Reduced spinal microglial activation and neuropathic pain after nerve injury in mice lacking all three nitric oxide synthases

<p>Abstract</p> <p>Background</p> <p>Several studies have investigated the involvement of nitric oxide (NO) in acute and chronic pain using mice lacking a single NO synthase (NOS) gene among the three isoforms: neuronal (nNOS), inducible (iNOS) and endothelial (eNOS). However, the precise role of NOS/NO in pain states remains to be determined owing to the substantial compensatory interactions among the NOS isoforms. Therefore, in this study, we used mice lacking all three NOS genes (<it>n/i/eNOS^-/-</it>mice) and investigated the behavioral phenotypes in a series of acute and chronic pain assays.</p> <p>Results</p> <p>In a model of tissue injury-induced pain, evoked by intraplantar injection of formalin, both <it>iNOS^-/-</it>and <it>n/i/eNOS^-/-</it>mice exhibited attenuations of pain behaviors in the second phase compared with that in wild-type mice. In a model of neuropathic pain, nerve injury-induced behavioral and cellular responses (tactile allodynia, spinal microglial activation and Src-family kinase phosphorylation) were reduced in <it>n/i/eNOS^-/-</it>but not <it>iNOS^-/-</it>mice. Tactile allodynia after nerve injury was improved by acute pharmacological inhibition of all NOSs and nNOS. Furthermore, in MG-5 cells (a microglial cell-line), interferon-γ enhanced NOSs and Mac-1 mRNA expression, and the Mac-1 mRNA increase was suppressed by L-NAME co-treatment. Conversely, the NO donor, sodium nitroprusside, markedly increased mRNA expression of Mac-1, interleukin-6, toll-like receptor 4 and P2X4 receptor.</p> <p>Conclusions</p> <p>Our results provide evidence that the NOS/NO pathway contributes to behavioral pain responses evoked by tissue injury and nerve injury. In particular, nNOS may be important for spinal microglial activation and tactile allodynia after nerve injury.</p

Crucial role of nitric oxide synthases system in endothelium-dependent hyperpolarization in mice

The endothelium plays an important role in maintaining vascular homeostasis by synthesizing and releasing several relaxing factors, such as prostacyclin, nitric oxide (NO), and endothelium-derived hyperpolarizing factor (EDHF). We have previously demonstrated in animals and humans that endothelium-derived hydrogen peroxide (H2O2) is an EDHF that is produced in part by endothelial NO synthase (eNOS). In this study, we show that genetic disruption of all three NOS isoforms (neuronal [nNOS], inducible [iNOS], and endothelial [eNOS]) abolishes EDHF responses in mice. The contribution of the NOS system to EDHF-mediated responses was examined in eNOS−/−, n/eNOS−/−, and n/i/eNOS−/− mice. EDHF-mediated relaxation and hyperpolarization in response to acetylcholine of mesenteric arteries were progressively reduced as the number of disrupted NOS genes increased, whereas vascular smooth muscle function was preserved. Loss of eNOS expression alone was compensated for by other NOS genes, and endothelial cell production of H2O2 and EDHF-mediated responses were completely absent in n/i/eNOS−/− mice, even after antihypertensive treatment with hydralazine. NOS uncoupling was not involved, as modulation of tetrahydrobiopterin (BH4) synthesis had no effect on EDHF-mediated relaxation, and the BH4/dihydrobiopterin (BH2) ratio was comparable in mesenteric arteries and the aorta. These results provide the first evidence that EDHF-mediated responses are dependent on the NOSs system in mouse mesenteric arteries

Assessment of Humeral Retroversion Angle in Baseball Players: A Chronological Study

The objective of this study was to compare the humeral retroversion angles (HRA) between baseball players, including children, and those without a history of playing baseball, clarify the characteristics of the HRA in baseball players, and to determine whether or not chronological changes of the HRA are affected by a throwing motion. We studied 32 young baseball players (Group A), 10 elementary and junior high school students who had never played competitive overhead throwing sports (Group B), 65 adult baseball players who had been playing baseball since childhood in a little league or boy\u27s baseball team (Group C), and 11 adults who had never played competitive overhead throwing sports such as baseball or handball (Group D). Computed tomography of both humeri in these subjects was taken with a 5mm slice thickness. For the measurement of HRA, slices from the center of the humeral head and slices from the humeral epicondyle were examined. In baseball players, the mean HRA on the throwing side was larger than that on the non-throwing side, regardless of age and carrier. The HRAs of the elementary and junior high school baseball players as well as those of adult baseball players were larger on the throwing side. The HRA of the throwing side was significantly greater than that of the non-throwing side in both groups of baseball players. Furthermore, the mean HRA on the throwing side of young baseball players was significantly larger than that of adult baseball players, suggesting that the adaptive bony change of the humerus was caused by throwing stress and might occur in the early formative years of a player\u27s career

Edgewise Bending Strain in Helical Coils With Geodesic Windings Based on Virial Theorem

Distributions of edgewise bending strain in helical coils with the geodesic winding based on virial theorem are analyzed theoretically and numerically. A force-balanced coil (FBC) is a multipole helical coil combining toroidal field (TF) coils and a solenoid helically wound on a torus. The combination reduces the net electromagnetic force in the direction of the major radius by canceling out the centering force due to the TF coil current and the hoop force due to the solenoid current. The FBC concept was extended using the virial theorem, which shows the theoretical lower limit of stress in the coils and their supporting structure. High-field coils should accordingly have the same averaged principal stresses in all directions, which is named the virial-limit condition. Since FBC winding is modulated to reduce the tilting force, the winding is slightly similar to but different from the shortest geodesic trajectory and has no tensile load. To apply FBC to high-temperature superconducting tapes, the degradation of superconducting properties originating from edgewise bending strain is an important problem. Since the geodesic trajectory is a kind of a straight line on a curved surface and curves only to the normal direction of the surface, it is expected that the tape with geodesic trajectories has a small residual stress. In this paper, we analyze the effect of the winding modulations including the geodesic modulation for the optimization of residual stress in helical windings

An Early-warning System for Electromagnetic Follow-up of Gravitational-wave Events

Binary neutron stars (BNSs) will spend ≃10–15 minutes in the band of Advanced Laser Interferometer Gravitational-Wave Observatory (LIGO) and Virgo detectors at design sensitivity. Matched-filtering of gravitational-wave (GW) data could in principle accumulate enough signal-to-noise ratio (S/N) to identify a forthcoming event tens of seconds before the companions collide and merge. Here we report on the design and testing of an early-warning GW detection pipeline. Early-warning alerts can be produced for sources that are at low enough redshift so that a large enough S/N accumulates ~10–60 s before merger. We find that about 7% (49%) of the total detectable BNS mergers will be detected 60 s (10 s) before the merger. About 2% of the total detectable BNS mergers will be detected before merger and localized to within 100 deg² (90% credible interval). Coordinated observing by several wide-field telescopes could capture the event seconds before or after the merger. LIGO–Virgo detectors at design sensitivity could facilitate observing at least one event at the onset of merger