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John Hallenbeck

Publications and source records attributed to John Hallenbeck.

10 recordsLinked to original sources
PubMed2006

Intranasal administration of E-selectin to induce immunological tolerization can suppress subarachnoid hemorrhage-induced vasospasm implicating immune and inflammatory mechanisms in its genesis.

Evidence that inflammatory and immune mechanisms may have a critical role in the development of vasospasm after subarachnoid hemorrhage is accumulating. We examined, therefore, whether induction of immunological tolerance to the adhesion molecule that is uniquely expressed on activated endothelium, E-selectin, could inhibit the vasospasm provoked by subarachnoid blood in a rat subarachnoid hemorrhage model. We found that intranasal instillation of E-selectin every other day for 10 days on a mucosal tolerization schedule suppressed delayed type hypersensitivity to E-selectin confirming tolerance to that molecule and markedly suppressed basilar artery spasm after subarachnoid hemorrhage. The results of this proof-of-concept study suggest that agents that can mimic the local effects of the mediators of mucosal tolerance could have therapeutic potential for the management of post-subarachnoid hemorrhage vasospasm.

Administration, Intranasal↗
PubMed2006

Immunomodulation strategies for preventing vascular disease of the brain and heart: workshop summary.

This workshop examined the opportunities for translational research directed at immune and inflammatory mechanisms. This summary presents the background data in 3 general areas: (1) inflammation and hemostasis in cerebrovascular and cardiovascular disease, (2) immune interactions in the central nervous system and heart, and (3) translation of immune modulation in the brain and heart, all of which supported a consensus derivation of the opportunities for future research in these areas. The summary concludes with 11 recommendations.

Animals↗
PubMed2006

Mucosal tolerance to E-selectin and response to systemic inflammation.

Mucosal tolerance to E-selectin has been shown to prevent stroke and reduce brain infarcts in experimental stroke models. However, the effective E-selectin dose range required to achieve mucosal tolerance and the precise mechanisms of neuroprotection remain unclear. We sought to examine the mechanisms of cytoprotection using gene expression profiling of tissues in the setting of mucosal tolerance and inflammatory challenge. Using spontaneously hypertensive rats (SHRs), we achieved immune tolerance with 0.1 to 5 microg E-selectin per nasal instillation and observed a dose-related anti-E-selectin immunoglobulin G antibody production. We also show the distinct patterns of gene expression changes in the brain and spleen with the different tolerizing doses and lipopolysaccharide (LPS) exposure. Prominent differences were seen with such genes as insulin-like growth factors in the brain and downregulation of those encoding the major histocompatibility complex class I molecules in the spleen. In all, mucosal tolerance to E-selectin and subsequent exposure to LPS resulted in significant tissue changes. These changes, while giving an insight to the underlying mechanisms, serve as possible targets for future studies to facilitate translation to human clinical trials.

Animals↗
PubMed2004

Cloning and characterization of a forkhead transcription factor gene, FoxO1a, from thirteen-lined ground squirrel.

This research analyzes the regulation of ischemic tolerance in hibernating thirteen-lined ground squirrels (Spermophilus tridecemlineatus). Hibernation is studied because it represents a unique state of reversible suspended animation associated with tolerance to an otherwise lethal reduction of core body temperature and metabolism. An integral aspect of hibernation is the profound decrease of cerebral perfusion without neurological damage. As such, hibernation serves as a model for studying natural tolerance to brain ischemia. Identification of regulatory mechanisms that control hibernation in ground squirrels may guide efforts to develop improved treatments for stroke and brain trauma. It was previously shown that phosphorylation of Akt (protein kinase B), an insulin-like growth factor-regulated serine/threonine kinase, was significantly reduced as was its kinase activity in hibernating thirteen-lined ground squirrels. Here we studied the forkhead (FH) in rhabdomyosarcoma (FKHR) transcription factor, which is controlled by Akt signaling and is involved in regulating cell cycle progression and cell death. A cDNA derived from brains of S. tridecemlineatus, encoding a specific FKHR transcription factor, FoxO1a, was cloned and sequenced, and the amino acid sequence of the protein was deduced. FoxO1a is composed of 653 amino acids and has a predicted molecular mass of 69.4 kilodaltons (kDa). Here, for the first time, we report the contrary expression of phosphorylation of two members in the insulin-like growth factor signaling pathway during hibernation (i.e., phosphorylated FKHR was significantly up-regulated as phosphorylation of its upstream kinase, Akt, was significantly down-regulated). Further study is required to identify the possible connection between FoxO1a and Akt activity and the possible of such interactions in hibernation.

Animals↗
PubMed2004

Akt phosphorylation and kinase activity are down-regulated during hibernation in the 13-lined ground squirrel.

Hibernation in mammals is a reversible state of suspended animation associated with tolerance to an otherwise lethal reduction of core body temperature and metabolism. An integral aspect of hibernation is tolerance to a profound decrease of cerebral perfusion. Identification of regulatory mechanisms that control hibernation in ground squirrels can guide efforts to develop improved treatment for stroke and brain trauma. In this study, we show in multiple tissues that S473 phosphorylation of Akt (Protein kinase B), a phosphatidylinositol-3 kinase-regulated serine/threonine kinase, was significantly reduced (P<0.001) as was its kinase activity (P=0.023) in the 13-lined ground squirrel, Spermophilus tridecemlineatus, during hibernation. T308 phosphorylation of Akt was relatively preserved. Brain immunohistochemical staining confirmed these results. In hibernating animals, reduction of immunoreactive phospho (S473)-Akt was noted throughout the brain. Akt is a key molecule in the insulin/insulin-like growth factor signal transduction pathway, which plays a critical role in the balance between survival and apoptosis. The data presented here raise the possibility that down-regulation of Akt phosphorylation plays a regulatory role in hibernation. This would resemble dauer larva formation in Caenorhabditis elegans where Akt inhibition is associated with energy conservation, fat storage, expression of antioxidant enzymes and growth arrest.

Animals↗
PubMed2003

Adoptive transfer of myelin basic protein-tolerized splenocytes to naive animals reduces infarct size: a role for lymphocytes in ischemic brain injury?

BACKGROUND AND PURPOSE: Breakdown of the blood-brain barrier during stroke allows central nervous system antigens to leak into the systemic circulation and allows circulating leukocytes access to the brain. Encounter of central nervous system antigens by the peripheral immune system can be capitalized on to modulate the postischemic inflammatory response and potentially improve outcome from stroke. METHODS: Male Lewis rats were tolerized to myelin basic protein (MBP) or ovalbumin (OVA) and subjected to 3 hours of middle cerebral artery occlusion (MCAO) or used as splenocyte donors for immunologically naive animals undergoing MCAO. Infarct size was determined at 24 hours by 2,3,5-triphenyltetrazolium chloride staining. In separate studies, mononuclear cells were removed from the brains of animals after MCAO for enzyme-linked immunospot (ELISPOT) assay and flow cytometry. RESULTS: Median infarct volume in animals tolerized to MBP and those receiving splenocytes from MBP-tolerized donors was less than in animals tolerized to OVA and those receiving splenocytes from OVA-tolerized donors (87.7+/-54.9 versus 148+/-61.6 mm3 [P=0.01] and 89.2+/-77.5 versus 153+/-77.1 mm3 [P=0.05], respectively). There was an increase in the number of transforming growth factor-beta1-secreting mononuclear cells in MBP-tolerized animals undergoing sham surgery (P=0.001) as well as in ischemic animals 48 hours (P=0.02) and 336 hours (P=0.04) after stroke. A distinct subset of gammadelta T cells was present in the brains of MBP-tolerized but not control animals after stroke. CONCLUSIONS: Immunologic tolerance and its neuroprotective effects can be transferred to naive animals and appear to be related to antigen-specific induction of transforming growth factor-beta1.

Administration, Intranasal↗
PubMed2003

Impact of establishing a primary stroke center at a community hospital on the use of thrombolytic therapy: the NINDS Suburban Hospital Stroke Center experience.

BACKGROUND AND PURPOSE: To increase the proportion of ischemic stroke patients treated with thrombolytic therapy, the establishment of primary stroke centers in community hospitals has been advocated. We evaluated the use of thrombolytic therapy before and after institution of a primary stroke center in a community hospital. METHODS: The availability of an on-call stroke emergency response team was the only significant additional resource required for this hospital. All eligible patients were treated with intravenous tissue plasminogen activator (tPA). The number of patients with cerebrovascular disease, number and proportion of patients treated with tPA, times to treatment, and patient outcomes were recorded during the first 2 years of the stroke center. RESULTS: During the 12 months before institution of the stroke center, 3 ischemic stroke patients (1.5%) were treated with tPA. During the 2-year period of around-the-clock coverage, 44 of 420 ischemic stroke patients (10.5%) were treated with intravenous tPA, a significant increase in tPA use (P<0.0001). CONCLUSIONS: Establishment of a primary stroke center at a community hospital resulted in a substantial increase in the proportion of patients receiving thrombolytic therapy for ischemic stroke. If this experience is generalized, the beneficial impact of primary stroke centers on stroke outcomes and costs to the healthcare system may be substantial.

Adult↗
PubMed2002

Induction of mucosal tolerance to E-selectin prevents ischemic and hemorrhagic stroke in spontaneously hypertensive genetically stroke-prone rats.

BACKGROUND AND PURPOSE: Inflammatory and immune mechanisms can precipitate cerebrovascular thrombosis and hemorrhage. Immunologic tolerance can be induced to a specific antigen by intranasal instillation of that antigen. Lymphocytes tolerized in this way provide local immunosuppression on restimulation with the same antigen. This study tests whether tolerization of lymphocytes to E-selectin can suppress local vessel activation and prevent stroke. METHODS: Spontaneously hypertensive genetically stroke-prone rats (n=113) were distributed among the following studies: comparison of ischemic infarcts/intraparenchymal hemorrhages after single or repetitive tolerization schedules with ovalbumin, E-selectin, or PBS; comparison of E-selectin tolerization- and PBS tolerization-induced suppression of delayed-type hypersensitivity in animals subsequently sensitized to E-selectin; and comparison of PBS-, ovalbumin-, and E-selectin-tolerized groups (after intravenous lipopolysaccharide to activate vessels) regarding transforming growth factor-beta1-positive splenocyte counts, plasma interferon-gamma levels, anti-human E-selectin antibodies, endothelial intercellular adhesion molecule-1, and anti-endothelial cell antibodies. RESULTS: Nasal instillation of E-selectin, which is specifically expressed on activated endothelium, potently inhibited the development of ischemic and hemorrhagic strokes in spontaneously hypertensive stroke-prone rats with untreated hypertension. Repeated schedules of tolerization were required to maintain the resistance to stroke. Suppression of delayed-type hypersensitivity to E-selectin and increased numbers of transforming growth factor-beta1-positive splenocytes showed that intranasal exposure to E-selectin induced immunologic tolerance. E-selectin tolerization also reduced endothelial activation and immune responses after intravenous lipopolysaccharide, as shown by marked suppression of intercellular adhesion molecule-1 expression, anti-endothelial cell antibodies on luminal endothelium, and plasma interferon-gamma levels compared with the control condition. CONCLUSIONS: The novel findings in this study support further investigation of immunologic tolerance as applied to the prevention of stroke.

Animals↗