http://hdl.handle.net/10150/595893 Sun, 09 Jul 2017 18:03:48 GMT 2017-07-09T18:03:48Z http://hdl.handle.net/10150/624635 Title: Mediation of Movement-Induced Breakthrough Cancer Pain by IB4-Binding Nociceptors in Rats Author: Havelin, Joshua; Imbert, Ian; Sukhtankar, Devki; Remeniuk, Bethany; Pelletier, Ian; Gentry, Jonathan; Okun, Alec; Tiutan, Timothy; Porreca, Frank; King, Tamara E. Abstract: Cancer-induced bone pain is characterized by moderate to severe ongoing pain that commonly requires the use of opiates. Even when ongoing pain is well controlled, patients can suffer breakthrough pain (BTP), episodic severe pain that "breaks through" the medication. We developed a novel model of cancer-induced BTP using female rats with mammary adenocarcinoma cells sealed within the tibia. We demonstrated previously that rats with bone cancer learn to prefer a context paired with saphenous nerve block to elicit pain relief (i.e., conditioned place preference, CPP), revealing the presence of ongoing pain. Treatment with systemic morphine abolished CPP to saphenous nerve block, demonstrating control of ongoing pain. Here, we show that pairing BTP induced by experimenter-induced movement of the tumor-bearing hindlimb with a context produces conditioned place avoidance (CPA) in rats treated with morphine to control ongoing pain, consistent with clinical observation of BTP. Preventing movement-induced afferent input by saphenous nerve block before, but not after, hindlimb movement blocked movement-induced BTP. Ablation of isolectin B4 (IB4)-binding, but not TRPV1(+), sensory afferents eliminated movement-induced BTP, suggesting that input from IB4-binding fibers mediates BTP. Identification of potential molecular targets specific to this population of fibers may allow for the development of peripherally restricted analgesics that control BTP and improve quality of life in patients with skeletal metastases. Wed, 17 May 2017 00:00:00 GMT http://hdl.handle.net/10150/624635 2017-05-17T00:00:00Z http://hdl.handle.net/10150/624636 Title: Targeting a Potassium Channel/Syntaxin Interaction Ameliorates Cell Death in Ischemic Stroke Author: Yeh, Chung-Yang; Bulas, Ashlyn M.; Moutal, Aubin; Saloman, Jami L.; Hartnett, Karen A.; Anderson, Charles T.; Tzounopoulos, Thanos; Sun, Dandan; Khanna, Rajesh; Aizenman, Elias Abstract: The voltage-gated K+ channel Kv2.1 has been intimately linked with neuronal apoptosis. After ischemic, oxidative, or inflammatory insults, Kv2.1 mediates a pronounced, delayed enhancement of K+ efflux, generating an optimal intracellular environment for caspase and nuclease activity, key components of programmed cell death. This apoptosis-enabling mechanism is initiated via Zn2+-dependent dual phosphorylation of Kv2.1, increasing the interaction between the channel's intracellular C-terminus domain and the SNARE(soluble N-ethylmaleimide-sensitive factor activating protein receptor) protein syntaxin 1A. Subsequently, an upregulation of de novo channel insertion into the plasma membrane leads to the critical enhancement of K+ efflux in damaged neurons. Here, we investigated whether a strategy designed to interfere with the cell death-facilitating properties of Kv2.1, specifically its interaction with syntaxin 1A, could lead to neuroprotection following ischemic injury in vivo. The minimal syntaxin 1A-binding sequence of Kv2.1 C terminus (C1aB) was first identified via a far-Western peptide screen and used to create a protherapeutic product by conjugating C1aB to a cell-penetrating domain. The resulting peptide (TAT-C1aB) suppressed enhanced whole-cell K+ currents produced by a mutated form of Kv2.1 mimicking apoptosis in a mammalian expression system, and protected cortical neurons from slow excitotoxic injury in vitro, without influencing NMDA-induced intracellular calcium responses. Importantly, intraperitoneal administration of TAT-C1aB in mice following transient middle cerebral artery occlusion significantly reduced ischemic stroke damage and improved neurological outcome. These results provide strong evidence that targeting the proapoptotic function of Kv2.1 is an effective and highly promising neuroprotective strategy. Wed, 07 Jun 2017 00:00:00 GMT http://hdl.handle.net/10150/624636 2017-06-07T00:00:00Z http://hdl.handle.net/10150/624649 Title: Development and Validation of a Decision-Making Stratification Algorithm to Optimize the Use of Rapid Diagnostic Testing for Patients with Staphylococcus Bacteremia Author: Almangour, Thamer A.; Alhifany, Abdullah A.; Tabb, Deanne E. Abstract: Purpose. To evaluate whether introducing rapid diagnostic testing in conjunction with implementing a stratification algorithm for testing eligibilitywould be an appropriate clinical and cost saving approach. Method. An internal concurrent 4-month observational study was performed. Positive blood cultures continued to be worked up in accordance with standard of care. An additional call to the infectious disease (ID) pharmacy service occurred for all positive blood cultures with Gram-positive cocci in clusters (GPCC). The ID pharmacy service investigated each case using a prespecified stratification algorithm to minimize unnecessary use of rapid identification testing. Results. 43 patients with GPCC were screened. Only nine patients met inclusion criteria for QuickFISH (TM) testing. The average expected time avoided to optimize antibiotic therapy is 35 perpendicular to 16 hours. If the QuickFISH test had been indiscriminately implemented for all cases, the cost for performing this test would have been $5,590. However, using the prespecified algorithm, only 9 patients were tested for a projected cost of $1,170. Conclusion. Introducing rapid diagnostic testing in conjunction with implementing patient stratification algorithm for rapid identification of GPCC from blood cultures in addition to the ID pharmacy intervention will provide a positive impact on the clinical and economic outcomes in our health care setting. Sun, 01 Jan 2017 00:00:00 GMT http://hdl.handle.net/10150/624649 2017-01-01T00:00:00Z http://hdl.handle.net/10150/624650 Title: Can local adaptation explain varying patterns of herbivory tolerance in a recently introduced woody plant in North America? Author: Long, Randall W.; Bush, Susan E.; Grady, Kevin C.; Smith, David S.; Potts, Daniel L.; D'Antonio, Carla M.; Dudley, Tom L.; Fehlberg, Shannon D.; Gaskin, John F.; Glenn, Edward P.; Hultine, Kevin R. Abstract: Patterns of woody-plant mortality have been linked to global-scale environmental changes, such as extreme drought, heat stress, more frequent and intense fires, and episodic outbreaks of insects and pathogens. Although many studies have focussed on survival and mortality in response to specific physiological stresses, little attention has been paid to the role of genetic heritability of traits and local adaptation in influencing patterns of plant mortality, especially in non-native species. Tamarix spp. is a dominant, non-native riparian tree in western North America that is experiencing dieback in some areas of its range due to episodic herbivory by the recently introduced northern tamarisk leaf beetle (Diorhabda carinulata). We propose that genotype x environment interactions largely underpin current and future patterns of Tamarix mortality. We anticipate that (i) despite its recent introduction, and the potential for significant gene flow, Tamarix in western North America is generally adapted to local environmental conditions across its current range in part due to hybridization of two species; (ii) local adaptation to specific climate, soil and resource availability will yield predictable responses to episodic herbivory; and (iii) the ability to cope with a combination of episodic herbivory and increased aridity associated with climate change will be largely based on functional tradeoffs in resource allocation. This review focusses on the potential heritability of plant carbon allocation patterns in Tamarix, focussing on the relative contribution of acquired carbon to non-structural carbohydrate (NSC) pools versus other sinks as the basis for surviving episodic disturbance. Where high aridity and/or poor edaphic position lead to chronic stress, NSC pools may fall below a minimum threshold because of an imbalance between the supply of carbon and its demand by various sinks. Identifying patterns of local adaptation of traits related to resource allocation will improve forecasting of Tamarix population susceptibility to episodic herbivory. Sun, 01 Jan 2017 00:00:00 GMT http://hdl.handle.net/10150/624650 2017-01-01T00:00:00Z