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RESEARCH PROGRAM IN THE DEPARTMENT OF NEUROLOGICAL SURGERY |
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Ischemic Area Infusion and Regional Hypothermia: A Potential Therapy in Stroke |
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Clinically, there are no effective therapeutic tools for amelioration of cerebral
ischemia/reperfusion caused by stroke. It has been emphasized that ischemia/reperfusion
injury is initiated by a series of events occurring at the blood-vascular-parenchymal
interface, leading to inflammatory injury, disruption of endothelial integrity,
and neuron death. Brain cooling is a remarkable neuroprotectant in stroke therapy
if applied soon after onset of ischemia.Due to management difficulties, hypothermic
induction by surface cooling in current clinical settings is vastly limited. Results
from our recent studies indicate that highly localized intra-arterial “flushing”
of the ischemic territory prior to reperfusion significantly reduces brain injury
in experimental stroke. The mechanisms of neuroprotection conferred by hypothermia
or vascular infusion are thought to be multifunctional. This leads to a new hypothesis
that local intraarterial cold hypertonic solution infusion, concurrent with regional
cerebral hypothermia in ischemic areas prior to reperfusion, synergistically minimizes
brain injury.This may provide the ultimate neuroprotective “cocktail” that limits
inflammation and neurovascular disruption during reperfusion. In our labrotary,
we define the therapeutic and systematic optimization of a combined infusion and
cooling procedure in our stroke model by evaluating long-term motor deficits, brain
infarct volume, as well as cerebral and pulmonary edema. We also elucidate protective
mechanisms of the novel model that targets the brains vascular-parenchymal interface
by reducing inflammatory mediators, endothelial activation of nuclear factor kappa-B,
leukocyte infiltration, matrix metalloproteinase expression, and blood-brain barrier
disruption.
Results from these studies will provide fundamental information on the establishment
of a novel therapeutic procedure in stroke beyond the levels achieved by current
therapy. Intravascular cold infusion into the ischemic region, which combines recanalization
of the occluded middle cerebral artery (mechanically or thrombolytically) and administration
of neuroprotective drugs, may improve outcome in stroke patients.
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Recent Publications in Peer-reviewed Journals |
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Ding, Y., Yao, B., Yang, D-Z, Park, H., McAllister J.P., Diaz,
FG. (2002) Pre-reperfusion Flushing of Ischemic Territory: A Therapeutic Study on
Ischemia-reperfusion Injury in Stroked Rats Using Histological and Behavioral Assessments.
Journal of Neurosurgery. 96:310-319.
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Ding, Y., Li, J., Phillis J.W. Rafols J.A., Diaz, FG. (2002) Pre-reperfusion
Flushing into Ischemic Territory Reduces Inflammatory Injury in Rat with Transient
Middle Cerebral Artery Occlusion. Stroke. 33: (10) 2492-2498.
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Ding Y., Young C, Li C, Luan X, McAllister JP, II, Clark J, Diaz
FG (2003) Reduced Inflammatory Mediator expression by Pre-reperfusion Infusion into
Ischemic Territory: A real-time Polymerase Chain Reaction Analysis. Neurosci.Lett.
353: 173-176
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Ding YH; Li J, Rafols, JA, Ding Y (2004) Reduced Brain Edema and
Matrix Metalloproteinase (MMP) Expression By Pre-reperfusion Infusion into Ischemic
Territory in Rat. Neuroscience Letters. 372: 35-39.
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Ding Y, Li, J., Luan XD, Lai Q., McAllister JP II, Phillis, JW,
Guthikonda, M., Diaz, FG (2004) Neuroprotection of Regional Brain Cooling and Local
Saline Infusion into Ischemic Territory in Rats with Transient Middle Cerebral Artery
Occlusion. Neurosurgery. 54 (4):956-965.
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Luan XD, Li J, McAllister JP, II, Clark J, Diaz FG, Fessler RD., Ding Y.
(2004) Regional Brain Cooling Induced by Local Saline Infusion into Ischemic Territory
Reduces Brain Inflammation in Stroke. Acta Neuropathologica. 107:227-234.
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Li J, Luan X, Clark J, Rafols JA, McAllister JP, II, Diaz, FG. Ding Y.
(2004) Regional Brain Cooling Induced by Local Saline Infusion into Ischemic Territory
Produced A Long-term Neuroprotection in Ischemic Rats Using a Behavioral Assessment.
Neurological Res 26:677-683.
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Zhao WH, Ji XM, Ling F, Ding Y (2008) Local Mild Hypothermia Induced
by Intra-arterial Cold Saline Infusion Can Prolong the Therapeutic Time Window of
Reperfusion in Temporary Local Brain Ischemia in Rats. Neurological Res.
2008 Aug 7. [Epub ahead of print] |
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Cheng H, Ji X, Ding Y, Luo Y, Wang G, Sun X, Chen J, Ling F Focal
perfusion of circulating cooled blood reduces the infarction volume and improves
neurological outcome in middle artery occlusion. Neurological Res. (in press). |
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Exercise-Induced Endogenous Neuroprotection in Stroke |
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There is increasing evidence from us and other investigators that exercise produces
endogenous protection in the brain after transient ischemia. Our goal is
to establish an endogenous neuroprotective concept of exercise preconditioning in
stroke and identify the cellular and molecular mechanisms by which exercise induces
neuroprotection. We elucidate TNF and HSP signaling pathways that mediate differential
endothelial activation and downstream inflammatory, neurovascular integrity and
apoptotic events. The proposed strategy of exercised-induced endogenous neuroprotection
can be translated to other therapeutic approaches, such as pharmacology. This strategy
will allow the development of combined approaches to inhibit and stimulate appropriate
targets simultaneously, thus reaching the highest therapeutic potential. |
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Recent Publications in Peer-reviewed Journals |
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Ding, Y, Li, J., Lai Q., Azam, S., Rafols, JA., Diaz, FG. (2002)
Functional Improvement After Motor Training Is Correlated with Synaptic Plasticity
in Rat Thalamus. Neurological Research. 24:(12) 829-836.
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Ding, Y, Li, J., Clark J., Diaz F.G., Rafols, JA. (2003) Synaptic
Plasticity in Thalamic Nuclei Enhanced by Motor Skill Training in Rat with Transient
Middle Cerebral Artery Occlusion. Neurological Research. 23:(2) 189-194.
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Ding, Y, Li, J., Luan, XD, Lai Q., Rafols, JA, Diaz, FG (2004)
Motor Balance and Coordination Training Enhances Functional Outcome in Rat with
Transient Middle Cerebral Artery Occlusion. Neuroscience. 123: 667-674.
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Ding, Y, Li, J., Luan XD, Rafols JA, Phillis, JW, Diaz, FG (2004)
Exercise Pre-conditioning Reduces Brain Damage in Ischemic Rats That May be Associated
with Regional Angiogenesis and Cellular Overexpression of Neurotrophin. Neuroscience
124: 583-591 |
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Li J, Luan X, Clark J, Rafols JA, Ding Y. (2004) Neuroprotection
against transient cerebral ischemia by exercise pre-conditioning in rats. Neurological
Res 26 (6):404-408. |
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Ding YH; Li J, Rafols, JA, Clark JC; McAllister II JP, Diaz, F. G.; Guthikonda,
M., Ding, Y. (2004) Exercise-induced angiogenic factors and reduction
in ischemia/reperfusion injury. Current Neurovascular Res 1 (5): 411-420. |
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Ding Y, Ding YH, Young C, Luan X, Li J, Rafols JA, Phillis JW,
Clark JC. (2005) Exercise pre-conditioning reduces inflammatory injury in ischemic
rats during reperfusion. Acta Neuropathologica. 109:237-246. |
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Li J, Ding YH, Rafols JA, Lai Q, McAllister JP II, Ding Y (2005)
Increased Astrocyte Proliferation in Rats After Running Exercise. Neurosci.Lett.
386(3):160-4.
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Ding YH, Rafols, JA, Li J, McAllister JP II, Guthinkonda, M, Ding Y
(2006) Neuroprotective Effect of Exercise Pre-conditioning on Brain Integrity After
Experimental Stroke in Rats. Neurological Res. 2006 Mar;28(2):184-9.
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Ding Y, Clark JC. (2006) Cerobrovascular Injury in Stroke. Neurological
Res. 2006; 28 (1):3-10. |
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Ding YH, Li J, Rafols, JA, Clark JC, Guthinkonda, M, Ding Y (2006).
Angiogenesis and Expression of Angiogenic Factors in Aging Rats after Exercise.
Current Neurovascular Res. 2006 Feb;3 (1):15-23. |
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Ding YH, Li J, Rafols, JA, Clark JC, Ding Y (2006) Upregulation
of Tumor Necrosis Factor-and Integrins After Exercise Pre-conditioning Enhances
Cerebrovascular Integrity in Ischemic rats. Acta Neuropathologica. 2006
Jul;112 (1):74-84.
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Ding YH, Mrizek M, Lai Q, Wu Y, Li J, Davis W, Ding Y (2006) Exercise
Preconditioning Inhibit Expressions of TNF-a
Receptors in Stroke. Current Neurovascular Res 3 (4):263-71.
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Davis W, Mahale S, Carranza A, Cox B, Hayes K, Jimenez FD, Ding Y
(2007) Exercise Ameliorates BBB Dysfunction in Stroke by Enhancing Basal Lamina.
Neurological Res. 29 (4): 382-387.
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Guo M, Cox B, Mahale S, Davis W, Carranza A, Hayes K, Sprague S, Jimenez D,
Ding Y (2007) Pre-ischemic Exercise Reduces Matrix Metalloproteinase
(MMP)-9 Expression and Ameliorates Blood Brain Barrier Dysfunction in Stroke. Neuroscience.
151(2):340-51. |
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Hayes K, Sprague S, Guo M, Davis W, Friedman A, David F. Jimenez DF, Ding Y
(2008) Forced Exercise Procedure Effectively Induces Neuroprotection in Stroke.
Acta Neuropathologica 115 (13):289-296
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Guo M, Davis W, Carranza A, Sprague S, Reyes R, Jimenez D, Ding Y
(2008) Pre-ischemic Induction of TNF-á by Physical Exercise Reduces Blood Brain
Barrier (BBB) Dysfunction in Stroke. J Cereb Blood Flow Metab. 28(8):1422-30 |
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TRAUMTIC BRAIN INJURY (TBI)
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Close Head Injury: |
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Memory storage and learning have been found to be associated with synaptic plasticity.
During acute closed head injury and its aftermath, rapid acceleration and deceleration
of the head causes diffuse axonal injury in the entire brain, leading to severe
synapse loss and damage. Recent work suggests that brain extracellular matrix (ECM)
proteins and their regulatory matrix metalloproteinases (MMPs) such as MMP-2 and
MMP-9, play a role in synaptic plasticity. Our study assessed the role of MMP-2
and -9 in synaptic damage after TBI and the role of hypoxia inducible factor-1α
(HIF-1α), a transcription factor upregulated during hypoxia, in the regulation
of MMP-2 and -9 expression post TBI.
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TBI causes vasogenic brain edema, where the extracellular space is expanded by fluids
from abnormally permeabilized blood vessels. The detrimental effect of AQPs in brain
edema has been reported. AQPs, such as AQP4 and 9, can cause either cytotoxic or
vasogenic edema in TBI. HIF-1α is a key component of the cellular response
to pathophysiologic conditions and can be harmful in cerebral ischemia. Our study
determines the role of HIF-1α in regulating expression of AQP-4 and -9 and
associated brain edema after close head TBI.
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Thermal Injury: |
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Thermal injury is characterized by increased microvascular permeability, which causes
massive fluid volume requirements during resuscitation. Peripheral tissue thermal
injury often causes systemic reactions, such as fever, hyperalgesia, anorexia, and
increased permeability of the blood-brain-barrier (BBB). Since thermal injury remains
one of the leading causes of childhood death in the United States (one million children
are injured and 3,000 children die each year as a result of burn trauma, according
to the Chidren’s burn Awareness Program, Chicago), and since generalized encephalophthy
is the most common neurologic complication of thermal injury in children occurring
with a 14% incidence, research on the effect of peripheral thermal injury on cerebrovascular
integrity is essential.
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The two specific aims of our current studies are
1) to evaluate injurious effect of peripheral thermal injury on BBB integrity;
2) to investigate inflammatory mechanisms underlying BBB dysfunction. These studies
could provide important new information on the mechanistic tissues in thermal injury
on the central nervous system in the rat model. The results may lead to development
of effective therapies on thermal injury beyond the level that current treatments
achieve.
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Hydrocephalus: |
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The objective of this project is to investigate neurotolerance during chronic ischemia
in hydrocephalus. The hypothesis was tested by comparing the death of cortical and
hippocampal neuron during global ischemia, with death of neuron in hydrocephalic
animals subjected to a severe, acute episode of cerebral ischemia. Effect of expression
of growth-associated protein (GAP-43) on neuronal tolerance is investigated. In
order to elucidate motor learning behavior in children with chronic brain injury,
a novel computerized rhythmic sequential test is used to compare the motor skill
acquisition and retention in two different age groups of children with and without
hydrocephalus. To elucidate pathophysiological mechanisms associated with cognitive
motor disorders in hydrocephalus, we determine motor activation produced by stimulation
of motor cortex with Motor Evoked Potential (MEP) Equipment (MAGSTIM), and impairment
in motor learning and memory formation. We also determine if a combination of part-practice
and variable-practice method benefits motor-skill learning for the children with
hydrocephalus.
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Recent Publications in Peer-reviewed Journals |
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Ding Y, Yao B., Lai Q, McAllister JP II. (2001) Impaired motor
learning following traumatic brain injury in the rat. Neurological Research,
Special issue on Neurotrauma. 23:193-202. |
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Ding Y, Lai Q, McAllister JP II, Canady AI (2001) Impaired motor
learning in children with hydrocephalus. Pediatric Neurosurgery. 34:182-189. |
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Ding Y, McAllister JP II, Yao B, Yan N, Canady AI (2001) Neuron
tolerance during hydrocephalus. Neuroscience. 106:659-667 |
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Ding Y, McAllister JP II, Yao B, Yan N, Canady AI (2001) Axonal
Damage Associated with Enlargement of Ventricles during Hydrocephalus: A Silver
Impregnation Study. Neurological Research. 23: 581-587. |
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Eskandari R, McAllister JP II, Miller JM, Ding Y, Ham SD, Shearer
DM, Way JS (2004) Effects of hydrocephalus and ventriculoperitoneal shunting on
afferent and efferent connections of the feline sensorimotor cortex. Journal of
Neurosurgery-Pediatrics-2 101:196-210. |
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Reyes Jr. R, Wu YM, Lai Q, Mrizek M, Berger J, Jimenez DF, Barone CM,
Ding Y (2006). Early Inflammatory Response in Rat
Brain after Peripheral Thermal Injury. Neuroscience Letters. 407(1):11-5.
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Swann K, Berger J, Sprague S, Wu Y, Davis W, Jimenez D.F, Barone C.M., Ding
Y (2007) Peripheral Thermal Injury Causes Blood Brain Barrier Dysfunction
Associated with Expression of Matrix Metalloproteinase (MMP) in Rat. Brain Res.
Brain Res. 1129:26-33.
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Berger J, Sprague S, Wu Y, Davis W, Jimenez D.F, Barone C.M., Ding Y
(2007) Peripheral Thermal Injury Causes Early Blood Brain Barrier Dysfunction Associated
with Expression of Matrix Metalloproteinase (MMP) in Rat. Neurological Res.
29 (6) 610-614. |
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Patel TH, Wu Y, Lai Q, Jimenez DF, Barone CM, Ding Y (2008) Blood
Brain Barrier Dysfunction Resulting from Expression of Tissue Plasminogen Activator
& Urokinase Plasminogen Activator Following Peripheral Thermal Injury. Neurosci
Lett. 444(3):222-6.
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Reyes R, Guo M, Swann K, Shetgeri SU, Sprague SM, Jimenez DF, Barone CM, Ding
Y (2009) Skin-burn-caused blood–brain barrier (BBB) dysfunction is
mediated by tumor necrosis factor-α (TNF-α) and matrix metalloproteinase-9
(MMP-9) in rat. J Neurosurgery (in press). |
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OTHER PROJECTS |
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Recent Publications in Peer-reviewed Journals
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Ding, Y, Yang, D-Z, Lai, Q., Li, J. Diaz, FG. (2001) Long Term
Neuroprotective Effect of Inhibiting Poly (ADP-Ribose) Polymerase in Rats with Middle
Cerebral Artery Occlusion Using A Behavioral Assessment. Brain Research.
915: 210-217.
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Ding, Y, Yang, D-Z, Lai, Q., Li, J., Diaz, FG. (2002) Impaired
Motor Activity and Motor Learning Function in Rat with Middle Cerebral Artery Occlusion.
Behavioural Brain Research. 132:29-36. |
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Shostak, Y., Ding, Y, Mavity-Hudson, J, and Casagrande, V.A. (2002)
Cortical synaptic arrangement of the third visual pathway in three primate species:
Macaca mulatta, Saimiri sciureus and Aotus trivirgatus. Journal of Neuroscience.
22:2885-2893. |
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Shostak, Y., Ding, Y, and Casagrande, V.A. (2003) Neurochemical
Comparison of Synaptic Arrangement of Parvocellular (P), Magnocellular (M), and
Koniocellular (K) geniculate Pathways in Owl Monkey (Aotus trivirgatus) visual cortex
(V1). Journal of Comparative Neurology. 456:12-28. |
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Dujovny M., Ding YH, Ding Y, Agner C, Perez-Arjona E. (2004) Current
concepts on the expression of neurotrophins in the greater omentum. Neurological
Res. 26 (4):226-229. |
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Wei G., Ji XM, Bai H, Ding Y (2006) Stroke Research in China. Neurological
Res. 2006; 28 (1):11-5. |
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Casagrande VA, Yazart F, Jones KD, Ding Y (2007) The morphology
of Koniocellular Axon Pathway in the Macaque Monkey. Cerebral Cortex. 17(10):2334-45.
Epub 2007 Jan 10. |
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Zhang X, Ji X, Luo Y, Liu D, Guo Li, Wu H, Miao Z, Zhu F, Jiao L, Ding Y,
Ling F (2009) Intra-arterial thrombolysis for acute central retinal artery occlusion.
Neurological Res. (in press). |
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Meng R, Ji X, Zhou J, Li B, Ding Y (2009) Study on the value of
dynamically monitoring the levels of serum F1+2 and D-dimer in patients suffered
from acute cerebral infarction during intravenous urokinase thrombolysis. Neurological
Res. (in press). |
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Chen J, Ji X, Ding Y, Luo Y, Cheng H, Ling F (2009) Role of residual
flow on the neuroprotective efficacy of human albumin in the rat with transient
cerebral ischemia. Neurological Res. (in press). |
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Medical Students for Cerebrovascular Research Project
Mentored by Dr. Ding and Dr. Guthikonda
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Nathan Zwagerman, MS 3
Toll-Like receptor (TLR)-4 and Cytokine Cascade in Stroke after Exercise
Pre-ischemic Exercise Preserves Cerebral Blood Flow (CBF) During Reperfusion in
Stroke: A MicroPET Study
Increased Cerebral Glycolysis Metabolism during Physical Exercise and Neuroprotection
in Stroke
Effect of Cerebral Extracellular Glycerol Content in TBI-induced Brain Edema
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Ahmer Ali, MS 3
Exercise Preconditioning Reduces Neuronal Apoptosis in Stroke by Up-regulating HSP-70
(HSP-72) and ERK 1/2
Traumatic brain injury and brain edema
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Geol Gunjan, MS 3
Pre-ischemic Exercise Preserves Cerebral Blood Flow (CBF) During Reperfusion in
Stroke: A MicroPET Study
Traumatic brain injury and brain edema
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Harish Kinni, MS 2
The difference of Cerebral Glycolysis Metabolism between Forced and Voluntary Physical
Exercise and Neuroprotection in Stroke
Effect of Cerebral Extracellular Glycerol Content in Stroke
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Peter Papapetrou, MS 2
Effect of TNF-α, HSP-70 and ERK 1/2 on Reducing Apoptosis in Stroke Following Exercise
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Khawar Chandhry, MS 2
Physical Exercise Reduces Matrix Metalloproteinase-9 (MMP-9) Activity and Neuronal
Apoptosis via Extracellular Signal-Regulated Kinase 1 and 2 (ERK1/2) Activation
in Stroke
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Rachel Beredo, MS 2
Increased Cerebral Glycolysis Metabolism during Physical Exercise and Neuroprotection
in Stroke
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Tetsuhiro Higashida, MD, PhD, Neurosurgery Fellow
Hypoxia-Inducible Factor-1a Signaling in Aquaporin Upregulation After Ischemia/reperfusion
Injury
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