Stable Operation of a Free-Electron Laser Driven by a Plasma Accelerator.

The breakthrough provided by plasma-based accelerators enabled unprecedented accelerating fields by boosting electron beams to gigaelectronvolt energies within a few centimeters [1-4]. This, in turn, allows the realization of ultracompact light sources based on free-electron lasers (FELs) [5], as demonstrated by two pioneering experiments that reported the observation of self-amplified spontaneous emission (SASE) driven by plasma-accelerated beams [6,7]. However, the lack of stability and reproducibility due to the intrinsic nature of the SASE process (whose amplification starts from the shot noise of the electron beam) may hinder their effective implementation for user purposes. Here, we report a proof-of-principle experiment using plasma-accelerated beams to generate stable and reproducible FEL light seeded by an external laser. FEL radiation is emitted in the infrared range, showing the typical exponential growth of its energy over six consecutive undulators. Compared to SASE, the seeded FEL pulses have energies 2 orders of magnitude larger and stability that is 3 times higher.

Free-electron lasing with compact beam-driven plasma wakefield accelerator.

The possibility to accelerate electron beams to ultra-relativistic velocities over short distances by using plasma-based technology holds the potential for a revolution in the field of particle accelerators1-4. The compact nature of plasma-based accelerators would allow the realization of table-top machines capable of driving a free-electron laser (FEL)5, a formidable tool to investigate matter at the sub-atomic level by generating coherent light pulses with sub-ångström wavelengths and sub-femtosecond durations6,7. So far, however, the high-energy electron beams required to operate FELs had to be obtained through the use of conventional large-size radio-frequency (RF) accelerators, bound to a sizeable footprint as a result of their limited accelerating fields. Here we report the experimental evidence of FEL lasing by a compact (3-cm) particle-beam-driven plasma accelerator. The accelerated beams are completely characterized in the six-dimensional phase space and have high quality, comparable with state-of-the-art accelerators8. This allowed the observation of narrow-band amplified radiation in the infrared range with typical exponential growth of its intensity over six consecutive undulators. This proof-of-principle experiment represents a fundamental milestone in the use of plasma-based accelerators, contributing to the development of next-generation compact facilities for user-oriented applications9.

Obsessive compulsive personality disorder in Progressive Supranuclear Palsy, Multiple System Atrophy and Essential Tremor.

INTRODUCTION: aim of the study was to evaluate the presence of the Obsessive Compulsive Personality Disorder (OCPeD) in Multiple System Atrophy (MSA), Progressive Supranuclear Palsy (PSP) and Essential Tremor (ET) and in a group of healthy subjects. METHODS: patients affected by MSA, PSP and ET diagnosed according to currently accepted diagnostic criteria and a group of healthy controls were enrolled in the study. Patients with cognitive impairment were excluded from the study. The Structured Clinical Interview for Personality Disorders-II (SCID-II) has been performed to evaluate the presence of personality disorders (PeDs). The diagnosis of OCPeD was confirmed by a psychiatric interview. RESULTS: fifteen MSA patients (8 men and 7 women; aged 62.9 ± 7.6 years), 14 PSP patients (8 men and 6 women; aged 69.8 ± 4.4 years), 16 ET patients (10 men and 6 women; aged 70.4 ± 6.4 years) and 20 healthy subjects (10 men and 10 women; aged 65.5 ± 6.0 years) were enrolled. OCPeD was recorded in 5 (35.7%) PSP patients, 2 (13.3%) MSA patients, 2 (12.5%) ET patient and 2 (10%) controls. CONCLUSION: a low frequency of OCPeD, close to those recorded in healthy subjects, was recorded in both MSA and ET patients. Conversely an higher frequency of OCPeD, similar to PD was found among PSP patients, supporting the possibility of an impairment of common basal ganglia network possibly involving the orbito-frontal circuits.

Tremor pattern differentiates drug-induced resting tremor from Parkinson disease.

OBJECTIVE: DAT-SPECT, is a well-established procedure for distinguishing drug-induced parkinsonism from Parkinson's disease (PD). We investigated the usefulness of blink reflex recovery cycle (BRrc) and of electromyographic parameters of resting tremor for the differentiation of patients with drug-induced parkinsonism with resting tremor (rDIP) from those with resting tremor due to PD. METHODS: This was a cross-sectional study. In 16 patients with rDIP and 18 patients with PD we analysed electrophysiological parameters (amplitude, duration, burst and pattern) of resting tremor. BRrc at interstimulus intervals (ISI) of 100, 150, 200, 300, 400, 500 and 750 msec was also analysed in patients with rDIP, patients with PD and healthy controls. All patients and controls underwent DAT-SPECT. RESULTS: Rest tremor amplitude was higher in PD patients than in rDIP patients (p < 0.001), while frequency and burst duration were higher in rDIP than in PD (p < 0.001, p < 0.003, respectively). Resting tremor showed a synchronous pattern in all patients with rDIP, whereas it had an alternating pattern in all PD patients (p < 0.001). DAT-SPECT was normal in rDIP patients while it was markedly abnormal in patients with PD. CONCLUSIONS: In the absence of DAT-SPECT, the pattern of resting tremor can be considered a useful investigation for differentiating rDIP from PD.

Redox modulation of cellular stress response and lipoxin A4 expression by Coriolus versicolor in rat brain: Relevance to Alzheimer's disease pathogenesis.

Increasing evidence supports the notion that oxidative stress-driven neuroinflammation is an early pathological feature in neurodegenerative diseases. As a prominent intracellular redox system involved in neuroprotection, the vitagene system is emerging as a potential neurohormetic target for novel cytoprotective interventions. Vitagenes encode for cytoprotective heat shock proteins 70, heme oxygenase-1, thioredoxin and lipoxin A4. Emerging interest is now focusing on molecules capable of activating the vitagene system as novel therapeutic targets to minimize deleterious consequences associated with free radical-induced cell damage, such as in neurodegeneration. Mushroom-derived lipoxin A4 (LXA4) is an emerging endogenous eicosanoid able to promote resolution of inflammation, acting as an endogenous "braking signal" in the inflammatory process. Mushrooms have long been used in traditional medicine for thousands of years, being now increasingly recognized as rich source of polysaccharopeptides endowed with significant antitumor, antioxidant, antiviral, antibacterial and cytoprotective effects, thereby capable of stimulating host immune responses. Here we provide evidence of a neuroprotective action of the Coriolus mushroom when administered orally to rat. Expression of LXA4 was measured in different brain regions after oral administration of a Coriolus biomass preparation, given for 30 days. LXA4 up-regulation was associated with an increased content of redox sensitive proteins involved in cellular stress response, such as Hsp72, heme oxygenase-1 and thioredoxin. In the brain of rats receiving Coriolus, maximum induction of LXA4 was observed in cortex and hippocampus. Hsps induction was associated with no significant changes in IkBα, NFkB and COX-2 brain levels. Conceivably, activation of LXA4 signaling and modulation of stress-responsive vitagene proteins could serve as a potential therapeutic target for AD-related inflammation and neurodegenerative damage.

Two-Color Radiation Generated in a Seeded Free-Electron Laser with Two Electron Beams.

We present the experimental evidence of the generation of coherent and statistically stable two-color free-electron laser radiation obtained by seeding an electron beam double peaked in energy with a laser pulse single spiked in frequency. The radiation presents two neat spectral lines, with time delay, frequency separation, and relative intensity that can be accurately controlled. The analysis of the emitted radiation shows a temporal coherence and a shot-to-shot regularity in frequency significantly enhanced with respect to the self-amplified spontaneous emission.

Paliperidone palmitate in non-acute patients with schizophrenia previously unsuccessfully treated with risperidone long-acting therapy or frequently used conventional depot antipsychotics.

PALMFlexS, a prospective multicentre, open-label, 6-month, phase IIIb interventional study, explored tolerability, safety and treatment response in adults (n = 231) with non-acute but symptomatic schizophrenia switching to flexibly dosed paliperidone palmitate (PP) after unsuccessful treatment with risperidone long-acting injectable therapy (RLAT) or conventional depot antipsychotics (APs). Treatment response was measured by change in Positive and Negative Syndrome Scale (PANSS) total score from baseline (BL) to last-observation-carried-forward (LOCF) endpoint (EP). Safety and tolerability assessments included Extrapyramidal Symptom Rating Scale (ESRS) total score and treatment-emergent adverse events. Significant reductions in mean PANSS total score were observed for all groups (-7.5 to -10.6; p ⩽ 0.01 [BL to LOCF EP]). After switching to PP, more than 50% of all patients achieved ⩾20% and one-third of RLAT-treated patients even achieved ⩾50% improvement in PANSS total score. Across groups, there were significant improvements (p < 0.05) in symptom severity as measured by Clinical Global Impression-Severity (CGI-S; trend for improvement with RLAT; p = 0.0568), subjective well-being, medication satisfaction, and patient functioning with PP. PP was generally well tolerated. Clinically relevant benefits were observed in non-acute patients with schizophrenia switched from RLAT or conventional depot APs to PP.

Analytical approaches to the diagnosis and treatment of aging and aging-related disease: redox status and proteomics.

Basal levels of oxidants are indispensible for redox signaling to produce adaptive cellular responses such as vitagenes linked to cell survival; however, at higher levels, they are detrimental to cells, contributing to aging and to the pathogenesis of numerous age-related diseases. Aging is a complex systemic process and the major gap in aging research reminds the insufficient knowledge about pathways shifting from normal "healthy" aging to disease-associated pathological aging. The major complication of normal "healthy" aging is in fact the increasing risk of age-related diseases such as cardiovascular diseases, diabetes mellitus, and neurodegenerative pathologies that can adversely affect the quality of life in general, with enhanced incidences of comorbidities and mortality. In this context, global "omics" approaches may help to dissect and fully study the cellular and molecular mechanisms of aging and age-associated processes. The proteome, being more close to the phenotype than the transcriptome and more stable than the metabolome, represents the most promising "omics" field in aging research. In the present study, we exploit recent advances in the redox biology of aging and discuss the potential of proteomics approaches as innovative tools for monitoring at the proteome level the extent of protein oxidative insult and related modifications with the identification of targeted proteins.

Spatial properties of odd and even low order harmonics generated in gas.

High harmonic generation in gases is developing rapidly as a soft X-ray femtosecond light-source for applications. This requires control over all the harmonics characteristics and in particular, spatial properties have to be kept very good. In previous literature, measurements have always included several harmonics contrary to applications, especially spectroscopic applications, which usually require a single harmonic. To fill this gap, we present here for the first time a detailed study of completely isolated harmonics. The contribution of the surrounding harmonics has been totally suppressed using interferential filtering which is available for low harmonic orders. In addition, this allows to clearly identify behaviors of standard odd orders from even orders obtained by frequency-mixing of a fundamental laser and of its second harmonic. Comparisons of the spatial intensity profiles, of the spatial coherence and of the wavefront aberration level of 5ω at 160 nm and 6ω at 135 nm have then been performed. We have established that the fundamental laser beam aberrations can cause the appearance of a non-homogenous donut-shape in the 6ω spatial intensity distribution. This undesirable effect can be easily controlled. We finally conclude that the spatial quality of an even harmonic can be as excellent as in standard generation.

Observation of time-domain modulation of free-electron-laser pulses by multipeaked electron-energy spectrum.

We present the experimental demonstration of a new scheme for the generation of ultrashort pulse trains based on free-electron-laser (FEL) emission from a multipeaked electron energy distribution. Two electron beamlets with energy difference larger than the FEL parameter ρ have been generated by illuminating the cathode with two ps-spaced laser pulses, followed by a rotation of the longitudinal phase space by velocity bunching in the linac. The resulting self-amplified spontaneous emission FEL radiation, measured through frequency-resolved optical gating diagnostics, reveals a double-peaked spectrum and a temporally modulated pulse structure.

Two color free-electron laser and frequency beating.

We review the theory of two color high gain free-electron laser emission, derive the integral equation characterizing the evolution of the optical intensities, and provide a description of the relevant dynamics. The characteristic feature of this regime is the existence of a mutual bunching, whose origin and role are discussed.

Superradiant cascade in a seeded free-electron laser.

We report measurements demonstrating the concept of the free-electron laser (FEL) superradiant cascade. Radiation (λ(rad) = 200 nm) at the second harmonic of a short, intense seed laser pulse (λ(seed) = 400 nm) was generated by the cascaded FEL scheme at the transition between the modulator and radiator undulator sections. The superradiance of the ultrashort pulse is confirmed by detailed measurements of the resulting spectral structure, the intensity level of the produced harmonics, and the trend of the energy growth along the undulator. These results are compared to numerical particle simulations using the FEL code GENESIS 1.3 and show a satisfactory agreement.

High-order-harmonic generation and superradiance in a seeded free-electron laser.

Higher order harmonic generation in a free-electron laser amplifier operating in the superradiant regime [R. H. Dicke, Phys. Rev. 93, 99 (1954).] has been observed. Superradiance has been induced by seeding a single-pass amplifier with the second harmonic of a Ti:sapphire laser, generated in a ß-Barium borate crystal, at seed intensities comparable to the free-electron laser saturation intensity. Pulse energy and spectral distributions of the harmonics up to the 11th order have been measured and compared with simulations.

High-gain harmonic-generation free-electron laser seeded by harmonics generated in gas.

The injection of a seed in a free-electron laser (FEL) amplifier reduces the saturation length and improves the longitudinal coherence. A cascaded FEL, operating in the high-gain harmonic-generation regime, allows us to extend the beneficial effects of the seed to shorter wavelengths. We report on the first operation of a high-gain harmonic-generation free-electron laser, seeded with harmonics generated in gas. The third harmonics of a Ti:sapphire laser, generated in a gas cell, has been amplified and up-converted to its second harmonic (λ(rad)=133 nm) in a FEL cascaded configuration based on a variable number of modulators and radiators. We studied the transition between coherent harmonic generation and superradiant regime, optimizing the laser performances with respect to the number of modulators and radiators.

Self-amplified spontaneous emission free-electron laser with an energy-chirped electron beam and undulator tapering.

We report the first experimental implementation of a method based on simultaneous use of an energy chirp in the electron beam and a tapered undulator, for the generation of ultrashort pulses in a self-amplified spontaneous emission mode free-electron laser (SASE FEL). The experiment, performed at the SPARC FEL test facility, demonstrates the possibility of compensating the nominally detrimental effect of the chirp by a proper taper of the undulator gaps. An increase of more than 1 order of magnitude in the pulse energy is observed in comparison to the untapered case, accompanied by FEL spectra where the typical SASE spiking is suppressed.

Multicentre randomised phase III study comparing the same dose and schedule of cisplatin plus the same schedule of vinorelbine or gemcitabine in advanced non-small cell lung cancer.

This study compares two cytotoxic regimens comprising the same dose and schedule of cisplatin (CP) plus vinorelbine (VNR) or gemcitabine (GEM) administered under the same schedule to patients with advanced non-small cell lung cancers (NSCLC). From April 1998 to February 2003, 285 patients were randomised to receive either VNR 25 mg/m(2) on days 1 and 8 as an intravenous (i.v.) bolus plus CP 75 mg/m(2) on day 1 (regimen A) or GEM 1200 mg/m(2) on days 1 and 8 as an i.v. 30-min infusion plus CP 75 mg/m(2) on day 1 (regimen B). Both treatments were recycled every 21 days. If no progression had occurred after six cycles, the patients continued to receive VNR or GEM monochemotherapy weekly. Cross-over of the two single agents was considered if disease progression occurred. Objective response (OR), time to progression (TTP) and overall survival (OS) were analysed according to the intention-to-treat principle. 272 patients were ultimately eligible (137 on A and 135 on B). Their main characteristics were: male/female ratio 214/58; median age 63 (range 32-77) years; median Karnofsky Performance Status (PS) 80 (range 70-100); stage IIIB 34%, stage IV 61%, recurrent disease 5%; histology - epidermoid 29%, adenocarcinoma 53%, other NSCLC 18%. The characteristics of the patients in the two arms were well matched. The following response rates were observed in regimens A and B, respectively: complete response (CR) 0.7% and 3.7%, partial response (PR) 31.9% and 22.2% (P = 0.321). Median CR+PR duration was 8 months in both arms. Clinical benefit represented by an improvement in symptoms was evident in 25.7% and 28.1%, respectively. Median TTP was 5 months in both arms and median OS 11 months in both arms. Grade III-IV neutropenia occurred in 30.7% and 17.7% of the patients in arms A and B, respectively (P = 0.017); thrombocytopenia occurred in 0% and 9.3% (P = 0.004), respectively. No difference in the incidence of anaemia was observed. Non-haematological toxicity was generally mild: a higher incidence of grade 1-2 peripheral neurotoxicity and grade 1-2 local toxicity with regimen A and grade 1-2 liver toxicity with regimen B was reported. A pharmaco-economic comparison showed a difference between the two doublets, principally due to the different costs of VNR and GEM. Under the study conditions the combination of VNR or GEM with the same dose and schedule of CP produced similar OR, clinical benefits, TTP and OS in advanced NSCLC, and only mild toxicological differences were observed. Pharmaco-economic evaluation favoured the CP + VNR doublet.

Multicenter randomized clinical trial on high-dose epirubicin plus cis-platinum versus vinorelbine plus cis-platinum in advanced non small cell lung cancer.

BACKGROUND: High dose Epirubicin (HD-EPI) (>90 mg/m2) and Vinorelbine (VNR) demonstrated antitumor activity as single agent (about 20%) in the treatment of advanced NSCLC. This trial compares these two agents combined with cisplatin (CP). PATIENTS AND METHODS: From August 1992 to February 1996, 228 patients with locally advanced or metastatic NSCLC were randomized to receive either EPI 120 mg/m2 as i.v. bolus plus Cisplatin (CP) 60 mg/m2 on day 1 (regimen A) or VNR 25 mg/m2 as i.v. bolus on day 1 and 8 plus CP 60 mg/m2 on day 1 (regimen B). Both treatments were recycled every 21 days up to a maximum cumulative dose of EPI of 840 mg/m2 or 12 cycles. Eligible patients were 212 and 198 patients were evaluable for objective response (95 in arm A and 103 in arm B). The main characteristics of eligible patients were: male/female 179/33; median age 61 (42-72); median Karnofsky PS 80 (70-100); stage IIIA 12%, stage IIIB 40%, stage IV 41%, recurrence 7%; histotype: epidermoid 48%, adenoca 36%, others 16%. RESULTS: The following response rates were observed in regimens A and B, respectively; CR, 1 and 2%, PR, 32 and 25% (P = 0.4567). Median CR + PR duration was 9 and 8 months, respectively. Median survival was 10.5 and 9.6 months, respectively. Grade III-IV leucopenia occurred in 38 and 21% in arm A and arm B, respectively(P = 0.01), thrombocytopenia in 6 and 0% (P = 0.02), anemia in 8 and 7% (n.s.). Non-hematological toxicity was moderate and the only difference between the treatments was alopecia (88 vs. 33% in arm A and B, respectively). Supraventricular arrhythmia occurred in three patients on regimen A; a >15% LVEF absolute decrease was observed in 9 (22.5%) and three (14%) patients on arm A and arm B, respectively (n.s.). No congestive heart failure was observed. CONCLUSION: HD-EPI+CP and VNR+CP are both active combinations in advanced NSCLC with a similar response rate, response duration and survival but regimen A was significantly more toxic (myelosuppression and alopecia).

[Simple cysts of the liver]. / Le cisti semplici del fegato.

OBJECTIVE: To evaluate the treatment of symptomatic benign non-parasitic cysts of the liver by percutaneous drainage and sclerotherapy with alcohol or surgery. DESIGN: Descriptive, prospective. SETTING: The study was conducted at the University Hospital of Catania (Italy), which serves as a general community hospital. SUMMARY BACKGROUND DATA: Solitary biliary cysts are among the most frequent cystic lesions of the liver and have a prevalence of 1 to 2 percent. They are almost always asymptomatic and do not require treatment. Ultrasonography shows a regular, round or oval, entirely liquid and trans-sonic image sufficient to make the diagnosis. Complications are exceptional. PATIENTS: Eight out of 40 patients who presented with symptomatic benign non-parasitic cysts of the liver during the period 1987-1994 and in whom percutaneous drainage was not contraindicated. INTERVENT: Drainage sclerotherapy with absolute alcohol was carried out, after which suction was applied until oozing stopped. RESULTS: Eight patients were treated, all women, 49-61 years old. In 7 patients, the cyst did not recur during the follow-up period which ranged from 8 to 60 months. Only one patient needed another percutaneous drainage. No complications of the drainage were encountered. CONCLUSION: Percutaneous drainage followed by alcohol sclerotherapy and suction is the treatment of choice in patients with symptomatic benign non-parasitic cysts of the liver. Surgical treatment should be reserved for patients who fail to respond to repeated percutaneous drainage and cases in which the location of the cyst makes it technically difficult to use a percutaneous route.