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1.  Vagus Nerve Stimulation in Ischemic Stroke: Old Wine in a New Bottle 
Vagus nerve stimulation (VNS) is currently Food and Drug Administration-approved for treatment of both medically refractory partial-onset seizures and severe, recurrent refractory depression, which has failed to respond to medical interventions. Because of its ability to regulate mechanisms well-studied in neuroscience, such as norepinephrine and serotonin release, the vagus nerve may play an important role in regulating cerebral blood flow, edema, inflammation, glutamate excitotoxicity, and neurotrophic processes. There is strong evidence that these same processes are important in stroke pathophysiology. We reviewed the literature for the role of VNS in improving ischemic stroke outcomes by performing a systematic search for publications in Medline (1966–2014) with keywords “VNS AND stroke” in subject headings and key words with no language restrictions. Of the 73 publications retrieved, we identified 7 studies from 3 different research groups that met our final inclusion criteria of research studies addressing the role of VNS in ischemic stroke. Results from these studies suggest that VNS has promising efficacy in reducing stroke volume and attenuating neurological deficits in ischemic stroke models. Given the lack of success in Phase III trials for stroke neuroprotection, it is important to develop new therapies targeting different neuroprotective pathways. Further studies of the possible role of VNS, through normally physiologically active mechanisms, in ischemic stroke therapeutics should be conducted in both animal models and clinical studies. In addition, recent advent of a non-invasive, transcutaneous VNS could provide the potential for easier clinical translation.
doi:10.3389/fneur.2014.00107
PMCID: PMC4067569
stroke; middle cerebral artery occlusion; glutamate excitotoxicity; neuroinflammation; cerebral blood flow
2.  Thunderclap headache: It is always sub-arachnoid hemorrhage. Is it? – A case report and Review 
Background:
Spontaneous intracranial hypotension (SIH) is one of the relatively misdiagnosed pathophysiological entities by virtue of its presentation. SIH is a condition involving reduced intracranial pressure usually secondary to dural tear. There is recent increase in reporting of its varied presentation in literature. Critical care physicians and neurosurgeons are recognizing it in higher numbers than before. SIH is characterized by sudden onset of orthostatic headache and may be associated with neck stiffness, nausea, vomiting, tinnitus, deafness, and cognitive abnormalities. Since its imaging characteristics resemble classic subdural hematoma from other causes wrong diagnosis and intervention might have devastating outcome.
Case Description:
Here we discuss a case presented to us with severe headache of sudden onset without any associated problems. Patient was initially being treated as sinusitis and later diagnosed as bilateral subdural hematoma and surgical intervention was being considered. Thorough history taking and physical examination lead to strong suspicion of intracranial hypotension (IH) and patient showed dramatic improvement with epidural blood patch.
Conclusion:
IH is a commonly misdiagnosed entity. A high index of suspicion is required for timely diagnosis, in order to minimize unwanted therapeutic interventions that can worsen the patient's condition and to help initiate early and simple interventions.
doi:10.4103/2152-7806.127756
PMCID: PMC3994686  PMID: 24778910
Diagnosis; hypotension; intracranial; presentation; spontaneous
3.  Complementary Cell-Based High Throughput Screens Identify Novel Modulators of the Unfolded Protein Response 
Journal of Biomolecular Screening  2011;16(8):825-835.
Despite advances toward understanding the prevention and treatment of many cancers, patients who suffer from oral squamous cell carcinoma (OSCC) confront a survival rate that has remained unimproved for more than two decades indicating our ability to treat them pharmacologically has reached a plateau. In an ongoing effort to improve the clinical outlook for this disease, we previously reported that an essential component of the mechanism by which the proteasome inhibitor bortezomib (PS-341, Velcade) induced apoptosis in OSCC required the activation of a terminal unfolded protein response (UPR). Predicated on these studies, we hypothesized that high throughput screening (HTS) of large diverse chemical libraries might identify more potent or selective small molecule activators of the apoptotic arm of the UPR to control or kill OSCC. We have developed complementary cell-based assays using stably transfected CHO-K1 cell lines that individually assess the PERK/eIF2α/CHOP (apoptotic) or the IRE1/XBP1 (adaptive) UPR sub-pathways. A ~66K compound collection was screened at the University of Michigan Center for Chemical Genomics that included a unique library of pre-fractionated natural product extracts. The mycotoxin methoxycitrinin was isolated from a natural extract and found to selectively activate the CHOP-luciferase reporter at 80μM. A series of citrinin derivatives were isolated from these extracts, including a unique congener that has not been previously described. In an effort to identify more potent compounds we examined the ability of citrinin and the structurally related mycotoxins ochratoxin A and patulin to activate the UPR. Strikingly, we found that patulin at 2.5 – 10μM induced a terminal UPR in a panel of OSCC cells that was characterized by an increase in CHOP, GADD34 and ATF3 gene expression and XBP1 splicing. A luminescent caspase assay and the induction of several BH3-only genes indicated that patulin could induce apoptosis in OSCC cells. These data support the use of this complementary HTS strategy to identify novel modulators of UPR signaling and tumor cell death.
doi:10.1177/1087057111414893
PMCID: PMC3374590  PMID: 21844328
unfolded protein response; endoplasmic reticulum stress; cell-based assay; luciferase reporter; natural products

Results 1-3 (3)