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A realistic X‐ray energy spectrum is essential for accurate dose calculation using the Monte Carlo (MC) algorithm. An energy spectrum for dose calculation in the radiation treatment planning system is modeled using the MC algorithm and adjusted to obtain acceptable agreement with the measured percent depth dose (PDD) and off‐axis ratio. The simulated energy spectrum may not consistently reproduce a realistic energy spectrum. Therefore, direct measurement of the X‐ray energy spectrum from a linac is necessary to obtain a realistic spectrum. Previous studies have measured low photon fluence directly, but the measurement was performed with a nonclinical linac with a thick target and a long target‐to‐detector distance. In this study, an X‐ray energy spectrum from a clinical linac was directly measured using a NaI(Tl) scintillator at an ultralow dose rate achieved by adjusting the gun grid voltage. The measured energy spectrum was unfolded by the Gold algorithm and compared with a simulated spectrum using statistical tests. Furthermore, the PDD was calculated using an unfolded energy spectrum and a simulated energy spectrum was compared with the measured PDD to evaluate the validity of the unfolded energy spectrum. Consequently, there was no significant difference between the unfolded and simulated energy spectra by nonparametric, Wilcoxon's rank‐sum, chi‐square, and two‐sample Kolmogorov–Smirnov tests with a significance level of 0.05. However, the PDD calculated from the unfolded energy spectrum better agreed with the measured compared to the calculated PDD results from the simulated energy spectrum. The adjustment of the incident electron parameters using MC simulation is sensitive and takes time. Therefore, it is desirable to obtain the energy spectrum by direct measurement. Thus, a method to obtain the realistic energy spectrum by direct measurement was proposed in this study. [ABSTRACT FROM AUTHOR]

Purpose: Ionization chambers are widely used for dosimetry with megavoltage photon beams. Several properties of ionization chambers, including the cable effect, polarity effect, and ion recombination loss, are described in standard dosimetry protocols. The cable effect is categorized as the leakage current and Compton current, and careful consideration of these factors has been described not only in reference dosimetry but also in large fields. However, the mechanism of Compton current in the cable has not been investigated thoroughly. The cable effect of ionization chambers in 6 MV X‐ray beam was evaluated by measurement, and the mechanism of Compton current was investigated by Monte Carlo simulation. Materials and Methods: Four PTW ionization chambers (TM30013, TM31010, TM31014, and TM31016) with the same type of mounted cable, but different ionization volumes, were used to measure output factor (OPF) and cable effect measurement. The OPF was measured to observe any variation resulting from the cable effect. The cable effect was evaluated separately for the leakage current and Compton current, and its charge per absorbed dose to water per cable length was estimated by a newly proposed method. The behavior of electrons and positrons in the core wire was analyzed and the Compton current for the photon beam was estimated by Monte Carlo simulation. Results: In OPF measurement, the difference in the electrometer readings by polarity became obvious for the mini‐ or microchamber and its difference tended to be larger for a chamber with a smaller ionization volume. For the cable effect measurement, it was determined that the contribution of the leakage current to the cable effect was ignorable, while the Compton current was dominant. The charge due to the Compton current per absorbed dose to water per cable length was estimated to be 0.36 ± 0.03 pC Gy−1 cm−1 for PTW ionization chambers. As a result, the contribution of the Compton current to the electrometer readings was estimated to be 0.002% cm−1 for the Farmer‐type, 0.011% cm−1 for the scanning, and 0.088% cm−1 for microchambers, respectively. By the simulation, it was determined that the Compton current for MV x‐ray could be explained by not only recoil electrons due to Compton scattering but also positron due to pair production. The Compton current estimated by the difference in outflowing and inflowing charge was 0.45 pC Gy−1 cm−1 and was comparable with the measured value. Conclusion: The cable effect, which includes the leakage current and Compton current, was quantitatively estimated for several chambers from measurements, and the mechanism of Compton current was investigated by Monte Carlo simulation. It was determined that the Compton current is a dominant component of the cable effect and its charge is consistently positive and nearly the same, irrespective of the ionization chamber volume. The contribution of Compton current to the electrometer readings was estimated for chambers. The mechanism of Compton current was analyzed and it was confirmed that the Compton current can be estimated from the difference in outflowing and inflowing charge to and from the core wire. [ABSTRACT FROM AUTHOR]

The coloration is one kind of interesting and important properties of diamond‐like carbon (DLC) films, but lack of in‐depth study. The micro/nanostructure composition of material determines its macroscopic properties. Here, the Commission Internationale de I'Eclairage (CIE) color space, quantitative micro/nanostructure composition analysis, and ab initio molecular‐dynamics simulations are used to quantitatively analyze the generation mechanism for coloration of DLC films. It is found that as a typical amorphous thin film, the generation of DLC film coloration can be explained by the thin film interference and amorphous photonic crystal structural color theory, but the generation mechanisms of coloration for different types of DLC films are not the same. The micro/nanostructure in terms of hydrogen content and carbon atom state plays vital roles in the generation of DLC film structural colors and even determines whether the noniridescent structure color exists or not. These results demonstrate the possibility of utilizing the human eyes to directly distinguish different types of DLC films and accelerate the application of DLC film in energy saving, optical filter, sensor, color gradient coating, advanced luxury products, and bionics fields. [ABSTRACT FROM AUTHOR]

Purpose: The ICRU has published new recommendations for ionizing radiation dosimetry. In this work, the effect of recommendations on the water‐to‐air and graphite‐to‐air restricted mass electronic stopping power ratios (sw, air and sg, air) and the individual perturbation correction factors Pi was calculated. The effect on the beam quality conversion factors kQ for reference dosimetry of high‐energy photon beams was estimated for all ionization chambers listed in the Addendum to AAPM's TG‐51 protocol. Methods: The sw, air, sg, air, individual Pi, and kQ were calculated using EGSnrc Monte Carlo code system and key data of both ICRU report 37 and ICRU report 90. First, the Pi and kQ were calculated using precise models of eight ionization chambers: NE2571 (Nuclear Enterprise), 30013, 31010, 31021 (PTW), Exradin A12, A12S, A1SL (Standard imaging), and FC‐65P (IBA). In this simulation, the radiation sources were one 60Co beam and ten photon beams with nominal energy between 4 MV and 25 MV. Then, the change in kQ for ionization chambers listed in the Addendum to AAPM's TG‐51 protocol was calculated by changing the specification of the simple‐model of ionization chamber. The simple‐models were made with only cylindrical component modules. In this simulation, the radiation sources of 60Co beam and 24 MV photon beam were used. Results: The significant changes (p < 0.05) were observed for sw, air, sg, air, the wall correction factor Pwall, and the waterproofing sleeve correction factor Psleeve. The decrease in sw, air varied from −0.57% for a 60Co beam to −0.36% for the highest beam quality. The decrease in sg, air varied from −0.72% to −1.12% in the same range. The changes in Pwall and Psleeve were up to 0.41% and 0.14% and those maximum changes were observed for the 60Co beam. All changes in the central electrode correction factor Pcel, the stem correction factor Pstem, and the replacement correction factor Prepl were from −0.02% to 0.12%. Those changes were statistically insignificant (p = 0.07 or more) and were independent of photon energy. The change in kQ was mainly characterized by the change in sw, air, Pwall, and Psleeve. The relationship between the change in kQ and the beam quality index was linear approximately. The changes in kQ of the simple‐models were agreed with those of the precise‐models within 0.08%. Conclusion: The effects of ICRU‐90 recommendations on kQ for the ionization chambers listed in the Addendum to AAPM's TG‐51 protocol were from −0.15% to 0.30%. To remove the known systematic effect on the clinical reference dosimetry, the kQ based on ICRU‐37 should be updated to the kQ based on ICRU‐90. [ABSTRACT FROM AUTHOR]

Oxaliplatin, which is widely used as chemotherapy for certain solid cancers, frequently causes peripheral neuropathy. Commonly described neuropathic symptoms include aberrant sensations such as mechanical allodynia (hypersensitivity to normally innocuous stimuli). Although oxaliplatin neuropathy is a dose‐limiting toxicity, there are no established preventive strategies available at present. By screening several sets of small‐molecule chemical libraries (more than 3,000 compounds in total) using a newly established in vitro high‐throughput phenotypic assay, we identified fulvestrant, a clinically approved drug for the treatment of breast cancer in postmenopausal women, as having a protective effect on oxaliplatin‐induced neuronal damage. Furthermore, histological and behavioural analyses using a rat model of oxaliplatin neuropathy demonstrated the in vivo efficacy of fulvestrant to prevent oxaliplatin‐induced axonal degeneration of the sciatic nerve and mechanical allodynia. Furthermore, fulvestrant did not interfere with oxaliplatin‐induced cytotoxicity against cancer cells. Thus, our findings reveal a previously unrecognised pharmacological effect of fulvestrant to prevent oxaliplatin‐induced painful peripheral neuropathy without impairing its cytotoxicity against cancer cells and may represent a novel prophylactic option for patients receiving oxaliplatin chemotherapy. What's new? The anti‐cancer drug oxaliplatin frequently causes severe peripheral neuropathy. Although oxaliplatin neuropathy is a dose‐limiting toxicity, there are no established preventive strategies currently available. Using several sets of small‐molecule chemical libraries (more than 3,000 compounds in total), here the authors identified fulvestrant, a clinically approved drug for breast cancer, as having a previously unrecognised preventive effect against oxaliplatin‐induced peripheral neuropathy. Fulvestrant thus attenuated oxaliplatin‐induced neurodegeneration in both in vitro and in vivo models. Importantly, fulvestrant did not impede oxaliplatin‐induced cytotoxicity against cancer cells, raising the possibility that fulvestrant may be useful as a novel prophylactic drug against oxaliplatin‐induced peripheral neuropathy. [ABSTRACT FROM AUTHOR]

Respiratory‐gated volumetric modulated arc therapy (gated VMAT) involves further complexities to the dose delivery process because the gantry rotation must repeatedly stop and restart according to the gating signals. In previous studies, the gantry rotation performances were evaluated by the difference between the plan and the machine log. However, several reports pointed out that log analysis does not sufficiently replicate the machine performance. In this report, a measurement‐based quality assurance of the relation between the gantry angle and gate‐on or gate‐off using triggered kilovoltage imaging and a cylinder phantom with 16 ball bearings is proposed. For the analysis, an in‐house program that estimates and corrects the phantom offset was developed. The gantry angle in static and gated arc delivery was compared between the machine log and the proposed method. The gantry was set every 5 deg through its full motion range in static delivery, and rotated at three speeds (2, 4 and 6 deg s‐1) with different gating intervals (1.5 or 3.0 s) in gated arc delivery. The mean and standard deviation of the angular differences between the log and the proposed method was −0.05 deg ± 0.12 deg in static delivery. The mean of the angular difference was within ±0.10 deg and the largest difference was 0.41 deg in gated arc delivery. The log records the output of the encoder so that miscalibration and mechanical sagging will be disregarded. However, the proposed method will help the users to detect the mechanical issues due to the repeated gantry stops and restarts in gated VMAT. [ABSTRACT FROM AUTHOR]

Y2O3 films were synthesized on an aluminum alloy (A5052) substrate directly using a flame‐spray apparatus with a H2‐O2 flame. The Y2O3/A5052 joining was also annealed under atmospheric conditions. Although the joining was annealed close to the melting point of the A5052 substrate, the joining showed strong adhesion without delaminations. The resultant Y2O3 coating exhibits a strong adhesion with the aluminum alloy substrate. Elemental diffusion in the joining was not observed from cross‐sectional EDX analysis. Directly ceramic film deposition method by a reactive spraying process was proposed. Cross‐sectional EDX images of the films synthesized on the A5052 substrates, (a) as‐synthesized, (b) after annealing at 400°C for 1 h, (c) after annealing at 500°C for 1 h, (d) after annealing at 600° C for 1 h [ABSTRACT FROM AUTHOR]

Abstract: In this study, the optimum density scaling factors of phantom materials for a commercially available three‐dimensional (3D) dose verification system (Delta4) were investigated in order to improve the accuracy of the calculated dose distributions in the phantom materials. At field sizes of 10 × 10 and 5 × 5 cm2 with the same geometry, tissue‐phantom ratios (TPRs) in water, polymethyl methacrylate (PMMA), and Plastic Water Diagnostic Therapy (PWDT) were measured, and TPRs in various density scaling factors of water were calculated by Monte Carlo simulation, Adaptive Convolve (AdC, Pinnacle3), Collapsed Cone Convolution (CCC, RayStation), and AcurosXB (AXB, Eclipse). Effective linear attenuation coefficients (μeff) were obtained from the TPRs. The ratios of μeff in phantom and water ((μeff)pl,water) were compared between the measurements and calculations. For each phantom material, the density scaling factor proposed in this study (DSF) was set to be the value providing a match between the calculated and measured (μeff)pl,water. The optimum density scaling factor was verified through the comparison of the dose distributions measured by Delta4 and calculated with three different density scaling factors: the nominal physical density (PD), nominal relative electron density (ED), and DSF. Three plans were used for the verifications: a static field of 10 × 10 cm2 and two intensity modulated radiation therapy (IMRT) treatment plans. DSF were determined to be 1.13 for PMMA and 0.98 for PWDT. DSF for PMMA showed good agreement for AdC and CCC with 6 MV x ray, and AdC for 10 MV x ray. DSF for PWDT showed good agreement regardless of the dose calculation algorithms and x‐ray energy. DSF can be considered one of the references for the density scaling factor of Delta4 phantom materials and may help improve the accuracy of the IMRT dose verification using Delta4. [ABSTRACT FROM AUTHOR]

Purpose: We evaluated the energy responses of a radiophotoluminescent glass dosimeter (RPLD) to variations in small‐field and intensity‐modulated radiation therapy (IMRT) conditions using experimental measurements and Monte Carlo simulation. Methods: Several sizes of the jaw and multileaf collimator fields and various plan‐class IMRT‐beam measurements were performed using the RPLD and an ionization chamber. The field‐size correction factor for the RPLD was determined for 6‐ and 10‐MV x rays. This correction factor, together with the perturbation factor, was also calculated using Monte Carlo simulation with the EGSnrc/egs_chamber user code. In addition, to evaluate the response of the RPLD to clinical‐class‐specific reference fields, the field‐size correction factor for the clinical IMRT plan was measured. Results: The calculated field‐size correction factor ranged from 1.007 to 0.981 (for 6‐MV x rays) and from 1.012 to 0.990 (for 10‐MV x rays) as the jaw‐field size ranged from 1 × 1 cm2 to 20 × 20 cm2. The atomic composition perturbation factor for these jaw fields decreased by 3.2% and 1.9% for the 6‐ and 10‐MV fields, respectively. The density perturbation factor was unity for field sizes ranging from 3 × 3 cm2 to 20 × 20 cm2, whereas that for field sizes ranging from 3 × 3 cm2 to 1 × 1 cm2 decreased by 3.2% (for 6‐MV x rays) and 4.3% (for 10‐MV x rays). The volume‐averaging factor rapidly increased for field sizes below 1.6 × 1.6 cm2. The results for the MLC fields were similar to those for the jaw fields. For plan‐class IMRT beams, the field‐size correction and perturbation factors were almost unity. The difference between the doses measured using the RPLD and ionization chamber was within 1.2% for the clinical IMRT plan at the planning‐target volume (PTV) region. Conclusions: For small fields of size 1.6 × 1.6 cm2 or less, it was clarified that the volume averaging and density perturbation were the dominant effects responsible for the variation in the RPLD response. Moreover, perturbation correction is required when measuring a field size 1.0 × 1.0 cm2 or less. Under the IMRT conditions, the difference in the responses of the RPLD between the reference conditions and the PTV region calculated by Monte Carlo simulation did not exceed 0.8%. These results indicate that it is feasible to measure IMRT dosage using an RPLD at the PTV region. [ABSTRACT FROM AUTHOR]

For patient setup of the IGRT technique, various imaging systems are currently available. MV portal imaging is performed in identical geometry with the treatment beam so that the portal image provides accurate geometric information. However, MV imaging suffers from poor image contrast due to larger Compton scatter photons. In this work, an original image processing algorithm is proposed to improve and enhance the image contrast without increasing the imaging dose. Scatter estimation was performed in detail by MC simulation based on patient CT data. In the image processing, scatter photons were eliminated and then they were reprojected as primary photons on the assumption that Compton interaction did not take place. To improve the processing efficiency, the dose spread function within the EPID was investigated and implemented on the developed code. Portal images with and without the proposed image processing were evaluated by the image contrast profile. By the subtraction process, the image contrast was improved but the EPID signal was weakened because 15.2% of the signal was eliminated due to the contribution of scatter photons. Hence, these scatter photons were reprojected in the reprojection process. As a result, the tumor, bronchi, mediastinal space and ribs were observed more clearly than in the original image. It was clarified that image processing with the dose spread functions provides stronger contrast enhancement while maintaining a sufficient signal-to-noise ratio. This work shows the feasibility of improving and enhancing the contrast of portal images. [ABSTRACT FROM AUTHOR]

Microglia are widely accepted as surveillants in the central nervous system that are continually searching the local environment for signs of injury. Following an inflammatory situation, microglia alter their morphology, extend ramified processes, and undergo cell body hypertrophy. Extracellular nucleotides are recognized as a danger signal by microglia. ADP acting on P2Y12 receptors induce process extension of microglia thereby attracting microglia to the site of adenosine tri-phosphate/ ADP leaking or release. However, the question whether ADP/P2Y12 receptor signaling directly stimulates the production or release of inducible factors such as cytokines remains unclear. In this study, we found that CC chemokine ligand 3 ( CCL3) is induced by ADP-treated primary microglia. Pharmacological characterization using pertussis toxin, a P2Y12 receptor inhibitor, and a calcium chelator revealed that CCL3 induction was caused by P2Y12 receptor-mediated intracellular calcium elevation. Next, nuclear factor of activated T-cell dephosphorylation and nuclear translocalization were observed. Calcineurin, an inhibitor for nuclear factor of activated T cell, suppressed CCL3 induction. These data indicate that microglial P2Y12 receptors are utilized to trigger an acute inflammatory response in microglia via rapid CCL3 induction after ADP stimulation. [ABSTRACT FROM AUTHOR]

The luminescence properties of strontium aluminate (Sr-Al-O) phosphors change strongly depending on the starting metal composition ratio of strontium oxide (SrO) and alumina (Al2O3). In this study, the starting metal composition effect on blue Sr-Al-O:Eu2+ phosphor synthesized on single crystalline magnesia (MgO) was investigated. The crystal structure and the emission property of the obtained Sr-Al-O:Eu2+ blue phosphors, were independent of the Al2O3/SrO ratio in the raw material. In addition, the obtained emission phases were not contained Al atom. These results indicated the correct starting metal composition for the blue phosphor synthesized on MgO is SrO:Eu. (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim) [ABSTRACT FROM AUTHOR]

A violet divalent europium-doped strontium aluminate ( Sr- Al- O: Eu2+) phosphor particle was synthesized from a metal-ethylenediaminetetraacetic acid ( EDTA) solution of Sr, Al, Eu, and particulate alumina via spray drying and sintering in a reducing atmosphere. The emission properties, crystal structures, cross-sectional emissions, and elemental distributions of the obtained Sr- Al- O: Eu2+ phosphor particles were investigated. The product was determined to be secondary Sr Al12 O19: Eu2+ particles with an average diameter of 20 μm. The violet Sr Al12 O19: Eu2+ emission phase was found in a 1-μm-thick coating of the particles where elemental Al diffusion occurred. These particles are anticipated to find commercial applications such as paints. [ABSTRACT FROM AUTHOR]

Purpose: Microdosimetry has been developed for the evaluation of radiation quality, and single-event dose-mean lineal energy yD is well-used to represent the radiation quality. In this study, the changes of the relative biological effectiveness (RBE) values under the therapeutic conditions using a 6 MV linac were investigated with a microdosimetric method. Methods: The yD values under the various irradiation conditions for x-rays from a 6 MV linac were measured with a tissue-equivalent proportional counter (TEPC) at an extremely low dose rate of a few tens of μGy/min by decreasing the gun grid voltage of the linac. According to the microdosimetric kinetic model (MK model), the RBEMK values for cell killing of the human salivary gland (HSG) tumor cells can be derived if the yD values are obtained from TEPC measurements. The Monte Carlo code GEANT4 was also used to calculate the photon energy distributions and to investigate the changes of the yD values under the various conditions. Results: The changes of the yD values were less than approximately 10% when the field size and the depth in a phantom varied. However, in the measurements perpendicular to a central beam axis, large changes were observed between the yD values inside the field and those outside the field. The maximum increase of approximately 50% in the yD value outside the field was obtained compared with those inside the field. The GEANT4 calculations showed that there existed a large relative number of low energy photons outside of the field as compared with inside of the field. The percentages of the photon fluences below 200 keV outside the field were approximately 40% against approximately 8% inside the field. By using the MK model, the field size and the depth dependence of the RBEMK values were less than approximately 2% inside the field. However, the RBEMK values outside the field were 6.6% higher than those inside the field. Conclusions: The increase of the RBEMK values by 6.6% outside the field was observed. This increase is caused by the change of the photon energy distributions, especially the increase of the relative number of low energy photons outside the field. [ABSTRACT FROM AUTHOR]

J. Neurochem. (2010) 114, 810–819. Microglia plays an important role in many neurodegenerative conditions. ATP leaked or released by damaged cells triggers microglial activation through P2 receptors, and stimulates the release of oxygen radicals, proinflammatory cytokines and chemokines from activated microglia. However, little is known about mechanisms underlying ATP-induced chemokine release from microglia. In this study, we found that a high concentration of ATP induces the mRNA expression and release of CXCL2 from microglia. A similar effect was observed following treatment of microglia with a P2X7 receptor (P2X7R) agonist, 2′-and 3′- O-(4-benzoylbenzoyl) ATP, and this was inhibited by pre-treatment with a P2X7R antagonist, Brilliant Blue G. ATP induced both activation of nuclear factor of activated T cells (NFAT) and MAPKs (p38, ERK, and JNK) through P2X7R. ATP-induced mRNA expression of CXCL2 was inhibited by INCA-6 (an NFAT inhibitor), SB203580 (a p38 inhibitor), U0126 (a MEK-ERK inhibitor) and JNK inhibitor II (a JNK inhibitor). However, MAPK inhibitors did not inhibit activation of NFAT. In addition, protein kinase C inhibitors suppressed ATP-induced ERK and JNK activation, and also inhibited ATP-induced CXCL2 expression in microglia. These results suggest that ATP increased CXCL2 production via both NFAT and protein kinase C/MAPK signaling pathways through P2X7 receptor stimulation in microglia. [ABSTRACT FROM AUTHOR]

Microglia are resident immune cells in the central nervous system that become activated and produce pro-inflammatory and neurotrophic factors upon activation of various cell-surface receptors. The P2X4 receptor (P2X4R) is a sub-type of the purinergic ion-channel receptors expressed in microglia. P2X4R expression is up-regulated under inflammatory or neurodegenerative conditions, and this up-regulation is implicated in disease pathology. However, the molecular mechanism underlying up-regulation of P2X4R in microglia remains unknown. In the present study, we investigated the intracellular signal transduction pathway that promotes P2X4R expression in microglia in response to fibronectin, an extracellular matrix protein that has previously been shown to stimulate P2X4R expression. We found that in fibronectin-stimulated microglia, activation of phosphatidylinositol 3-kinase (PI3K)–Akt and mitogen-activated protein kinase kinase (MAPK kinase, MEK)–extracellular signal-regulated kinase (ERK) signalling cascades occurred divergently downstream of Src-family kinases (SFKs). Pharmacological interference of PI3K–Akt signalling inhibited fibronectin-induced P2X4R gene expression. Activation of PI3K–Akt signalling resulted in a decrease in the protein level of the transcription factor p53 via mouse double minute 2 (MDM2), an effect that was prevented by MG-132, an inhibitor of the proteasome. In microglia pre-treated with MG-132, fibronectin failed to up-regulate P2X4R expression. Conversely, an inhibitor of p53 caused increased expression of P2X4R, implying a negative regulatory role of p53. On the other hand, inhibiting MEK–ERK signalling activated by fibronectin suppressed an increase in P2X4R protein but interestingly did not affect the level of P2X4R mRNA. We also found that fibronectin stimulation resulted in the activation of the translational factor eIF4E via MAPK-interacting protein kinase-1 (MNK1) in an MEK–ERK signalling-dependent manner, and an MNK1 inhibitor attenuated the increase in P2X4R protein. Together, these results suggest that the PI3K–Akt and MEK–ERK signalling cascades have distinct roles in the up-regulation of P2X4R expression in microglia at transcriptional and post-transcriptional levels, respectively. [ABSTRACT FROM AUTHOR]

Microglia are implicated as a source of diverse proinflammatory factors in the CNS. Extracellular nucleotides are well known to be potent activators of glial cells and trigger the release of cytokines from microglia through purinergic receptors. However, little is known about the role of purinoceptors in microglial chemokine release. In this study, we found that high concentrations of ATP evoked release of CC-chemokine ligand 3 (CCL3)/macrophage inflammatory protein-1α from MG-5 cells, a mouse microglial cell line, and rapid up-regulation of CCL3 mRNA was elicited within 30 min of ATP stimulation. The release of CCL3 was also stimulated by 2′- and 3′- O-(4-benzoylbenzoyl) ATP, an agonist of P2X7 receptors. Brilliant Blue G, an antagonist of P2X7 receptors, strongly inhibited this ATP-induced CCL3 release. Similar pharmacological profile was observed in primary microglia. In MG-5 cells, ATP caused de-phosphorylation and nuclear translocation of the transcription factor nuclear factor of activated T cells (NFAT). ATP-induced NFAT de-phosphorylation was also dependent on P2X7 receptor activation. Furthermore, ATP-induced CCL3 release and production were prevented by a selective inhibitor of NFAT. Taken together, the results of this study demonstrate an involvement of NFAT in the mechanism underlying P2X7 receptor-mediated CCL3 release. [ABSTRACT FROM AUTHOR]

This article is intended to improve the certainty of the absorbed dose determination for reference dosimetry in CyberKnife beams. The CyberKnife beams do not satisfy some conditions of the standard reference dosimetry protocols because of its unique treatment head structure and beam collimating system. Under the present state of affairs, the reference dosimetry has not been performed under uniform conditions and the beam quality correction factor kQ for an ordinary 6 MV linear accelerator has been temporally substituted for the kQ of the CyberKnife in many sites. Therefore, the reference conditions and kQ as a function of the beam quality index in a new way are required. The dose flatness and the error of dosimeter reading caused by radiation fields and detector size were analyzed to determine the reference conditions. Owing to the absence of beam flattening filter, the dose flatness of the CyberKnife beam was inferior to that of an ordinary 6 MV linear accelerator. And if the absorbed dose is measured with an ionization chamber which has cavity length of 2.4, 1.0 and 0.7 cm in reference dosimetry, the dose at the beam axis for a field of 6.0 cm collimator was underestimated 1.5%, 0.4%, and 0.2% on a calculation. Therefore, the maximum field shaped with a 6.0 cm collimator and ionization chamber which has a cavity length of 1.0 cm or shorter were recommended as the conditions of reference dosimetry. Furthermore, to determine the kQ for the CyberKnife, the realistic energy spectrum of photons and electrons in water was simulated with the BEAMnrc. The absence of beam flattening filter also caused softer photon energy spectrum than that of an ordinary 6 MV linear accelerator. Consequently, the kQ for ionization chambers of a suitable size were determined and tabulated as a function of measurable beam quality indexes in the CyberKnife beam. [ABSTRACT FROM AUTHOR]

Peripheral tissue injury causes the release of various mediators from damaged and inflammatory cells, which in turn activates and sensitizes primary sensory neurons and thereby produces persistent pain. The present study investigated the role of platelet-activating factor (PAF), a phospholipid mediator, in pain signaling using mice lacking PAF receptor ( pafr−/ − mice). Here we show that pafr−/ − mice displayed almost normal responses to thermal and mechanical stimuli but exhibit attenuated persistent pain behaviors resulting from tissue injury by locally injecting formalin at the periphery as well as capsaicin pain and visceral inflammatory pain without any alteration in cytoarchitectural or neurochemical properties in dorsal root ganglion (DRG) neurons and a defect in motor function. However, pafr−/ − mice showed no alterations in spinal pain behaviors caused by intrathecally administering agonists for N-methyl-d-aspartate (NMDA) and neurokinin1 receptors. A PAFR agonist evoked an intracellular Ca2+ response predominantly in capsaicin-sensitive DRG neurons, an effect was not observed in pafr−/ − mice. By contrast, the PAFR agonist did not affect C- or Aδ-evoked excitatory post-synaptic currents in substantia gelatinosa neurons in the dorsal horn. Interestingly, mice lacking PAFR showed reduced phosphorylation of extracellular signal-related protein kinase (ERK), an important kinase for the sensitization of primary sensory neurons, in their DRG neurons after formalin injection. Furthermore, U0126, a specific inhibitor of the ERK pathway suppressed the persistent pain by formalin. Thus, PAFR may play an important role in both persistent pain and the sensitization of primary sensory neurons after tissue injury. [ABSTRACT FROM AUTHOR]

Hypocholesterolemic effects in older animals after long-term feeding are unknown. Therefore, aged rats (24 wk of age) fed a conventional diet were shifted to diets containing 10% perilla oil [PEO; oleic acid+linoleic acid+α-linolenic acid; n−6/n−3, 0.3; polyunsaturated fatty acid/saturated fatty acid (P/S), 9.6], borage oil [oleic acid+linoleic acid+α-linolenic acid; n−6/n−3, 15.1; P/S, 5.3], evening primrose oil (FPO; linoleic acid+γ-linolenic acid; P/S, 10.5), mixed oil (MIO; oleic acid+linoleic acid+γ-linolenic acid+α-linolenic acid; n−6/n−3, 1.7; P/S, 6.7), or palm oil (PLO; palmitic acid+oleic acid+linoleic acid; n−6/n−3, 25.3; P/S, 0.2) with 0.5% cholesterol for 15 wk in this experiment. There were no significant differences in the food intake and body weight gain among the groups. The liver weight in the PEO (n−6/n−3, 0.3) group was significantly higher than those of other groups in aged rats. The serum total cholesterol and very low density lipoprotein (VLDL) +intermediate density lipoprotein (IDL)+low density lipoprotein (LDL)-cholesterol concentrations of the PLO (25.3) group were consistently higher than those in the other groups. The serum high density lipoprotein cholesterol concentrations of the PEO (0.3) and EPO groups were significantly lower than in the other groups at the end of the 15-wk feeding period. The liver cholesterol concentration of the PLO (25.3) group was significantly higher than those of other groups. There were no significant differences in the hepatic LDL receptor mRNA level among the groups. Hepatic apolipoprotein (apo) B mRNA levels were not affected by the experimental conditions. The fecal neutral steroid excretion of the PLO (25.3) group tended to be low compared to the other groups. The results of this study demonstrate that both n\t-6 fatty acid and n\t-3 fatty acids such as \gg-linolenic acid and \ga-linolenic acid inhibit the increase of serum total cholesterol and VLDL+IDL+LDL-cholesterol concentrations of aged rats in the presence of excess cholesterol in the diet compared with dietary saturated fatty acid. [ABSTRACT FROM AUTHOR]

Microglia are resident immune cells in the central nervous system that become activated and produce pro-inflammatory and neurotrophic factors upon activation of various cell-surface receptors. The P2X(4) receptor (P2X(4)R) is a sub-type of the purinergic ion-channel receptors expressed in microglia. P2X(4)R expression is up-regulated under inflammatory or neurodegenerative conditions, and this up-regulation is implicated in disease pathology. However, the molecular mechanism underlying up-regulation of P2X(4)R in microglia remains unknown. In the present study, we investigated the intracellular signal transduction pathway that promotes P2X(4)R expression in microglia in response to fibronectin, an extracellular matrix protein that has previously been shown to stimulate P2X(4)R expression. We found that in fibronectin-stimulated microglia, activation of phosphatidylinositol 3-kinase (PI3K)-Akt and mitogen-activated protein kinase kinase (MAPK kinase, MEK)-extracellular signal-regulated kinase (ERK) signalling cascades occurred divergently downstream of Src-family kinases (SFKs). Pharmacological interference of PI3K-Akt signalling inhibited fibronectin-induced P2X(4)R gene expression. Activation of PI3K-Akt signalling resulted in a decrease in the protein level of the transcription factor p53 via mouse double minute 2 (MDM2), an effect that was prevented by MG-132, an inhibitor of the proteasome. In microglia pre-treated with MG-132, fibronectin failed to up-regulate P2X(4)R expression. Conversely, an inhibitor of p53 caused increased expression of P2X(4)R, implying a negative regulatory role of p53. On the other hand, inhibiting MEK-ERK signalling activated by fibronectin suppressed an increase in P2X(4)R protein but interestingly did not affect the level of P2X(4)R mRNA. We also found that fibronectin stimulation resulted in the activation of the translational factor eIF4E via MAPK-interacting protein kinase-1 (MNK1) in an MEK-ERK signalling-dependent manner, and an MNK1 inhibitor attenuated the increase in P2X(4)R protein. Together, these results suggest that the PI3K-Akt and MEK-ERK signalling cascades have distinct roles in the up-regulation of P2X(4)R expression in microglia at transcriptional and post-transcriptional levels, respectively.