Electro-optic spatial decoding on the spherical-wavefront Coulomb fields of plasma electron sources.

Detections of the pulse durations and arrival timings of relativistic electron beams are important issues in accelerator physics. Electro-optic diagnostics on the Coulomb fields of electron beams have the advantages of single shot and non-destructive characteristics. We present a study of introducing the electro-optic spatial decoding technique to laser wakefield acceleration. By placing an electro-optic crystal very close to a gas target, we discovered that the Coulomb field of the electron beam possessed a spherical wavefront and was inconsistent with the previously widely used model. The field structure was demonstrated by experimental measurement, analytic calculations and simulations. A temporal mapping relationship with generality was derived in a geometry where the signals had spherical wavefronts. This study could be helpful for the applications of electro-optic diagnostics in laser plasma acceleration experiments.

Burst intensification by singularity emitting radiation in multi-stream flows.

Burst Intensification by Singularity Emitting Radiation (BISER) is proposed. Singularities in multi-stream flows of emitting media cause constructive interference of emitted travelling waves, forming extremely localized sources of bright coherent emission. Here we for the first time demonstrate this extreme localization of BISER by direct observation of nano-scale coherent x-ray sources in a laser plasma. The energy emitted into the spectral range from 60 to 100 eV is up to ~100 nJ, corresponding to ~1010 photons. Simulations reveal that these sources emit trains of attosecond x-ray pulses. Our findings establish a new class of bright laboratory sources of electromagnetic radiation. Furthermore, being applicable to travelling waves of any nature (e.g. electromagnetic, gravitational or acoustic), BISER provides a novel framework for creating new emitters and for interpreting observations in many fields of science.

Soft-x-ray harmonic comb from relativistic electron spikes.

We demonstrate a new high-order harmonic generation mechanism reaching the "water window" spectral region in experiments with multiterawatt femtosecond lasers irradiating gas jets. A few hundred harmonic orders are resolved, giving µJ/sr pulses. Harmonics are collectively emitted by an oscillating electron spike formed at the joint of the boundaries of a cavity and bow wave created by a relativistically self-focusing laser in underdense plasma. The spike sharpness and stability are explained by catastrophe theory. The mechanism is corroborated by particle-in-cell simulations.

Electron optical injection with head-on and countercrossing colliding laser pulses.

A high stability electron bunch is generated by laser wakefield acceleration with the help of a colliding laser pulse. The wakefield is generated by a laser pulse; the second laser pulse collides with the first pulse at 180 degrees and at 135 degrees realizing optical injection of an electron bunch. The electron bunch has high stability and high reproducibility compared with single pulse electron generation. In the case of 180 degrees collision, special measures have been taken to prevent damage. In the case of 135 degrees collision, since the second pulse is countercrossing, it cannot damage the laser system.

Enhancement of photon number reflected by the relativistic flying mirror.

Laser light reflection by a relativistically moving electron density modulation (flying mirror) in a wake wave generated in a plasma by a high intensity laser pulse is investigated experimentally. A counterpropagating laser pulse is reflected and upshifted in frequency with a multiplication factor of 37-66, corresponding to the extreme ultraviolet wavelength. The demonstrated flying mirror reflectivity (from 3 x 10(-6) to 2 x 10(-5), and from 1.3 x 10(-4) to 0.6 x 10(-3), for the photon number and pulse energy, respectively) is close to the theoretical estimate for the parameters of the experiment.

Sub-MeV tunably polarized X-ray production with laser Thomson backscattering.

Reported in this article is the generation of unique polarized x-rays in the sub-MeV region by means of the Thomson backscattering of the Nd:YAG laser photon with a wavelength of 1064 nm on the 150 MeV electron from the microtron accelerator. The maximum energy of the x-ray photons is estimated to be about 400 keV. The total energy of the backscattered x-ray pulse is measured with an imaging plate and a LYSO scintillator. The angular divergence of the x-rays is also measured by using the imaging plate. We confirm that the x-ray beam is polarized according to the laser polarization direction with the Compton scattering method. In addition, we demonstrate the imaging of the object shielded by lead with the generated x-rays.

Demonstration of laser-frequency upshift by electron-density modulations in a plasma wakefield.

In a plasma wake wave generated by a high power laser, modulations of the electron density take the shape of paraboloidal dense shells, moving almost at the speed of light. A counterpropagating laser pulse is partially reflected from the shells, acting as relativistic flying mirrors, producing a time-compressed frequency-multiplied pulse due to the double Doppler effect. The counterpropagating laser pulse reflection from the plasma wake wave accompanied by its frequency multiplication (with a factor from 50 to 114) was detected in our experiment.

Estimation of photon dose generated by a short pulse high power laser.

The authors obtain a new equation to estimate the forward component of a photon dose generated through the interaction between a target and a short pulse high power laser. As the equation is quite simple, it is useful for calculating the photon dose. The equation shows that the photon dose is proportional to the electron temperature in the range>3 MeV and proportional to the square of the electron temperature in the range<3 MeV. The dose estimated with this method is roughly consistent with the result of Monte Carlo simulation. With some assumptions and corrections, it can reproduce experimental results obtained and the dose result calculated at other laboratories.

Burkholderia pickettii spondylitis.

STUDY DESIGN: Case report describing Burkholderia pickettii spondylitis in a healthy adult. OBJECTIVES: To describe this very rare form of spondylitis and to discuss some of the difficulties in the diagnosis of B. pickettii spondylitis. SETTING: Department of Orthopaedic Surgery, Nayoro City General Hospital, Japan. METHODS: A 48-year-old woman presented with a complaint of severe back pain radiating from the right side of her chest. Plain radiographs of the spine showed osteolytic destruction of the right side of the T10 vertebral body at T10 level, with an involvement of the pedicle. Magnetic resonance image of the spine showed a low signal intensity from the T10 vertebral body on a Tl-weighted image and an increased signal intensity on T2-weighted sequence image. These lesions were enhanced when a contrast medium was used. The patient underwent open biopsy and specimens were collected through the right pedicle. RESULTS: Diagnosis was established on the basis of direct identification of the microorganism. Histological findings were consistent with examination of B. pickettii spondylitis. Chemotherapy (intravenous cefepime and per os minocycline) resulted in complete cure. CONCLUSION: B. pickettii is widely distributed in aqueous sources in nature and has not previously been considered to be an aggressive pathogen towards humans. This case report will help to improve our understanding of the ecology and virulent pathogenicity of this organism. A biopsy is an essential and reliable method for the early etiologic diagnosis, which will lead to prevent the development of more severe complications such as spinal cord compression.

Electron acceleration by a nonlinear wakefield generated by ultrashort (23-fs) high-peak-power laser pulses in plasma.

We study experimentally the interaction of the shortest at present (23-fs) , relativistically intense (20-TW), tightly focused laser pulses with underdense plasma. MeV electrons constitute a two-temperature distribution due to different plasma wave-breaking processes at a plasma density of 10(20) cm(-3). These two groups of electrons are shown numerically to constitute bunches with very distinctive time durations.

Glucocorticoid-regulated expression of exogenous human growth hormone gene in rats.

The aim of this study was to control in vitro and in vivo expression of the growth hormone (GH) gene using a glucocorticoid-sensitive promoter, the mouse mammary tumor virus long terminal repeat (MMTV LTR). We inserted the cDNA encoding the 20-kDa form of human GH (20K-GH) downstream of the MMTV LTR of plasmid pMSG, and used lipofection to transfer it to 3Y1 cells together with plasmid pMX, which contains a puromycin-resistant element. The secretion of GH from the selected transformants was dose-dependently augmented by the application of hydrocortisone, corticosterone, or dexamethasone, among which dexamethasone was the most potent. Analysis of the time course showed that 20K-GH secretion began to increase within 2 hours after the addition of glucocorticoid and reached a maximal level of about threefold over the unstimulated control at 3 hours; secretion then gradually declined and returned to near basal levels at 19 hours. Repeated glucocorticoid application led to repeated increases in GH secretion. When GH-producing cells were microcapsulated and transplanted into the abdominal cavities of rats, 20K-GH was detected in the plasma under control conditions and increased about 3.3-fold after administration of dexamethasone. We suggest that GH expression driven by the MMTV LTR promoter may be under the control of an endogenous glucocorticoid in vivo.

Simultaneous determination of the HIV protease inhibitors indinavir, amprenavir, saquinavir, ritonavir and nelfinavir in human plasma by high-performance liquid chromatography.

A reversed-phase high-performance liquid chromatographic method for the simultaneous quantitative determination of five HIV protease inhibitors (i.e. indinavir, amprenavir, saquinavir, ritonavir and nelfinavir) in human plasma is described. An aliquot of 500 microl plasma was extracted with 0.5 ml of 0.1 M NH4OH and 5 ml of methyl tert.-butyl ether. After evaporating, the residue was dissolved in eluent mixture of acetonitrile and 50 mM KH2PO4 adjusted to pH 5.6 with 50 mM Na2HPO4 (43:57, v/v). Subsequently, the eluent was washed with hexane. Chromatography was performed using a C18 reversed-phase column. Ultraviolet detection at 215 nm was used. Linearity of the method was obtained in the concentration range of 0.05-20 microg ml(-1) for all five protease inhibitors. Our method is now in use to analyse plasma samples from patients treated with co-administration of HIV protease inhibitors.

Prediction of midazolam-CYP3A inhibitors interaction in the human liver from in vivo/in vitro absorption, distribution, and metabolism data.

The extent of decreases in apparent hepatic clearance and intrinsic hepatic clearance of midazolam (MDZ) after intravenous administration of MDZ with concomitant oral administration of cimetidine (CIM), itraconazole (ITZ), or erythromycin (EM) was predicted using plasma unbound concentrations and liver unbound concentrations of inhibitors. When MDZ was concomitantly administered with CIM, the observed increase in MDZ concentration was successfully predicted using inhibition constants assessed by human liver microsome and liver-to-plasma unbound concentration ratios in rats. However, the extent of interaction with ITZ or EM was still underestimated even taking into account the concentrative uptake of inhibitors into liver. We could predict the degree of "mechanism-based" inhibition by EM on the hepatic metabolism of MDZ, after repeated administration of EM, by a physiological model incorporating the amount of active enzyme as well as the concentration of inhibitor. The maximum inactivation rate constant and the apparent inactivation constant of EM on MDZ metabolism were 0.0665 min(-1) and 81.8 microM, respectively. These kinetic parameters for the inactivation of the enzyme were applied to the physiological model with pharmacokinetic parameters of EM and MDZ obtained from published results. Consequently, we estimated that cytochrome P450 3A4 in the liver after repeated oral administration of EM was inactivated, resulting in 2.6-fold increase in the plasma concentration of MDZ. The estimated extent of increase in MDZ concentration in our study correlated well with the observed value based on metabolic inhibition by EM from published results.

Effect of anti-inflammatory bowel disease drug, E3040, on urate transport in rat renal brush border membrane vesicles.

To confirm the assumption that 6-hydroxy-5, 7-dimethyl-2-methylamino-4-(3-pyridylmethyl)benzothiazole (E3040) acts on urate reabsorption by inhibiting urate-anion exchange at the luminal membrane of renal tubules, we investigated the inhibitory effect of E3040 and its two conjugated metabolites on hydroxyl ion (OH(-)) gradient-dependent urate uptake into brush border membrane vesicles from rat renal cortex and compared it with other uricosuric agents. The order of potency was AA193 (5-chloro-7, 8-dihydro-3-phenylfuro[2,3-g]-1,2-benzisoxazole-7-carboxylic acid)>benzbromarone>E3040>probenecid>E3040 sulfate>E3040 glucuronide. Furthermore, kinetic analysis revealed that E3040 may be a competitive inhibitor of the OH(-) gradient-dependent uptake of urate into brush border membrane vesicles.

Comparative pharmacodynamic analysis of Q-T interval prolongation induced by the macrolides clarithromycin, roxithromycin, and azithromycin in rats.

In order to evaluate the arrhythmogenic potency of macrolide antibiotics in a quantitative manner, we analyzed the influence of clarithromycin (CAM), roxithromycin (RXM), and azithromycin (AZM) on Q-T intervals from pharmacokinetic and pharmacodynamic points of view and in comparison with the potency of erythromycin (EM) previously reported by us for rats. Male Sprague-Dawley rats were anesthetized, and CAM (6.6, 21.6, and 43.2 mg/kg of body weight/h), RXM (20 and 40 mg/kg/h), and AZM (40 and 100 mg/kg/h) were intravenously injected for 90 min to obtain the time courses of drug concentrations in plasma and the changes in the Q-T intervals during and after the drug injections. Distinct Q-T interval prolongation of up to 10 ms was observed with CAM at its clinical concentrations. RXM and AZM evoked Q-T interval prolongation at concentrations higher than their clinical ranges. The potencies for Q-T interval prolongation, assessed as the slope of the concentration-response relationship, were 6.09, 0.536, and 0.989 ms. ml/microg for CAM, RXM, and AZM, respectively. There was hysteresis between the change in the Q-T intervals and the time course of the plasma concentration of each drug. The rank order of clinical arrhythmogenicity was estimated to be EM > CAM > RXM > AZM, as assessed from the present results and our previous report for EM. In conclusion, RXM and AZM were estimated to be less potent at provoking arrhythmia than EM and CAM. These results should be useful for making a safer choice of an appropriate agent for patients with electrocardiographic risk factors.

Determination of erythromycin, clarithromycin, roxithromycin, and azithromycin in plasma by high-performance liquid chromatography with amperometric detection.

In this study, a high-performance liquid chromatographic method was developed for the quantitative determination of erythromycin (EM), roxithromycin (RXM), and azithromycin (AZM) in rat plasma with amperometric detection under a standardized common condition using clarithromycin (CAM) as an internal standard. This method was also proved to be applicable for the determination of CAM by employing RXM as an internal standard. Each drug was extracted from 150 microl of plasma sample spiked with internal standard under an alkaline condition with tert.-butyl methyl ether. The detector cell potential for the oxidation of the drugs was set at +950 mV. The linearity of the calibration curves were preserved over the concentration ranges of 0.1-10 microg/ml for EM and RXM, and 0.03-3.0 microg/ml for CAM and AZM. Coefficients of variation and relative error were less than 9% and +/-7%, respectively. The analytical method presented here was proved to be useful for the investigation of the pharmacokinetic characteristics of EM, CAM, RXM, and AZM in rats.

Influence of extracellular K+ concentrations on quinidine-induced K+ current inhibition in rat ventricular myocytes.

Hypokalaemia is one of the important risk factors for development of torsades de pointes. We recently reported that hypokalaemia increased the electrocardiographic QT interval in rats treated with quinidine, but did not alter the arrhythmogenic potency of quinidine. In this study, we have investigated the influence of extracellular potassium concentration ([K+]o) on the inhibition of several types of cardiac potassium currents by quinidine. Such types of currents include the delayed rectifier potassium current (I(K)), the transient outward current (Ito), and the inward rectifier potassium current (I(K1)), as measured in isolated rat ventricular cells using patch-clamp techniques. Concentration-dependent effects of quinidine on I(K), Ito, and I(K1) were evaluated under both normal ([K+]o = 5.4 mM) and hypokalaemic ([K+]o = 3.5 mM) conditions. In contrast to both I(K) and Ito, which were barely influenced by changes in [K+]o, I(K1) was significantly inhibited by hypokalaemia. Furthermore, while quinidine suppressed both I(K) and Ito in a concentration-dependent manner, the inhibitory potency of quinidine on these currents was not influenced by changes in [K+]o. The respective normal and hypokalaemic IC50 values for quinidine were 11.4 and 10.0 microM (I(K)), and 17.6 and 17.3 microM (Ito). Although higher concentrations of quinidine were required to inhibit I(K1), the inhibitory potency of quinidine was also found to be insensitive to changes in [K+]o. Thus, in rats, the inhibitory potency of quinidine for the K+ current-types I(K), Ito and I(K1) is barely influenced by changes in [K+]o. These findings are consistent with our previous report showing that the QT-prolonging potency of quinidine was not altered under hypokalaemic conditions. However, whilst hypokalaemia does not affect I(K) or Ito, it can inhibit I(K1) and can result in QT prolongation in-vivo.

Quantitative prediction of metabolic inhibition of midazolam by erythromycin, diltiazem, and verapamil in rats: implication of concentrative uptake of inhibitors into liver.

To evaluate the degree of drug-drug interaction concerning metabolic inhibition in the liver quantitatively, we tried to predict the plasma concentration increasing ratio (R) of midazolam (MDZ) by erythromycin (EM), diltiazem (DLZ), or verapamil (VER) in rats. MDZ was administered through the portal vein at the steady state of plasma concentration of these inhibitors. The R values in the area under the plasma concentration curve of MDZ in the presence of EM, DLZ, and VER were 2.02, 1.64, and 1.30, respectively. The liver to plasma unbound concentration ratios of EM, DLZ, and VER at the steady state after infusion were 20.8, 1.02, and 3.01, respectively, suggesting concentrative uptake of EM and VER into the liver. The predicted R value in the presence of EM calculated by use of plasma unbound concentration was 1.03, whereas the value calculated with liver unbound concentration was 1.61, which was very close to the observed value. These findings indicated the need to consider the concentrative uptake of inhibitors into the liver for the quantitative prediction of metabolic inhibition. However, the predicted values in the presence of DLZ or VER calculated by use of liver unbound concentration were still underestimated. This result may be due to the metabolic inhibition by the metabolites of both inhibitors. Therefore, when predicting the degree of metabolic inhibition quantitatively, the inhibitory effect by coadministered drugs and the disposition of these metabolites in the liver must also be considered.

Optical guidance of terrawatt laser pulses by the implosion phase of a fast Z-pinch discharge in a gas-filled capillary.

A new method of optical guidance by the implosion phase of a fast Z-pinch discharge in a gas-filled capillary is proposed. An imploding plasma column has a concave electron-density profile in the radial direction, just before a stagnation phase driven by a converging current sheet and a shock wave. The feasibility of optical guidance of a high-intensity (>1 x 10(17) W/cm(2)) Ti:sapphire laser pulse by use of this method over a distance of 2 cm, corresponding to 12.5 times the Rayleigh length, has been experimentally demonstrated. The guiding-channel formation process was directly probed with a He-Ne laser beam. The electron density in the fully ionized channel was estimated to be 2.0 x 10(17) cm(-3) on the axis and 7.0 x 10(17) cm(-3) on the peaks of the channel edge, with a diameter of 70 mum, as indicated by the experimental results, which were corroborated by a magnetohydrodynamics simulation.