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Search Results: 1 - 10 of 328038 matches for " Linda S Sorkin "
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Carrageenan induced phosphorylation of Akt is dependent on neurokinin-1 expressing neurons in the superficial dorsal horn
Jeong IL Choi, Fred J Koehrn, Linda S Sorkin
Molecular Pain , 2012, DOI: 10.1186/1744-8069-8-4
Abstract: Rats pretreated with spinal saporin conjugated to a stabilized form of substance P had substantial loss of neurons with neurokinin 1 receptors throughout their superficial, but not deep dorsal horns. Animals pre-treated with substance P-saporin exhibited no change in locomotor ability and a small, but significant decrease in carrageenan-induced mechanical allodynia when compared to animals pre-treated with spinal saporin alone. Importantly, carrageenan-induced phosphorylation of Akt was blocked, in the substance P-saporin treated group, throughout the spinal cord grey matter. In marked contrast, carrageenan induced-trafficking of the GluA1 receptor subunit increased equivalently in both treatment groups.We infer from these data that 1) phosphorylation of Akt in the deep dorsal horn is dependent on prior activation of NK1 receptor bearing cells in superficial dorsal horn, and 2) there are parallel spinal intracellular cascades initiated by the carrageenan injection downstream of PI-3K activation, including one containing Akt and another involving GluA1 trafficking into neuronal plasma membranes that separately lead to enhanced pain behavior. These results imply that the two pathways downstream of PI-3K can be activated separately and therefore should be able to be inhibited independently.Akt is a serine/threonine kinase that plays a pivotal role in many essential cellular processes including cell survival and apoptosis. Spinal phosphorylation of neuronal Akt at both the ser 473 and the thr 308 sites occurs following peripheral tissue injury; this can be observed throughout the superficial dorsal horn [1-4], but also is elicited prominently in lateral lamina V and in α-motor neurons [3]. This is a topic of interest, as spinal blockade of Akt phosphorylation (P-Akt) or phosphatidylinositol 3-kinase (PI-3K), its upstream activator, results in amelioration of injury-induced pain behavior [1,2,4,5]. More generally, phosphorylation of Akt is held to be an indicator of neur
Regulation of Peripheral Inflammation by Spinal p38 MAP Kinase in Rats
David L Boyle,Toni L Jones,Deepa Hammaker,Camille I Svensson,Sanna Rosengren,Salvatore Albani,Linda Sorkin,Gary S Firestein
PLOS Medicine , 2006, DOI: 10.1371/journal.pmed.0030338
Abstract: Background Somatic afferent input to the spinal cord from a peripheral inflammatory site can modulate the peripheral response. However, the intracellular signaling mechanisms in the spinal cord that regulate this linkage have not been defined. Previous studies suggest spinal cord p38 mitogen-activated protein (MAP) kinase and cytokines participate in nociceptive behavior. We therefore determined whether these pathways also regulate peripheral inflammation in rat adjuvant arthritis, which is a model of rheumatoid arthritis. Methods and Findings Selective blockade of spinal cord p38 MAP kinase by administering the p38 inhibitor SB203580 via intrathecal (IT) catheters in rats with adjuvant arthritis markedly suppressed paw swelling, inhibited synovial inflammation, and decreased radiographic evidence of joint destruction. The same dose of SB203580 delivered systemically had no effect, indicating that the effect was mediated by local concentrations in the neural compartment. Evaluation of articular gene expression by quantitative real-time PCR showed that spinal p38 inhibition markedly decreased synovial interleukin-1 and ?6 and matrix metalloproteinase (MMP3) gene expression. Activation of p38 required tumor necrosis factor α (TNFα) in the nervous system because IT etanercept (a TNF inhibitor) given during adjuvant arthritis blocked spinal p38 phosphorylation and reduced clinical signs of adjuvant arthritis. Conclusions These data suggest that peripheral inflammation is sensed by the central nervous system (CNS), which subsequently activates stress-induced kinases in the spinal cord via a TNFα-dependent mechanism. Intracellular p38 MAP kinase signaling processes this information and profoundly modulates somatic inflammatory responses. Characterization of this mechanism could have clinical and basic research implications by supporting development of new treatments for arthritis and clarifying how the CNS regulates peripheral immune responses.
Chimeric Antibody c.8B6 to O-Acetyl-GD2 Mediates the Same Efficient Anti-Neuroblastoma Effects as Therapeutic ch14.18 Antibody to GD2 without Antibody Induced Allodynia
Micka?l Terme, Mylène Dorvillius, Denis Cochonneau, Tanguy Chaumette, Wenhua Xiao, Mitchell B. Diccianni, Jacques Barbet, Alice L. Yu, Fran?ois Paris, Linda S. Sorkin, Stéphane Birklé
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0087210
Abstract: Background Anti-GD2 antibody is a proven therapy for GD2-postive neuroblastoma. Monoclonal antibodies against GD2, such as chimeric mAb ch14.18, have become benchmarks for neuroblastoma therapies. Pain, however, can limit immunotherapy with anti-GD2 therapeutic antibodies like ch14.18. This adverse effect is attributed to acute inflammation via complement activation on GD2-expressing nerves. Thus, new strategies are needed for the development of treatment intensification strategies to improve the outcome of these patients. Methodology/Principal Findings We established the mouse-human chimeric antibody c.8B6 specific to OAcGD2 in order to reduce potential immunogenicity in patients and to fill the need for a selective agent that can kill neuroblastoma cells without inducing adverse neurological side effects caused by anti-GD2 antibody immunotherapy. We further analyzed some of its functional properties compared with anti-GD2 ch14.18 therapeutic antibody. With the exception of allodynic activity, we found that antibody c.8B6 shares the same anti-neuroblastoma attributes as therapeutic ch14.18 anti-GD2 mAb when tested in cell-based assay and in vivo in an animal model. Conclusion/Significance The absence of OAcGD2 expression on nerve fibers and the lack of allodynic properties of c.8B6–which are believed to play a major role in mediating anti-GD2 mAb dose-limiting side effects–provide an important rationale for the clinical application of c.8B6 in patients with high-risk neuroblastoma.
An axisymmetric generalized harmonic evolution code
Evgeny Sorkin
Physics , 2009, DOI: 10.1103/PhysRevD.81.084062
Abstract: We describe the first axisymmetric numerical code based on the generalized harmonic formulation of the Einstein equations which is regular at the axis. We test the code by investigating gravitational collapse of distributions of complex scalar field in a Kaluza-Klein spacetime. One of the key issues of the harmonic formulation is the choice of the gauge source functions, and we conclude that a damped wave gauge is remarkably robust in this case. Our preliminary study indicates that evolution of regular initial data leads to formation both of black holes with spherical and cylindrical horizon topologies. Intriguingly, we find evidence that near threshold for black hole formation the number of outcomes proliferates. Specifically, the collapsing matter splits into individual pulses, two of which travel in the opposite directions along the compact dimension and one which is ejected radially from the axis. Depending on the initial conditions, a curvature singularity develops inside the pulses.
On critical collapse of gravitational waves
Evgeny Sorkin
Physics , 2010, DOI: 10.1088/0264-9381/28/2/025011
Abstract: An axisymmetric collapse of non-rotating gravitational waves is numerically investigated in the subcritical regime where no black holes form but where curvature attains a maximum and decreases, following the dispersion of the initial wave packet. We focus on a curvature invariant with dimensions of length, and find that near the threshold for black hole formation it reaches a maximum along concentric rings of finite radius around the axis. In this regime the maximal value of the invariant exhibits a power-law scaling with the approximate exponent 0.38, as a function of a parametric distance from the threshold. In addition, the variation of the curvature in the critical limit is accompanied by increasing amount of echos, with nearly equal temporal and spatial periods. The scaling and the echoing patterns, and the corresponding constants, are independent of the initial data and coordinate choices.
A critical dimension in the black-string phase transition
Evgeny Sorkin
Physics , 2004, DOI: 10.1103/PhysRevLett.93.031601
Abstract: In spacetimes with compact dimensions there exist several black object solutions including the black-hole and the black-string. These solutions may become unstable depending on their relative size and the relevant length scale set by the compact dimensions. The transition between these solutions raises puzzles and addresses fundamental questions such as topology change, uniquenesses and cosmic censorship. Here, we consider black strings wrapped over the compact circle of a $d$-dimensional cylindrical spacetime. We construct static perturbative non-uniform string solutions around the instability point of a uniform string. First we compute the instability mass for a large range of dimensions, $d$, and find that it follows essentially an exponential law $\gamma^d$, where $\gamma$ is a constant. Then we determine that there is a critical dimension, $d_*=13$, such that for $d\leq d_*$ the phase transition between the uniform and the non-uniform strings is of first order, while for $d>d_*$, it is, surprisingly, of higher order.
Nonuniform black strings in various dimensions
Evgeny Sorkin
Physics , 2006, DOI: 10.1103/PhysRevD.74.104027
Abstract: The nonuniform black strings branch, which emerges from the critical Gregory-Laflamme string, is numerically constructed in dimensions 6 <= D <= 11 and extended into the strongly non-linear regime. All the solutions are more massive and less entropic than the marginal string. We find the asymptotic values of the mass, the entropy and other physical variables in the limit of large horizon deformations. By explicit metric comparison we verify that the local geometry around the ``waist'' of our most nonuniform solutions is cone-like with less than 10% deviation. We find evidence that in this regime the characteristic length scale has a power-law dependence on a parameter along the branch of the solutions, and estimate the critical exponent.
How safe are the biologicals in treating asthma and rhinitis?
Linda S Cox
Allergy, Asthma & Clinical Immunology , 2009, DOI: 10.1186/1710-1492-5-4
Abstract: Clinical trials with other biologic agents that have targeted IL-4/IL-13, or IL-5, have not demonstrated any definite serious treatment-related adverse events. However, these clinical trials were generally done in small populations of asthma patients, which may be too small for uncommon side effects to be identified. There is conflicting information about the safety TNF-alpha blocking agents, which have been primarily used in the treatment of rheumatoid arthritis, with serious infections, cardiovascular disease and malignancies being the most frequent serious adverse events. An unfavorable risk-benefit profile led to early discontinuation of a TNF-blocking agent in a double-blind placebo controlled of severe asthmatics.In summary, the risk of anaphylaxis and other treatment-related serious events with of all of the biological agents in this review were relatively small. However, most of the clinical trials were done in relatively small patient populations and were of relatively short duration. Long term studies in large patient populations may help clarify the risk-benefit profile of these biologic agents in the treatment of asthma.A number of therapeutic agents are available to treat the symptoms and inflammation associated with allergic rhinitis and asthma. Despite the proven efficacy of these medications, there continues to be some patients whose asthma [1] or rhinitis [2] is not well controlled. In addition, medications currently available for allergic rhinitis and asthma treatment appear to be are only effective while taken and do not appear to provide a sustained benefit after discontinuation [3]. Limitations of current medications and a greater understanding of the pathogenesis of allergic disease, has lead to the development of number of a novel therapeutic approaches as well as renewed interest in an old therapeutic approach, specific allergen immunotherapy. Novel therapeutic approaches that have been used in the treatment of allergic rhinitis and asthma in
Reexamining age, race, site, and thermometer type as variables affecting temperature measurement in adults – A comparison study
Linda S Smith
BMC Nursing , 2003, DOI: 10.1186/1472-6955-2-1
Abstract: Setting 176 bed accredited healthcare facility, rural northwest USParticipants Convenience sample (N = 120) of hospitalized persons ≥ 18 years old.Instruments Temperatures (°F) measured at oral, skin (simultaneous), immediately followed by rectal sites with four each mercury-glass (BD) and Galinstan-glass (Geratherm) thermometers; 10 minute dwell times.Participants averaged 61.6 years (SD 17.9), 188 pounds (SD 55.3); 61% female; race: 85% White, 8.3% Native Am., 4.2% Hispanic, 1.7 % Asian, 0.8% Black. For both mercury and Galinstan-glass thermometers, within-subject temperature readings were highest rectally; followed by oral, then skin sites. Galinstan assessments demonstrated rectal sites 0.91°F > oral and ? 1.3°F > skin sites. Devices strongly correlated between and across sites. Site difference scores between devices showed greatest variability at skin sites; least at rectal site. 95% confidence intervals of difference scores by site (°F): oral (0.142 – 0.265), axilla (0.167 – 0.339), groin (0.037 – 0.321), and rectal (-0.111 – 0.111). Race correlated with age, temperature readings each site and device.Temperature readings varied by age, race. Mercury readings correlated with Galinstan thermometer readings at all sites. Site mean differences between devices were considered clinically insignificant. Still considered the gold standard, mercury-glass thermometers may no longer be available worldwide. Therefore, mercury-free, environmentally safe low-tech Galinstan-in-glass may be an appropriate replacement. This is especially important as we face new, internationally transmitted diseases.All health services need reliable, valid, readily available and accessible body temperature assessment devices. Obviously, body temperature assessments are key diagnostic indicators. Yet, the measurement of human body temperature has recently been cause for concern. Since Wunderlich's seminal work [1], mercury has been and continues to be the "gold standard" for temperature measure
The Role of Thrombospondin 1 on Intestinal Inflammation and Carcinogenesis
Linda S. Gutierrez
Biomarker Insights , 2008,
Abstract: Crohn’s disease and ulcerative colitis are inflammatory bowel diseases (IBD) quite common in the United States and other Western countries. Patients suffering IBD are at greater risk of developing colorectal adenocarcinoma than the general population. Both, the adenoma-carcinoma and the inflammation-carcinogenesis processes are characterized by active angiogenesis. Recent studies also have shown that anti-angiogenesis might be a novel therapeutic approach for IBD. Thrombospondin 1 (TSP1) is an extracellular protein well known for its anti-angiogenic properties. TSP1 also has key functions in inflammation, which is assumed to be the primary cause for carcinogenesis in IBD. This review is focused on the role of TSP1 in colorectal carcinogenesis. The therapeutic effects of TSP derived-peptides on inhibiting the inflammationcarcinogenesis progression are also discussed.
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