic stroke, elevated concentrations of IL-10 in CSF have been found [41]. Moreover, patients with low plasma levels (<6 pg/ml) of IL-10 during the first hours after stroke were three times more likely to have worsening neurological symptoms within 48 hours following the stroke [37]. IL-10 also seems to mediate the reduction in infarct size by regulatory T cells (see below).
Chemokines and brain inflammation
Chemokines, for example, monocyte chemoattractant protein 1, are a class of cytokines that guide the migration of blood borne inflammatory cells, such as neutrophils and macrophages, towards the source of the chemokine. Consequently, they play important roles in cellular communication and inflammatory cell recruitment. Expression of chemokines such as MCP-1, macrophage inflammatory protein-1α (MIP-1α), and fractakline following focal ischemia is thought to have a deleterious effect by increasing leukocyte infiltration [42]. The level of a variety of chemokines has been found to increase in animal models of ischemia and their inhibition or deficiency has been associated with reduced injury [43–45]. Mice without the chemokine receptor CCR2 are protected against ischemia-reperfusion injury [46].
Cellular adhesion molecules
There is increasing evidence that cellular adhesion molecules (CAMs) play an important role in the pathophysiology of acute ischemic stroke [21]. CAMs are upregulated in the first days after stroke by various cytokines and are responsible for the adhesion and migration of the leukocytes. Leukocytes roll on the endothelial surface and then adhere to the endothelial cells. The interaction between leukocytes and the vascular endothelium is mediated by three main groups of CAMs: the selectins, the immunoglobulin gene superfamily, and the integrins. Selectins, especially E- and P-selectins are upregulated and mediate leukocyte rolling and recruitment during the early stages of ischemia [47] Among the immunoglobulin family member, intercellular adhesions molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 have been the most extensively investigated in cerebral ischemia. Within hours after stroke onset, ICAM-1 expression increases upon stimulation by cytokines [48].
Patients with acute ischemic stroke had higher soluble intercellular adhesion molecule-1 (sICAM-1) levels compared to patients without cardiovascular disease. Moreover, sICAM-1 levels were significantly higher in patients who died compared to those who survived [49]. High sICAM-1 levels on admission are associated with early death is ischemic middle-aged stroke patients suggesting a pathogenic role of inflammation in the evolution of ischemic stroke.
A number of animal studies have shown that after transient and permanent focal ischemia the upregulation of CAMs, especially ICAM-1, P- and E-selectin, preceded the invasion of neutrophils into brain. There is ample evidence from animal models of MCAO that expression of CAMs is associated with cerebral infarct size. Thus, genetic ablation of CAMs resulted in reduced infarct size, which could be mimicked by treatment with anti-CAM antibodies [50, 51]. Inhibition of leukocyte activation and infiltration into the ischemic cerebral tissue has, therefore, been an important area of neuroprotection research. Thus far, anti-CAM treatment has not been successful in patients with acute ischemic stroke. However, further translational research into the therapeutic targeting of CAM is ongoing.
The spatiotemporal profile of CAMs is still largely unresolved, even though they are crucial for efficient anti-inflammatory therapies. More knowledge of the spatiotemporal profile of CAMs may lead the way to successful application and monitoring of promising anti-inflammatory treatment strategies after stroke.
Matrix metalloproteinases
MMPs are a family of proteolytic enzymes that are responsible for remodeling the extracellular matrix and that can degrade all its constituents. Expression of MMPs in the adult brain is very low to undetectable, but many MMPs are upregulated in the brain in response to injury [52]. Neurons, astrocytes, microglia, and endothelial cells have all been shown to express MMPs after injury. Stroke is associated with a biphasic disruption of the blood brain barrier (BBB) leading to vasogenic edema and hemorrhage and experimental studies have shown that that BBB breakdown and hemorrhage results from the expression and activation of MMPs [53].
MMP-2 and MMP-9 have been implicated in cerebral ischemia. Elevated MMP-9 levels were found in brain tissue and in serum from patients with acute ischemic stroke and in animal models of stroke beginning at 12 h after permanent MCAO [54]. MMP-9 is normally absent and this is the major MMP associated with neuroinflammation. Early (day 1) MMP-9 inhibition reduced infarction of day 14. However, benefit was lost when the treatment was delayed until day 3 and stroke pathology was exacerbated when administration was delayed until day 7 [55]. These studies all suggest that MMP inhibition could have a beneficial effect on the outcome of stroke but the effect will depend on the timing of treatment in relation to the stage of brain injury [55].
Regulatory T lymphocytes
Severe brain ischemia also perturbs innate and adaptive immune cells, resulting in systemic immunodepression that predisposes patients after stroke to life-threatening infections [56]. Postischemic alterations in the immune system might represent a useful immunomodulatory adaptation, preventing autoimmune reactions against CNS antigens after stroke.
Recently, regulatory T lymphocytes (Treg) were shown to play an important role in protecting cells in a mouse model for stroke [57]. Thymus-derived CD4+CD25+Foxp3 Treg cells play a key part in controlling immune responses under physiological conditions and in various systemic and CNS inflammatory diseases [58]. Treg are generated by dendritic or antigen-presenting cells expressing the immunosuppressive mediator indoleamine 2,3-dioxygenase, the first enzyme in the kynurenine pathway, that degrades and converts tryptophan to kynurenine [59]. Interferon-γ and TNF-α which are both present at high levels in the ischemic brain induce IDO in response to chronic immune activation, possibly in microglia [60].
A stroke in mice with no functioning Treg cells in their blood caused much greater damage to the brain and greater disabilities than in animals with functioning Treg cells. Treg cells protect cells by suppressing the harmful activation of the immune system and can thus also prevent autoimmune diseases from developing. IL-10 is a cytokine that is produced by the Treg cells and seems to play an important role during a stroke. Mice with no functioning Treg cells that were injected with IL-10 on the first day following a stroke had markedly less brain damage than mice that did not receive IL-10. On the other hand, the transfer of genetically modified Treg cells unable to produce IL-10 offered no protection [57]. Treg cells producing IL-10 induce IDO suggesting that IL-10 may act upstream by modulating the production of IDO.
Post-stroke recovery
Patients experiencing a typical large-vessel acute ischemic stroke will lose 120 million neurons each hour. Compared with the normal rate of neuron loss during aging, the ischemic brain will age 3.6 years for every hour the stroke goes untreated. Thus, it is not surprising that the majority of stroke patients exhibit certain levels of motor weakness and sensory disturbances [2]. However, over time, most will show a certain degree of functional recovery which may be explained by brain reorganization and brain plasticity.
Brain plasticity refers to the brain's ability to change its structure and function during development, learning, and pathology. For example, within the minutes following ischemia, rapid changes are observed in the number and length of dendritic spines of the neurons in the penumbra region. The initial loss is then followed by the re-establishment of the dendritic spine synapses several months after the initial stroke as part of the functional recovery process [61].
Functional MRI studies have demonstrated that the damaged adult brain is able to reorganize to compensate for motor deficits [62, 63]. The main mechanism underlying recovery of motor abilities appears to involve enhanced activity in preexisting networks. Studies in experimental stroke models demonstrate that focal cerebral ischemia promotes neurogenesis in the subventricular zone (SVZ) and subgranular zone (SGZ) of the dentate gyrus and induces SVZ neuroblast migration towards the ischemic boundary. More importantly, stroke-induced neurogenesis has also recently been demonstrated in the adult human brain, even in advanced age patients [64–66] These findings have led to a hope for a neurorestorative treatment of stroke which aims to manipulate endogenous neurogenesis and thereby enhance brain repair.
In conclusion, in the presented work, we sought to provide a brief overview of the current understanding of inflammatory mechanisms involved during acute ischemic stroke and neuroprotective agents that can curtail neuroinflammation and could have utility in the treatment of stroke (see Table 1). As discussed, evidence suggests that post-ischemic oxidative stress and inflammation contribute to brain injury and to the expansion of the ischemic lesion. On the other hand, an adequate adaptive immune response after acute brain ischemia also plays an important role in response to ischemic injury as shown by the tremendous potential of Treg cells to prevent secondary infarct growth by counteracting the production of proinflammatory cytokines and by modulating the activation of lymphocytes and microglia in the ischemic brain [57]. These results provide new insights into the immunopathogenesis of acute ischemic stroke and could lead to new approaches that involve immune modulation using Treg cells.
To date, 1,026 drugs have been tested in various animal models, of which 114 underwent clinical evaluation [8]. The greater part of the agents studied until now have failed. Consequently, rt-PA remains the only agent shown to improve stroke outcome in clinical trials, despite the many clinical trials conducted. However, its use is limited by its short therapeutic window (three hours), by its complications derived essentially from the risk of hemorrhage, and by the potential damage by R/I injury. Because of these drawbacks the optimum treatment of cerebral focal ischemia remains one of the major challenges in clinical medicine.
Antioxidant response element
brain-derived neutrotrophic factor
cell adhesion molecule
insulin-like growth factor I
interleukin-1 membrane receptor
interleukin-1 receptor antagonist
- Keap1:
kelch-like erythroid cell-derived protein with CNC homology associated protein 1
matrix metalloproteinase
- iNOS:
nitric oxide synthase type II
intracellular adhesion molecule 1
middle cerebral artery occlusion
monocyte chemoattractant protein-1
nitric oxide synthase
- Nrf2:
nuclear factor erythroid-related factor 2
reactive oxygen species
- rt-PA:
recombinant tissue plasminogen activator
- Treg:
regulatory T lymphocytes
- sICAM-1:
soluble intracellular adhesion molecule 1
superoxide dismutase
- t-BuOOH:
- tBHQ:
transforming growth factor
- TNF-α:
tumor necrosis factor-α.
The authors wish to extend special thanks to GNIF research associates Elissa Hamlat, Julie Aeschliman, and Lorraine Webster for their suggestions and editing support.
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This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


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Flippin' Out
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- The all new outrageous party game from endless games
- Category name game for whole family
- Recommended for ages 10 and up and for 2 or more players
- Fast paced board game that anyone can play
- Letter flipping elimination game
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For example: if the category was "minor but painful injuries," one player might say 'papercut,' and then flip over the P-chip. The next player might say "Stubbed Toe," and so on and so forth. If a player gives an answer starting with a letter that's already been given, play stops and the opposite team gets the point. Oh yeah... did I forget to mention there's an omnipresent ticking clock (er, sand timer)? No pressure.
As a little divulging of secret information between you, devoted reader, and me: I'm unequivocally horrible at quick recall games. I like them, don't get me wrong, I'm just more of an analytical player. Analysis Paralysis doesn't exist in my world. Needless to say, the fiancee thoroughly whupped me when we played. Even in that case, however, I had a good time playing; and I had fun when we upped the number of players to 6 during Game Night. I will say, however, that this game can (and should) easily qualify as a party game--or a drinking game, though I'm totally not advocating that if you happen to be under 21 . It can also be used as a good filler while other friends are setting up more complex games like Small World, Dominant Species, or Dominion.Read more ›
Then we had to come up with something relating to that topic using one of the available letters. Once we used the letter we turned it over and it was the next person's turn to come up with something from the same category. Sound easy? Wait until you only have letters like J, Q, or Z left. Oh, and did I mention there's a 10 second timer?
Whoever won the round got to move their pawn up one space. At first, I thought the game would go by pretty fast since there are only 5 spaces to move. However, going back and forth for each topic actually took some time and we were able to finish a game in about 15 - 20 minutes.
This is a great game to get you thinking outside the box. Some of the answers we thought of were not obvious choices but we decided that as long as we could justify our answers then it would be counted.
Flippin' Out is a great addition to our game library!
Most Recent Customer Reviews
I have not played this game yet. But my daughter and her in laws played it and raved about it. I am planning on getting one for me as well.Published on February 11, 2014 by mtn highlander
My family really had a great time playing this and had lots of laughs! I highly recommend this game and think it would be fun for kids age 8 and up!Published on February 8, 2014 by Amazon Customer
This game is simple and yet so good, it's addictive. If you like Scattergories and other word games, chances are you too will enjoy Flippin' Out.Published on January 16, 2014 by Nicole Wilde
A simple game that everyone can play. Gameplay is fun and fast. Opened the game and was playing in minutes!Published on October 24, 2013 by Neener
We have played it three times since it arrived in November. We enjoyed it with family at Thanksgiving time with ages spanning from 11 to 82; we played it with just adult couples... Read morePublished on January 14, 2013 by Diana
This was a pretty fun game and kept us entertained for awhile. The basics is that you pick a category card where you have to shout out items in that category that starts with a... Read morePublished on January 5, 2012 by R. mayer
For the past couple of weeks, we have been playing Flippin Out with friends and family. We've had a few disagreements and many laughs. Read morePublished on December 1, 2011 by More 4 Mom's Buck

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Robert Armor
38133 Memphis TN
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45240 Cincinnati OH
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Robert Armor | Aerotek Inc | ZoomInfo.com
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classmates: Robert Armor
Venice High School, Los Angeles, CA, 1944-1948
classmates: Robert Armor
Central Dauphin East High School, Harrisburg, PA, 1972-1974
classmates: Robert Armor
Mann High School, Gary, IN, 1976-1980
classmates: Robert Armor
Roosevelt High School, Gary, IN, 1976-1980
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legacy.com: Robert D. Armor
Robert D. Armor passed away on October 9, 2004 at the age of 73. He is survived by his wife of 40 years, Lois Armor; his only brother, David Armor and wife Joyce; niece, Tracy
findagrave: Armor, Robert
01/14/1796 - 09/4/1878, Lawrence County, Alabama
findagrave: Armor, Robert Cowden
08/11/1812 - 08/31/1860, Pleasant Hope (Polk County, Missouri)
findagrave: Armor, Robert DeHaven
07/13/1931 - 10/9/2004, San Antonio (Bexar County, Texas)
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Robert Armor (1796 - 1878) - Genealogy - Geni
Genealogy for Robert Armor (1796 - 1878) family tree on Geni, with over 150 million profiles of ancestors and living relatives.
Robert Armor (deceased) - Genealogy - Geni
Genealogy for Robert Armor (deceased) family tree on Geni, with over 140 million profiles of ancestors and living relatives.
Clementine Armor - Historical records and family trees ...
Clementine Armor was born circa 1837, at birth place, Alabama, to Robert Armor and Jane Armor. Robert was born circa 1796, in GA. Jane was born circa 1794, ...
Robert Armor | Family Tree Unknown - WikiTree
Genealogy collaboration for Robert Armor born 1709 Aghaderg, Down, , Ireland died 1784 including ancestry + more in the free family tree ...
Books & Literature
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Gilliane - Page 44 - Google Books Result
Sir Robert was bleeding from several small wounds. Saer eyed the red trickles for a moment and then bellowed for servants to remove Sir Robert's armor and for ...
The Knight - Google Books Result
As they fight, Maradan chips away at Robert's armor, shield, and sword. She continues to pound on Robert causing more chips and dents into his armor.
The New Tolerance: How a Cultural Movement Threatens to ...
For a split second, God had allowed Joan to catch a glimpse of a chink in Robert's armor. It was all she needed. Honoring her promise not to "preach" at him, ...
The Symposium of Justice - Page 56 - Google Books Result
Sir Robert's armor rattled as he took one cumbersome step after another up the long, twisting steps. Only the external windows lit the palace with spectacular ...
Full text of "Jenkins family book; being a partial record of the...
His sons, John Isaac and Joseph were made executors of his will, and his "loving friends Jacob Morgan and Robert Armor'* were therein appointed "overseers ...
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(2) stephen liu yiu keung & robert armor morris ... - Yumpu
(2) stephen liu yiu keung & robert armor morris - Equity Read more about keung, armor, morris, equity and equitynet.com.hk.
Hamilton County, TN 1860 Federal Census (File 13 of 15 ...
... Palina 34 F W SC Eliza 2 F W Tn Pauline 8/12 F W Tn Robert ARMOR 18 M W Farm Laborer Ala ...
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History Ligonier Township, Westmoreland County, Pa.
Robert Armor came there in 1814 and kept it as a hotel for many years afterwards. His son, John L., born in 1807, became a merchant in 1823. and for many ...
Coolest armor in Westeros - General (ASoIaF) - A Forum of ...
Renly's armor, Robert's armor and Tywin's armor have the coolest descriptions by far. ... Robert's Armor and Weapon are the coolest.
Image - Robert Armor.jpg - Game of Thrones: Ascent Wiki - Wikia
File:Robert Armor.jpg. No higher resolution available. Robert_Armor.jpg (137 × 137 pixels, file size: 62 KB, MIME type: image/jpeg). About; File History ...
Past and Present of Greene County, Missouri
... he was a soldier in the Federal army; Emma A., who became the wife of Robert Armor; Margaret M., who was a twin of Evaline (deceased);
Reports & Statements
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RootsWeb: ARMOUR-L Re: [ARMOUR] RE: Robert Armor ...
From: "Bob Smith" <email@example.com> Subject: Re: [ARMOUR] RE: Robert Armor, Hall Co. GA Date: Sat, 7 Dec 2002 13:21:07 -0800. References: ...
Re: Armour's in Illinois - Genealogy.com
Robert Armor : 250 acres in East Pennsboro Township, Lancaster County (Cumberland)July 20,1748. Joseph Armor : 300 acres in Duck Creek, ...
Google Groups: 2009-09-18 in bankruptcy proceedings 破產憲報 破產人資料公佈
04.12.2009: ... limited (in liquidation) name of liquidators ¡x stephen liu yiu keung robert armor
Google Groups: Rules FAQ
25.05.2004: But I do think it's just him, mostly. This is what I was driving at. :) Every now and
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ROBERT ARMOR CYNTHIA KENESON | Texas, Marriage ...
Texas, Marriage Record Index, 1966–2008 for ROBERT ARMOR CYNTHIA KENESON is available for free on Mocavo. Start searching for your ...
Robert Armor Bottom - ROBLOX
Robert Armor Bottom. ROBLOX Image. Oscuras. Creator: Oscuras. Created: 7/7/2015. Updated: 4 months ago. Pants Image Pants Image. Report Abuse. Genres:.
Robert Armor: person, pictures and information - Fold3.com
View Robert Armor's military memorial page on Fold3. Discover and add pictures, bio information and documents about the life of Robert Armor.
Robert Armor & his '64 Chevy — LMC Trucklife
I bought this C10 from a man in his fifties. He had owned it since he was 15. It had been sitting in a shed for the last 15 years or so. It was in bad ...
Robert Armor - CallHunter
Scammer that goes by an number of names and numbers. http://whoscall.in/1/3054142621/. +17028472060: (Upper East Side) 6:33 PM
Robert Armor b. Abt 1770: JHBL Genealogy
Sources. [S38] Claiborne of Virginia: The First Eight Generations, John Frederick Dorman, (Name: Baltimore, 1995;), p349.
Joseph Bryson - William Gregg Descendants - Person Page
Robert Armor was born in 1813 at Ireland. He married Barbara (?) after 1830. Robert Armor was buried after 1861 at Nickle Mine Mennonite Cemetary, ...
The Gaults - fine for the cabbages
(see below). Galt Graveyard Robert Gault memorial stone According to this site, "Grandson Robert Armor" was Robert Galt's grandson by daughter Elizabeth, ...
W078 - Commission Detail - CIB
Information Contact: Robert Armor • Supporting young researchers. Information Contacts: Assist Prof Jakob Beetz, TUE, the Netherlands • IDDS CIB Prioirity ...
Bailey, Robert (Armor) - Classic Aviation Art
Account Options. Username: Password: Remember me. Login. Forgot Password? Get an Account · Armor/Military Art; : Bailey, Robert (Armor) ...
ROBERT ARMOR 19111987 | Social Security Death Index
Robert Armor was born in 1911 and passed away in 1987 . Access the Social Security Death Index on Mocavo and find your ancestors for free!
Robert Armor
Villa Rica's Robert Armor was named to Oglethorpe University's dean's list for the fall 2012 semester. Armor, a psychology major, was one of approximately 260 ...
Armor - Names Encyclopedia
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Robert ARMOR: My Country Roots
Robert ARMOR: My Country Roots
Green Robert Armor b. 06 JUL 1863 d. : Routon and Riddle Family...
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Webb-site Who's Who: positions of Morris, Robert Armor
Morris, Robert Armor. Key data; Positions. Current; History; FAQ. Manager/adviser/other. Organisation · Position · From · Until · Total Return · CAGR. 1, *, Richly ...
iPHONE 6/6Plus Robert Armor Case
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Still life. Green leaf foliage and decorations. A single leaf with veins, and a small clear glass bead or objects, with facets which reflect light.
Credit: Mint Images/ David Arky
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Still Life Green Leaf Foliage And Decorations A Single Leaf With Veins And A Small Clear Glass Bead Or Objects With Facets Which Reflect Light Stock PhotoClose-Up,Colour Image,Coloured Background,Condition,Crystal,Elegance,Expense,Flora Colour,Fragility,Glass - Material,Grace,Green,Leaf,Luminosity,Material,Mineral,Nature,No People,Ornate,Photography,Plant,Plant Part,Precious Gemstone,Shiny,Simplicity,Small Group of Objects,Still Life,Studio Shot,Transparent,Vertical,White BackgroundPhotographer Mint Images/ David ArkyCollection: Mint Images RF


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Once upon a time there was a young student seeking peace and quiet. He ventured deep into a snow-covered forest and took up lodgings in the basement of a very strange house. So begins a twisted fairy-tale in which nothing and no-one can be taken at face value. The unnamed students landlords are an odd, unnamed couple with an 8-year-old son named Klaus. Trouble is, Klaus is actually a 30-year-old simpleton who believes he's going to be President of the United States one day. Compelled by bizarre forces to remain in the house the student becomes Klaus' home tutor. That's only the beginning to this giddy mix of melodrama, psychodrama, sci-fi and black comedy. Take a walk on the cinematic wild side with this delightfully twisted fairy-tale.
www.facebook.com/DerBunkerFilm FESTIVALS: Berlinale 2015
www.facebook.com/DerBunkerFilm FESTIVALS: Berlinale 2015
Nikias Chryssos was born in Leimen, just outside Heidelberg, in 1978. He studied Film, Video Production and Directing in Britain and Germany, and was selected for the Résidence du Festival de Cannes in 2008. His other films include Breakfast (2002), Hochhaus (2006) and The Grandfather (Der Großvater, 2009).


text: The amazing service began before we even arrived - Jake's phone manner when I called to make a booking was relaxed and friendly. Upon arrival, the trend continued and our party of three were looked after with attentive and friendly staff but importantly given plenty of time and space to chat amongst friends. Dinner was spot on. Fresh, delicious and... More


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Jennette Mullaney, Former Associate Email Marketing Manager, Digital Media
Posted: Friday, February 8, 2013
The Metropolitan Museum has a long history of making its collections accessible to blind and partially sighted visitors through touch and description. In the 1970s, the Museum established the Touch Collection, a group of small artworks from different curatorial departments, for the purpose of tactile exploration by blind and partially sighted visitors. Since 1998, these visitors have been invited to engage with a range of Museum objects through touch tours—guided or self-guided visits in which they can explore specific objects with their hands. For several years, photographer Matt Ducklo has captured participants on these tours at the Metropolitan and other museums, creating a body of work that explores how all people—both sighted and otherwise—experience art. I interviewed Matt about his work and how it has affected his own experience of looking at art.
Read More
Aleksandr Gelfand, Former Intern, Museum Archives
Posted: Monday, February 4, 2013
On Monday, February 4, 1963, a unique visitor entered The Metropolitan Museum of Art and remained in the building for the next three and a half weeks. Over one million people clamored to see her during her stay at the Museum, and the press reported extensively on her visit. To the great pleasure of the Metropolitan and its visitors, the Mona Lisa—perhaps the best known painting in the world—had come to the Museum as a loan from the Louvre.
Posted: Wednesday, January 16, 2013
On Friday, May 9, 1913, the ship La France steamed into New York Harbor carrying William Henry Riggs, a wealthy American and lifelong collector of arms and armor. Riggs was returning from France to his native city for the first time in over forty years in order to donate his impressive collection to The Metropolitan Museum of Art. Accompanying Riggs was Bashford Dean, curator of the Metropolitan Museum's recently established Department of Arms and Armor and a well-known collector in his own right. Dean had spent close to a decade trying to persuade Riggs to give his collection to the Museum. Now, as a result of Dean's efforts, the Museum's new Arms and Armor department was set to acquire one of the greatest collections of its day.
P. Grace Hernandez, 2010–11 Polaire Weissman Fellow, The Costume Institute
Posted: Monday, January 14, 2013
When the Brooklyn Museum transferred its costume collection to the Metropolitan Museum's Costume Institute in January 2009, the Met acquired an impressive array of garments from renowned European and American designers. Some highlights from the collection were featured in the related 2010 exhibitions American Woman: Fashioning a National Identity at the Met and American High Style: Fashioning a National Collection at the Brooklyn Museum. Yet the collection also contains a set of objects with noteworthy local origins: garments and accessories made by Brooklyn-based clothing and accessory makers—milliners, tailors, and dressmakers—working independently or in department stores during the nineteenth and twentieth centuries.
Donald J. La Rocca, Curator, Department of Arms and Armor
Posted: Wednesday, January 2, 2013
One hundred years ago, on October 28, 1912, the Trustees of The Metropolitan Museum of Art officially created the Department of Arms and Armor. From relatively modest beginnings, the department rapidly developed into one of the finest and most comprehensive collections of its type in the world.
Claire Moore, Assistant Museum Educator
Posted: Friday, November 30, 2012
The importance of the Islamic world within current geopolitics and the global context in which we live makes the study of these regions essential in K–12 classrooms around the world.
Posted: Wednesday, November 21, 2012
One hundred and thirty-seven years ago this weekend, on November 24, 1875, the American businessman and philanthropist William Backhouse Astor died. Just three years earlier, Astor had been responsible for a milestone in Metropolitan Museum of Art history: donating to the newly established institution its first work of art made by an American, the marble statue California by Hiram Powers.
Posted: Friday, October 26, 2012
October 28, 2012, marks the centennial of the election of Edward S. Harkness as Trustee and Fellow for Life of The Metropolitan Museum of Art. A lifelong philanthropist estimated to have donated one hundred million dollars to charity, Harkness spent twenty-eight years working on the Museum's behalf. A number of his gifts are among the most beloved and visited works of art within the Met's galleries.
Femke Speelberg, Associate Curator in Ornament and Architectural Prints, Drawings, and Modelbooks, Department of Drawings and Prints
Posted: Tuesday, October 23, 2012
In 1593, the Florence-born artist Antonio Tempesta (1555–1630) published one of his absolute masterpieces in print: a View of Rome composed out of twelve folio-sized, etched plates. When joined together in two rows of six, the print forms an impressive frieze measuring almost 3.5 by 8 feet (fig. 1).
Jennifer Babcock, 2009–2011 Hagop Kevorkian Curatorial Fellow, Department of Ancient Near Eastern Art
Posted: Wednesday, October 10, 2012
Although I am an Egyptologist, I recently worked for two years in the Museum's Department of Ancient Near Eastern Art as the 2009–2011 Hagop Kevorkian Curatorial Fellow. The experience was invaluable, not only for its curatorial training, but also for the opportunity to approach my dissertation topic—ancient Egyptian ostraca—from a cross-disciplinary perspective.
Céline Brugeat, 2011–2012 Annette Kade Fellow, Department of Medieval Art
Posted: Thursday, September 27, 2012
The Cloisters incorporates significant sculptural ensembles from medieval cloisters from the south of France, traditionally identified as coming from four sites: Saint-Guilhem-le-Désert, Saint-Michel-de-Cuxa, Trie-en-Bigorre, and Bonnefont-en-Comminges.
Posted: Wednesday, September 19, 2012
Twenty-five digital artists and programmers descended upon the Metropolitan Museum's Art Studio on June 1 and 2 for our first 3D scanning and printing Hackathon. The invited guests, along with staff from MakerBot Industries, spent two action-packed days photographing Museum objects and using specialized printers to convert their images into 3D models.
Denise Patry Leidy, Curator, Department of Asian Art
Posted: Wednesday, August 15, 2012
Hundreds of stories are embedded in the Chinese ceramics that have recently been reinstalled on the Great Hall Balcony (Gallery 200 through Gallery 205), at the heart of the Museum. Some of these stories tell of technological advances in ceramic production, others illustrate aspects of Chinese culture, and many—including comparative pieces from around the world—illustrate China's continuous and complicated impact in global ceramic history. All of these stories intertwine in fascinating and, sometimes, unexpected ways.
Maureen Coyle, Twelve-Month Intern, Digital Media
Posted: Thursday, August 9, 2012
We have quite a few new items in Met Media this week, including videos of several symposia. The Discoveries symposium, held in conjunction with the opening of the New Galleries for the Art of the Arab Lands, Turkey, Iran, Central Asia, and Later South Asia, featured scholarship focused on works on paper, textiles, the Damascus Room, the city of Nishapur, and stucco and ceramic figures.
Antoniette M. Guglielmo, 2011–2012 Sylvan C. Coleman and Pamela Coleman Memorial Fund Fellow, Department of Modern and Contemporary Art; and Robyn Fleming, Associate Museum Librarian, Thomas J. Watson Library
Posted: Monday, July 30, 2012
When the Museum Library took its first steps toward digitizing rare materials from its collection over two years ago, one of the first groups of items we selected for scanning was a set of pamphlets that accompanied a landmark series of American industrial arts exhibitions from 1917 to 1940.
Kurt Behrendt, Associate Curator, Department of Asian Art
Posted: Tuesday, June 19, 2012
At the end of the fifth century, the great Buddhist centers of Gandhara in Northern Pakistan collapsed in the wake of Hun invasions that swept in from the area north of Afghanistan. The current exhibition Buddhism along the Silk Road: 5th–8th Century (on view through February 10, 2013) focuses on art produced as a result of contact with the dispersed Gandharan Buddhist communities, who were moving into Afghanistan and up into the Western parts of Central Asia.
Jackie Terrassa, Managing Museum Educator for Gallery and Studio Programs, Education; and Don Undeen, Former Senior Manager of MediaLab, Digital Department
Posted: Thursday, May 31, 2012
Artists come to the Met every day to be inspired, discovering visual and technical solutions in works from every corner of the world, ranging from ancient times to the present day. They might attend a program, sketch from objects, or create their own copies of original paintings, as they have done since 1872 when the Met first allowed artists to re-create works of art on display.
Thomas B. Ling, Associate Manager, The Photograph Studio
Posted: Tuesday, May 22, 2012
Each spring, as soon as the weather gets warm, friends start asking me when the Museum's Roof Garden will be open. By the time they ask, I've already been excited for months, anticipating the installation process and the opportunity to collaborate with the exhibiting artist (or artists), curators, fabricators, and installers who, each year, transform one of my favorite places in the city into a totally new space.
Masha Turchinsky, Senior Manager & Senior Producer, Media Production & Online Features
Posted: Friday, May 11, 2012
It's springtime in New York, and to celebrate we've collaborated with the New York Botanical Garden on a free app that invites you to experience Claude Monet's living masterpiece, his garden at Giverny.
Alice W. Schwarz, Museum Educator; Masha Turchinsky, Senior Manager & Senior Producer, Media Production & Online Features; and Katherine Abbey, Twelve-Month Education Intern
Posted: Tuesday, May 1, 2012
What do Madame X, a murder, and a mobile phone have in common? They are all part of Murder at the Met: An American Art Mystery, the first mobile detective game created by The Metropolitan Museum of Art in collaboration with Green Door Labs and TourSphere.
Now at The Met offers in-depth articles and multimedia features about the Museum's current exhibitions, events, research, announcements, behind-the-scenes activities, and more.


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|Boxing Champions | Boxing Schedule | Boxing Video | Boxing History | Pound For Pound | Lounge | The Wire | Arcade
Undisputed Champion
Join Date: Jul 2009
Posts: 3,211
Quoted: 64 Post(s)
Rep Power: 15
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how does his skeet enter the turkey baster without ripping out and destroying his wives insides?
Undisputed Champion
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Location: Miami
Age: 27
Posts: 1,106
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So that's how they built the pyramids...
Undisputed Champion
Join Date: Feb 2006
Location: San Antonio Tejas AND Austin Tejas
Age: 32
Posts: 2,865
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I love listening to bull****ters...and this guy is hilarious.
He's got more horsepower then all of us combined.
Join Date: Dec 2009
Posts: 12,890
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Bank: 377,042,332.67
Total Points: 377,188,599.47
Even Kevin Jesus could whoop this faker's ass.
rugged individualist
Join Date: Oct 2007
Location: Ameritopia, U.S.S.A.
Posts: 22,265
Quoted: 38 Post(s)
Rep Power: 90
Points: 1,858,501.45
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Total Points: 1,126,842,395,085,256.00
I can't lift a car for you because I can't control the rage that follows.
Tearing this fake coin in half is not a problem though.
Allah is the source of all my strength, well that and drinking melted butter.
I didn't join the Army because of my ferocious strength.
I can't shake your hand because I would crush all the bones in it.
If anything, the guy is mildly amusing. I will say he can't be lasting very long if he's banging these wives of his 15 times a day.
Undisputed Champion
Join Date: Oct 2009
Location: San Diego-Tijuana Metropolis
Posts: 1,541
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hahahaha! why didnt allah make him bullet proof?
Join Date: Apr 2009
Posts: 2,750
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Rep Power: 13
Points: 1,019,156.98
Bank: 7,297,608.42
Total Points: 8,316,765.40
my strength is so great i musn't show you it for fear of splitting the oceans , tearing apart the sky and bringing armageddon to this planet
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Sleezy Beezy
Join Date: May 2007
Location: Nuevo Mexico
Posts: 4,021
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15 times a day!?!?! dammmmn the most ive ever done in one day was 7. and i thought that was pretty good till i heard that ****. 15 times.. .. A DAY!!! lol
floyd gobbler
Join Date: Jun 2006
Location: Playing with my marbles.
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He's so strong he tried getting a steel bridge pregnant and broke his penis in the process.
Don't ask me
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I think those dudes in "The World's Strongest Man" competition are alot stronger.
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Katy Perry's California Dreams tour will be making her way to a movie theater near you — in 3D. Perry took to Twitter yesterday to announce to the world that we can expect Katy Perry: Part of Me this summer.
FINALLY, my MOVIE is coming out with Paramount this summer! It's called "KATY PERRY: PART OF ME" Presented In 3D! KATYCATS-LETS TREND #KP3D
— Katy Perry (@katyperry) March 7, 2012
Negotiations behind the scenes are still going on, The Hollywood Reporter says, but things are heating up as Magical Elves, the folks behind Justin Bieber: Never Say Never, and the creators of Top Chef and Project Runway, are throwing their hat into the ring to work with Perry.
Perry is no stranger to the camera, having guest starred on How I Met Your Mother, voiced a Smurf, and just this week making a return to the small screen on Raising Hope. On the latter Perry played a rough and tumble security guard named Rikki, sporting the hint of a mustache and clownish red hair.
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Tokyo Babylon (2003)
Critic Consensus: No consensus yet.
Tokyo Babylon Videos
Tokyo Babylon Photos
Movie Info
Critic Reviews for Tokyo Babylon
There are no critic reviews yet for Tokyo Babylon. Keep checking Rotten Tomatoes for updates!
Audience Reviews for Tokyo Babylon
(Lazily copied from my animenfo review, which is why it's so fucking long.) Among the reams of throwaway one-shot or two-part OVAs that inundate the anime market, Tokyo Babylon manages to stand out for a few key reasons. Its pedigree, the animated adaptation of a CLAMP brainchild, certainly helps to win support, and its surprisingly engaging storytelling manages to keep it. Though there is no real impetus to propel these short stories forward, no beginning and ultimately no real ending, this anthology of supernatural tales maintains its entertainment value and overall quality. Of course, this isn't a CLAMP title for nothing. Many of the studio's typical trademarks find themselves sitting pretty among the exposition, including but not limited to: shonen-ai subtext, cherry blossoms, at least one oddly-dressed female character, at least one character who also appears in a different series, and tall buildings that play an important role in the plot. To be honest, I've never been a huge fan of CLAMP. Because of these surprisingly prominent hallmarks, their anime and manga has always been uniformly uninteresting to me. However, Tokyo Babylon actually went out of its way to keep me watching; its first offering was a surprisingly subdued, brooding atmosphere, offset only a few times by Subaru's obnoxious sister. In downtime between fights and action sequences, the anime is reserved and manages to communicate without showy displays of melodrama, both of which are certainly a plus. Unfortunately, I can't say that this works 100% of the time; I fell asleep during a fantastically boring conversation in the middle of the first episode and had to rewatch it all. This foray into slumber was probably prompted by my overall lack of interest in the main characters. Subaru Sumeragi, our exorcist protagonist, is mostly a loser. He is full of funny hats, women's clothing and kowtowing submissiveness, none of which tend to make for a very compelling protagonist. His lack of backstory can be forgiven because the OVA is short and focuses mostly on storytelling, but because most of the characterization is devoted to the episode-specific characters, he ends up very one-dimensional in the long run. Hokuto, his sister, is completely irritating as most anime sisters tend to be. She is the anime's outlet for 'cute' verbal humor and bizarre costumes and tends to find herself providing very unwanted comic relief. She has one plot-pertinent scene in the entire OVA and it's only thirty seconds long. Seishiro is an unexplained character who lives with the Sumeragis; there's no depth to him, but it seems like there could be potential for it. There's something a little bit creepy about his possessiveness of Subaru. The strongest parts of the characterization, however, are the two characters who find their duties or desires intertwined with Subaru's path in each episode. The first paints a compelling tale of revenge, and the second is a character tormented by a gift that she can do nothing with. The characters themselves are not that strong, but the plots they are embroiled in take the cake. The OVA is divided into two different stories; my personal favorite was the second one, but the first is not too far behind. Episode 1 of the OVA deals with a construction supervisor who is always surrounded by messy accidents that put him into a position of higher power and a widowed woman determined to stop the murders he commits. This plot is a little less interesting because we know right away that this man was responsible for all of their deaths and there's no real element of suspense to it. There's still a fairly engaging fight scene to be beheld, though. The second story is far stronger, chronicling the tale of a subway murderer and a woman with post-cognition who is called in to help with composite sketches. Her power tears her apart since she can only see what has happened in the past, making her feel helpless in the face of the tragedies she has witnessed. After this murderer strikes close to home, however, her demeanor changes. I put this tale above the previous one because not only is the character of Mirei stronger than the other woman in the first episode, but the ending is also a lot better. Tokyo Babylon makes for a good hour and a half of viewing entertainment. Chances are, you'll either like it or hate it, even more so if you're a CLAMP fan. If you're an X fan, however, keep in mind that this actually has very little to do with X TV, despite how the box bills itself. View this as an independent story or you will probably be disappointed.
Super Reviewer
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Chad Nelson, KSTP cameraman, filing criminal complaint [VIDEO]
The unnamed officer who pushed KSTP's camera to the ground.
rubicondrawn via YouTube
Chad Nelson, the photojournalist who was man-handled by a Minneapolis police officer while filming for KSTP Saturday night, has decided to file a criminal complaint.
That's according to his news director Lindsay Radford, who was in a meeting with him this morning. It's still not certain who the officer in question is. Radford says the station's attorneys are figuring that out now.
It shouldn't be long until the name is public -- new footage in color shows a close-up of the officer's face.
A protester who filmed the altercation with his own camera moments before getting arrested uploaded his recovered footage last night. It shows even clearer the moment the officer shoves Nelson, and the camera bounces off the pavement:
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MIAMI GARDENS, Fla. -- In the absence of the injured Jamaal Charles, the Kansas City Chiefs knew they would have to operate their offense smartly Sunday against the Miami Dolphins. They have no one else with the all-around abilities of Charles, so they would have to spread the ball around and hope quantity could make up for quality.
The Chiefs did that in their 34-15 victory at Sun Life Stadium. Seven receivers caught at least one pass and Knile Davis rushed for 132 yards.
But the best idea the Chiefs had was to get a little-used running back by the name of Joe McKnight involved. McKnight, playing mostly in passing situations, led the Chiefs in receptions (six), receiving yards (64) and touchdowns (two).
"He gives you a lot of options when he's back there," Chiefs coach Andy Reid said. "You got to see that today. That's why we kept him."
The Chiefs kept McKnight as a fifth running back despite having Charles, who by himself figured to consume a huge portion of the playing time. The decision looks brilliant now. McKnight certainly didn't win the game by himself, but it's likely the Chiefs wouldn't have defeated the Dolphins without him.
McKnight's first touchdown, an 11-yard catch-and-run, came in the third quarter after the Dolphins had gotten to within four points of the Chiefs. His second score, on a 4-yard reception, came in the fourth quarter and extended a six-point Chiefs lead into a 12-point advantage.
Suddenly the Chiefs have some offensive possibilities even without Charles. Maybe the best thing about his injury is they now know they can survive or even thrive without him.
The running back spot was a two-headed monster for the Chiefs. Davis pounded away with 32 carries, though he also fumbled twice (one lost) and will have to correct that before the Chiefs can truly trust him.
Then there's McKnight, who proved his worth as a receiver against the Dolphins. The Chiefs will soon also have Charles and De'Anthony Thomas, a rookie whose world-class speed needs to be put to good use.
"We've got a good group," quarterback Alex Smith said. "I think there's a reason we kept so many of them. I think you can see that now. They all have something to offer."
Sorting through the options at running back will be a pleasant problem for Reid. Where the Chiefs once relied to a ridiculous extent on Charles, they no longer have to do that.
"We have all these running backs," Reid said. "It's hard to dress all of them.
"I do like the other guys too. I'd like to dress all of them every week. You can do that sometimes and you can't other weeks."
The point is Reid now has flexibility. Davis at least knew he was going to be a big part of things against the Dolphins.
"We knew we'd give him the ball some," Reid said. "I didn't put a number on it."
McKnight's involvement was a revelation. He became a necessary component with Charles out of the lineup. One of Davis' weaknesses, in addition to his fumbling habit, is as a receiver.
That's McKnight's strength.
"We're just trying to keep things rolling while Jamaal is out," McKnight said.
Their mission was successful in their first try without Charles.


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We founded Flux Forge in the summer of 2008 as a consulting agency located near Dusseldorf in Germany. But soon after we decide to make our own products and in 2010 we released our first app: Kvlt. Ever since then we specialized in making Mac software.
Our most popular app is Vector which is an advanced audio recorder with sample editing capabilities. Currently we're working on Vector 3 which will add many requested features like support fur Audio Units or multi selections. We plan to release Vector 3 in summer 2016. So stay tuned!
If you need to get in touch with us just drop us a mail: email@example.com