Proton beam quality enhancement by spectral phase control of a PW-class laser system.

We report on experimental investigations of proton acceleration from solid foils irradiated with PW-class laser-pulses, where highest proton cut-off energies were achieved for temporal pulse parameters that varied significantly from those of an ideally Fourier transform limited (FTL) pulse. Controlled spectral phase modulation of the driver laser by means of an acousto-optic programmable dispersive filter enabled us to manipulate the temporal shape of the last picoseconds around the main pulse and to study the effect on proton acceleration from thin foil targets. The results show that applying positive third order dispersion values to short pulses is favourable for proton acceleration and can lead to maximum energies of 70 MeV in target normal direction at 18 J laser energy for thin plastic foils, significantly enhancing the maximum energy compared to ideally compressed FTL pulses. The paper further proves the robustness and applicability of this enhancement effect for the use of different target materials and thicknesses as well as laser energy and temporal intensity contrast settings. We demonstrate that application relevant proton beam quality was reliably achieved over many months of operation with appropriate control of spectral phase and temporal contrast conditions using a state-of-the-art high-repetition rate PW laser system.

Active fractions of mannoproteins derived from yeast cell wall stimulate innate and acquired immunity of adult and elderly dogs.

Nutritional intervention in older dogs aims to increase lifespan and improve life quality as well as delay the development of diseases related to ageing. It is believed that active fractions of mannoproteins (AFMs) obtained through extraction and fractionation of yeast cell walls (Saccharomyces cerevisiae) may beneficially modulate the immune system. However, studies that have evaluated this component and the effects of ageing on the immune system of dogs are scarce. This study aimed to evaluate the immunological effects of AFMs in adult and elderly dogs. Three extruded iso-nutrient experimental diets were formulated: without addition of AFM (T0); with AFM at 400 mg/kg (T400); and with AFM at 800 mg/kg (T800). Thirty-six beagle dogs were used, and six experimental treatments, resulting in combinations of age (adult and elderly) and diet (T0, T400, and T800), were evaluated. On days zero, 14, and 28, blood samples were obtained for leucocyte phenotyping and phagocytosis assays. On days zero and 28, a lymphoproliferation test, quantification of reactive oxygen (H2O2) and nitrogen (NO) intermediate production, evaluation of faecal immunoglobulin A (IgA) content, and a delayed cutaneous hypersensitivity test (DCHT) were performed. Statistical analyses were performed with SAS software. Repeated measure variance analyses were performed, and means were compared by the Tukey test. Values of P ≤ 0.05 were considered significant, and values of P ≤ 0.10 were considered tendencies. Dogs fed T400 tended to have higher neutrophilic phagocytic activity than dogs fed T800 (P = 0.073). Regarding reactive oxygen intermediates, bacterial lipopolysaccharide (LPS)-stimulated neutrophils from animals that were fed T400 had a tendency to produce more H2O2 than those from animals fed the control diet (P = 0.093). Elderly dogs, when compared to adult dogs, had lower absolute T and B lymphocyte counts, lower auxiliary T lymphocyte counts, and higher cytotoxic T lymphocyte counts (P < 0.05). A significant effect of diet, age, and time with saline inoculation was noted for the DCHT. There was no effect of diet or age on faecal IgA content in dogs. This study suggests beneficial effects of mannoproteins on the specific and nonspecific immune responses in adult and elderly dogs.

Laboratory study of stationary accretion shock relevant to astrophysical systems.

Accretion processes play a crucial role in a wide variety of astrophysical systems. Of particular interest are magnetic cataclysmic variables, where, plasma flow is directed along the star's magnetic field lines onto its poles. A stationary shock is formed, several hundred kilometres above the stellar surface; a distance far too small to be resolved with today's telescopes. Here, we report the results of an analogous laboratory experiment which recreates this astrophysical system. The dynamics of the laboratory system are strongly influenced by the interplay of material, thermal, magnetic and radiative effects, allowing a steady shock to form at a constant distance from a stationary obstacle. Our results demonstrate that a significant amount of plasma is ejected in the lateral direction; a phenomenon that is under-estimated in typical magnetohydrodynamic simulations and often neglected in astrophysical models. This changes the properties of the post-shock region considerably and has important implications for many astrophysical studies.

Chemical-vapor deposited ultra-fast diamond detectors for temporal measurements of ion bunches.

This article reports on the development of thin diamond detectors and their characterization for their application in temporal profile measurements of subnanosecond ion bunches. Two types of diamonds were used: a 20 µm thin polycrystalline chemical vapor deposited (CVD) diamond and a membrane with a thickness of (5 ± 1) µm etched out of a single crystal (sc) CVD diamond. The combination of a small detector electrode and an impedance matched signal outlet leads to excellent time response properties with a signal pulse resolution (FWHM) of τ = (113 ± 11) ps. Such a fast diamond detector is a perfect device for the time of flight measurements of MeV ions with bunch durations in the subnanosecond regime. The scCVD diamond membrane detector was successfully implemented within the framework of the laser ion generation handling and transport project, in which ion beams are accelerated via a laser-driven source and shaped with conventional accelerator technology. The detector was used to measure subnanosecond proton bunches with an intensity of 108 protons per bunch.

A light-weight compact proton gantry design with a novel dose delivery system for broad-energetic laser-accelerated beams.

Proton beams may provide superior dose-conformity in radiation therapy. However, the large sizes and costs limit the widespread use of proton therapy (PT). The recent progress in proton acceleration via high-power laser systems has made it a compelling alternative to conventional accelerators, as it could potentially reduce the overall size and cost of the PT facilities. However, the laser-accelerated beams exhibit different characteristics than conventionally accelerated beams, i.e. very intense proton bunches with large divergences and broad-energy spectra. For the application of laser-driven beams in PT, new solutions for beam transport, such as beam capture, integrated energy selection, beam shaping and delivery systems are required due to the specific beam parameters. The generation of these beams are limited by the low repetition rate of high-power lasers and this limitation would require alternative solutions for tumour irradiation which can efficiently utilize the available high proton fluence and broad-energy spectra per proton bunch to keep treatment times short. This demands new dose delivery system and irradiation field formation schemes. In this paper, we present a multi-functional light-weight and compact proton gantry design for laser-driven sources based on iron-less pulsed high-field magnets. This achromatic design includes improved beam capturing and energy selection systems, with a novel beam shaping and dose delivery system, so-called ELPIS. ELPIS system utilizes magnetic fields, instead of physical scatterers, for broadening the spot-size of broad-energetic beams while capable of simultaneously scanning them in lateral directions. To investigate the clinical feasibility of this gantry design, we conducted a treatment planning study with a 3D treatment planning system augmented for the pulsed beams with optimizable broad-energetic widths and selectable beam spot sizes. High quality treatment plans could be achieved with such unconventional beam parameters, deliverable via the presented gantry and ELPIS dose delivery system. The conventional PT gantries are huge and require large space for the gantry to rotate the beam around the patient, which could be reduced up to 4 times with the presented pulse powered gantry system. The further developments in the next generation petawatt laser systems and laser-targets are crucial to reach higher proton energies. However, if proton energies required for therapy applications are reached it could be possible in future to reduce the footprint of the PT facilities, without compromising on clinical standards.

Laboratory formation of a scaled protostellar jet by coaligned poloidal magnetic field.

Although bipolar jets are seen emerging from a wide variety of astrophysical systems, the issue of their formation and morphology beyond their launching is still under study. Our scaled laboratory experiments, representative of young stellar object outflows, reveal that stable and narrow collimation of the entire flow can result from the presence of a poloidal magnetic field whose strength is consistent with observations. The laboratory plasma becomes focused with an interior cavity. This gives rise to a standing conical shock from which the jet emerges. Following simulations of the process at the full astrophysical scale, we conclude that it can also explain recently discovered x-ray emission features observed in low-density regions at the base of protostellar jets, such as the well-studied jet HH 154.

Production of large volume, strongly magnetized laser-produced plasmas by use of pulsed external magnetic fields.

The production of strongly magnetized laser plasmas, of interest for laboratory astrophysics and inertial confinement fusion studies, is presented. This is achieved by coupling a 16 kV pulse-power system. This is achieved by coupling a 16 kV pulse-power system, which generates a magnetic field by means of a split coil, with the ELFIE laser facility at Ecole Polytechnique. In order to influence the plasma dynamics in a significant manner, the system can generate, repetitively and without debris, high amplitude magnetic fields (40 T) in a manner compatible with a high-energy laser environment. A description of the system and preliminary results demonstrating the possibility to magnetically collimate plasma jets are given.

Absolute response of Fuji imaging plate detectors to picosecond-electron bunches.

The characterization of the absolute number of electrons generated by laser wakefield acceleration often relies on absolutely calibrated FUJI imaging plates (IP), although their validity in the regime of extreme peak currents is untested. Here, we present an extensive study on the dependence of the sensitivity of BAS-SR and BAS-MS IP to picosecond electron bunches of varying charge of up to 60 pC, performed at the electron accelerator ELBE, making use of about three orders of magnitude of higher peak intensity than in prior studies. We demonstrate that the response of the IPs shows no saturation effect and that the BAS-SR IP sensitivity of 0.0081 photostimulated luminescence per electron number confirms surprisingly well data from previous works. However, the use of the identical readout system and handling procedures turned out to be crucial and, if unnoticed, may be an important error source.

Randomized trial comparing induction chemotherapy versus induction chemotherapy followed by maintenance chemotherapy in small-cell lung cancer. European Lung Cancer Working Party.

PURPOSE AND METHODS: The European Lung Cancer Working Party (ELCWP) performed a randomized trial with the primary end point to determine if maintenance chemotherapy with 12 courses of etoposide (120 mg/m2 on days 1 and 3) and vindesine (3 mg/m2 on day 3) could improve progression-free survival in small-cell lung cancer (SCLC) patients who responded to six courses of induction chemotherapy with ifosfamide, etoposide, and an anthracycline (doxorubicin or epirubicin). RESULTS: Among 235 eligible patients initially registered, 91 were randomized to receive maintenance therapy, including seven patients who were no longer responding. Among 84 randomized responders, progression-free survival was significantly improved (P = .003) by maintenance therapy, with median durations (maintenance v follow-up) of 25 versus 12 weeks after the second randomization, but survival was not significantly increased (P = .10), with median durations of 48 and 38 weeks. However, in a multi-variate analysis that took into account disease extent, maintenance therapy, Karnofsky performance status (PS), and absolute dose-intensity (ADI) of anthracycline given during induction, limited disease (LD) and maintenance were found to be independent positive predictors of survival. CONCLUSION: We conclude that maintenance chemotherapy in responding patients is beneficial in SCLC.

Coordination of a histidine residue of the protein-component S to the cobalt atom in coenzyme B12-dependent glutamate mutase from Clostridium cochlearium.

Electron paramagnetic resonance (EPR) spectroscopy of glutamate mutase from Clostridium cochlearium was performed in order to test the idea, that a histidine residue of component S replaces the dimethylbenzimidazole ligand of the Co-atom during binding of coenzyme B12 to the enzyme. The shapes and the superhyperfine splitting of the gz-lines of the Co(II) EPR spectra were used as indicators of the interaction of the axial base nitrogen with the Co-atom. A mixture of completely 15N-labelled component S, unlabelled component E, coenzyme B12 and glutamate gave slightly sharper gz-lines than that with unlabelled component S. A more dramatic change was observed in the Co(II) spectrum of the inactivated enzyme containing tightly bound cob(II)alamin, in which unlabelled component S caused a threefold superhyperfine-splitting of the gz-line, whereas the 15N-labelled protein only caused a twofold splitting, as expected for a direct interaction of a nitrogen of the enzyme with the Co-atom. By using a sample of 15N-labelled component S, in which only the histidines were 14N-labelled, the EPR spectra showed no difference to those with unlabelled component S. The experiments indeed demonstrate a replacement of the dimethylbenzimidazole ligand in coenzyme B12 by a histidine when bound to glutamate mutase. The most likely candidate is H16, which is conserved among the carbon skeleton rearranging mutases and methionine synthase.

Induction chemotherapy with ifosfamide, etoposide, and anthracycline for small cell lung cancer: experience of the European Lung Cancer Working Party.

Prospective trials comparing drug analogues in the treatment of small cell lung cancer are rare. The European Lung Cancer Working Party has conducted a randomized trial with a primary end point of determining the effect on survival of maintenance chemotherapy and a secondary end point of comparing doxorubicin (45 mg/m2) with a bioequivalent epirubicin dose (60 mg/m2) in one set of patients, and a standard with a high epirubicin dose (60 v 90 mg/m2) in a second set of patients. Anthracycline was given on day 1 of induction chemotherapy in combination with ifosfamide (1.5 g/m2 intravenously days 1 through 3) and etoposide (80 mg/m2 intravenously days 1 through 3). Six courses were given at 3-week intervals. In all, 235 eligible previously untreated patients with pathologically proven small cell lung cancer were randomized: 106 to the comparison of doxorubicin and epirubicin and 129 to the comparison of standard-dose versus high-dose epirubicin. There was no difference between the regimens in terms of objective response rate or survival, and the regimen containing the lower (60 mg/m2) epirubicin dose was better tolerated, with fewer toxic deaths and less need for dose and schedule adjustments.

A phase-ii study testing a combination chemotherapy with epirubicin and vindesine as 2nd line treatment for patients with advanced non-small-cell lung-cancer.

The European Lung Cancer Working Party conducted a phase II trial to determine the activity of a salvage regimen with high dose epirubicin (120 mg/m(2) on day 1) and vindesine (3 mg/m(2) on day 1) in patients with advanced non-small cell lung cancer failing to respond to first-line chemotherapy containing cisplatin and/or carboplatin. Courses were repeated every 3 weeks and evaluation of antitumoral response was performed after the 2 first courses. A total of 53 patients were registered, 4 were not eligible and 42 were evaluable for response. Two (5%) objective responses were documented. Although the regimen was very well tolerated, based oh the results it has to be considered inactive.

Albumin protects against capsaicin- and adenosine-induced bronchoconstriction and reduces overflow of calcitonin gene-related peptide from guinea-pig lung.

In the guinea-pig isolated, perfused lung, the effect of albumin on oedema formation and bronchoconstriction as well as on capsaicin-induced overflow of calcitonin gene-related peptide-like (CGRP-LI) immunoreactivity has been examined. CGRP was used as an indicator of sensory nerve activation since it is more stable than the tachykinins substance P and neurokinin A. As expected, the lung water content was significantly (P less than 0.001) higher in lungs perfused with albumin-free buffer than when the buffer contained 4.5% albumin. Also, in albumin-free buffer the baseline airway resistance (RL) was increased and dynamic compliance (CDYN) reduced (P less than 0.001). Capsaicin (1 x 10(-6) M) was about 100 times less potent as a bronchoconstrictor when preincubated with albumin for 45 min, and the associated overflow of CGRP-LI was inhibited (from 221.0 +/- 63.4 fmol to 8 fmol fraction-1). When CGRP (50-200 pM) was incubated for 60 min with albumin, the recovery of CGRP-LI was 48% lower (P less than 0.01) than in the absence of albumin, corresponding to a loss rate of about 1% min-1. Catabolism or binding of neuropeptides can therefore hardly explain the diminished bronchoconstrictor potency of capsaicin. Capsaicin was also less effective as a constrictor in isolated bronchi after preincubation with albumin, suggesting that capsaicin itself may be bound or absorbed to this macromolecule. The bronchoconstrictor response to adenosine was also diminished in the presence of albumin. Adenosine was about 1000 times less potent as a bronchoconstrictor if dissolved in albumin 45 min before infusion, but only 10 times less potent when administered as bolus doses to albumin buffer-perfused lungs. Metabolism of adenosine may be the reason for the decreased potency of adenosine. The enzymatic activity may have been associated with impurities in the albumin preparation used (bovine serum albumin fraction V is greater than or equal to 96% pure) or contained in the protein itself. Since the bronchoconstrictor effect of acetylcholine was not reduced in the presence of albumin, it is not likely that albumin affects directly the contractility of the smooth muscle. These data demonstrate the importance of studying the influence of albumin on the in-vitro actions of pharmacological agents. The absence or presence of albumin products in nutrient buffer solutions may mean dramatic differences in potencies of certain drugs. Furthermore, bolus injections of agents are preferable, and preincubation together with albumin should be avoided.

Rapid clearance of xanthines from airway and pulmonary tissues.

The airway and pulmonary fate of two antiasthma xanthines was examined in a guinea pig perfused lung preparation where the airway mechanics and airway microvascular perfusion are maintained at near normal values. 14C-theophylline or 14C-enprofylline was infused for 10, 30, and 300 s into the pulmonary artery of the guinea pig isolated lung. The radioactivity increased rapidly (within 10 s) in tracheobronchial as well as in lung tissue, confirming that the large airway microcirculation was well supplied also by the perfusion. The effluent concentrations of total 3H and 14C radioactivity at the onset, during, and after intrapulmonary infusion of 14C-labeled xanthines and 3H-sucrose were closely associated, suggesting that the xanthines, like sucrose, largely distributed in extracellular fluid and were not taken up by the tissues. No metabolites of enprofylline or theophylline could be detected in the lung tissue or lung effluent, suggesting that xanthines are not biotransformed by the guinea pig lung. After intratracheal instillation of 14C-theophylline, the peak radioactivity in the lung effluent appeared in the second 15-s fraction after instillation, and after 10 and 60 min, 68.1 +/- 4.7% and 86.9 +/- 8.4%, respectively, of the given dose had appeared in the lung effluent. The present data suggest a mainly extracellular distribution and a rapid clearance of xanthines from the lung and airway tissues. The rapid disappearance of topical theophylline may explain the lack of success of inhalation therapy with this drug.

Capsaicin-induced bronchoconstriction and neuropeptide release in guinea pig perfused lungs.

In the guinea pig isolated perfused lung, we have examined the relationship between the effects of capsaicin and neuropeptide release and the possible existence of an axon reflex arrangement. Bolus injections into the pulmonary artery of capsaicin (1-100 pmol), substance P (10-1,000 pmol), and neurokinin (NK) A (10-100 pmol) produced a concentration-dependent bronchoconstriction, whereas calcitonin gene-related peptide (CGRP, 20-40 nmol) was without effect. Repeated administration of capsaicin at 40- to 60-min intervals was not associated with tachyphylaxis. These data support the presence of a NK2- (or NKA) type of tachykinin receptor in the guinea pig airways. Tetrodotoxin (0.3-3 microM) inhibited the effect of capsaicin, indicating that an axon reflex was operant. Capsaicin increased overflow of CGRP-like immunoreactivity (-LI) and NKA-LI, the latter only during concurrent infusion of the enkephalinase inhibitor phosphoramidon (3 microM). Phosphoramidon also increased overflow of CGRP-LI, suggesting that both NKA and CGRP were catabolized by a similar enzyme. The purine nucleoside adenosine did not cause any detectable overflow of CGRP-LI, indicating that neuropeptides may not be involved in adenosine-evoked bronchoconstriction and that bronchoconstriction per se does not induce neuropeptide overflow. Capsaicin and NKA had only minor effects on buffer flow, whereas substance P produced pulmonary vasoconstriction. These data clearly demonstrate that capsaicin acts via an axon reflex in the guinea pig airways. Supramaximal concentrations of capsaicin are needed to detect neuropeptide overflow, but the possibility exists that released neuropeptides mediate its effects.

Hydroperoxide and cigarette smoke induced effects on lung mechanics and glutathione status in rat isolated perfused and ventilated lungs.

The effects of t-butylhydroperoxide (TBH) and cigarette smoke on lung mechanics (CDYN and RL) and glutathione status (GSH) were studied using an isolated perfused and ventilated rat lung preparation. TBH (200, 400, 1000 microM) infused via the pulmonary circulation caused a dose-related bronchoconstriction. The lung GSH-levels were also significantly reduced. Pretreatment of rats with diethylmaleate (DEM) potentiated the TBH elicited bronchoconstriction. DEM (1 mM) infused into the pulmonary circulation caused an almost complete depletion of GSH-content but no effects on lung mechanics were seen. Indomethacin (2.8 and 28 microM) infusion attenuated TBH (400 microM) induced bronchoconstriction. These findings suggest that the TBH induced bronchoconstriction is at least partly mediated via arachidonic acid metabolites. When TBH was administered intratracheally, weak and not dose-related bronchoconstriction was observed even though doses higher than those given intravascularly were used. However, the GSH-content of the lungs was markedly decreased. Cigarette smoke caused weak if any effects on lung mechanics but significantly decreased lung GSH-content.

Adenosine-induced bronchoconstriction in the guinea-pig isolated lung: interaction with theophylline and enprofylline.

Effects of purine nucleosides and asthma mediators on airway tone have been examined in the guinea-pig isolated perfused lung preparation. Acetylcholine (10 pmol-0.3 nmol), histamine (1-10 nmol), adenosine (10 nmol-0.3 mumol), ATP (10 nmol-0.3 mumol) and inosine (10 mumol-0.1 mmol) all produced a dose dependent increase in lung resistance (RL) and a decrease in dynamic compliance (CDYN). ATP was equipotent with adenosine whereas inosine was about 500 times less potent. The adenosine-induced bronchoconstriction was affected neither by disodium cromoglycate (150 microM) nor by the histamine H1-receptor antagonist, mepyramine (1 microM) suggesting that histamine is not involved in this response. Furthermore, it was studied whether the xanthines theophylline and enprofylline specifically interacted with the adenosine induced bronchoconstriction. Theophylline significantly (P less than 0.01-0.001) and concentration dependently prevented both acetylcholine and adenosine-induced increase in RL. The response to 0.1 nmol acetylcholine was reduced by 32.8 +/- 8.4% (mean +/- SEM) and 58.1 +/- 4.0%, respectively, by 75 and 150 microM theophylline. Theophylline, 75 and 150 microM, also inhibited the increase in RL caused by 0.1 mumol of adenosine by 61.4 +/- 9.6% and 83.4 +/- 5.2%, respectively. Theophylline, was significantly (P less than 0.05-0.01) more potent in preventing the RL increase produced by adenosine than that by acetylcholine. Enprofylline, 30 microM, equally well as 75 microM theophylline reduced the acetylcholine-induced bronchoconstriction by 41.8 +/- 7.6% (P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Lung mechanics of the guinea-pig isolated perfused lung.

In the isolated perfused guinea-pig lung, lung resistance (RL) and dynamic compliance (CDYN) as well as flow, pH, PO2 and PCO2 of the perfusate were recorded. The baseline values were stable up to 2.5 h. Mean values (+/- SEM) for RL and CDYN were 0.36 cm H2O ml-1 s-1 +/- 0.04 and 0.27 ml cm-1 H2O +/- 0.02, respectively, which agree with in vivo values reported for unanaesthetized guinea-pigs. The pH was always slightly raised and the PCO2 always lowered in the effluent compared to the inflowing medium (P less than 0.001), indicating that the lung had an operative ventilation. Intravascularly administered acetylcholine, histamine and adenosine caused reproducible dose-dependent bronchoconstrictions recorded as increased RL and decreased CDYN. It is noteworthy that adenosine in this model and in vivo consistently produced bronchoconstriction which is in contrast to findings in other in vitro airway preparations. We conclude that this isolated perfused guinea-pig lung preparation has stable in vivo-like characteristics offering interesting possibilities for combining studies of respiratory effects with, for example, metabolism, pharmacokinetic and vascular reactivity studies.