Ultrabroadband flying-focus using an axiparabola-echelon pair.

Flying-focus pulses promise to revolutionize laser-driven secondary sources by decoupling the trajectory of the peak intensity from the native group velocity of the medium over distances much longer than a Rayleigh range. Previous demonstrations of the flying focus have either produced an uncontrolled trajectory or a trajectory that is engineered using chromatic methods that limit the duration of the peak intensity to picosecond scales. Here we demonstrate a controllable ultrabroadband flying focus using a nearly achromatic axiparabola-echelon pair. Spectral interferometry using an ultrabroadband superluminescent diode was used to measure designed super- and subluminal flying-focus trajectories and the effective temporal pulse duration as inferred from the measured spectral phase. The measurements demonstrate that a nearly transform- and diffraction-limited moving focus can be created over a centimeter-scale-an extended focal region more than 50 Rayleigh ranges in length. This ultrabroadband flying-focus and the novel axiparabola-echelon configuration used to produce it are ideally suited for applications and scalable to >100 TW peak powers.

Erratum: Dephasingless Laser Wakefield Acceleration [Phys. Rev. Lett. 124, 134802 (2020)].

This corrects the article DOI: 10.1103/PhysRevLett.124.134802.

Dephasingless Laser Wakefield Acceleration.

Laser wakefield accelerators (LWFAs) produce extremely high gradients enabling compact accelerators and radiation sources but face design limitations, such as dephasing, occurring when trapped electrons outrun the accelerating phase of the wakefield. Here we combine spherical aberration with a novel cylindrically symmetric echelon optic to spatiotemporally structure an ultrashort, high-intensity laser pulse that can overcome dephasing by propagating at any velocity over any distance. The ponderomotive force of the spatiotemporally shaped pulse can drive a wakefield with a phase velocity equal to the speed of light in vacuum, preventing trapped electrons from outrunning the wake. Simulations in the linear regime and scaling laws in the bubble regime illustrate that this dephasingless LWFA can accelerate electrons to high energies in much shorter distances than a traditional LWFA-a single 4.5 m stage can accelerate electrons to TeV energies without the need for guiding structures.

Evolution of the Electron Distribution Function in the Presence of Inverse Bremsstrahlung Heating and Collisional Ionization.

The picosecond evolution of non-Maxwellian electron distribution functions was measured in a laser-produced plasma using collective electron plasma wave Thomson scattering. During the laser heating, the distribution was measured to be approximately super-Gaussian due to inverse bremsstrahlung heating. After the heating laser turned off, collisional ionization caused further modification to the distribution function while increasing electron density and decreasing temperature. Electron distribution functions were determined using Vlasov-Fokker-Planck simulations including atomic kinetics.

Photon Acceleration in a Flying Focus.

A high-intensity laser pulse propagating through a medium triggers an ionization front that can accelerate and frequency upshift the photons of a second pulse. The maximum upshift is ultimately limited by the accelerated photons outpacing the ionization front or the ionizing pulse refracting from the plasma. Here, we apply the flying focus-a moving focal point resulting from a chirped laser pulse focused by a chromatic lens-to overcome these limitations. Theory and simulations demonstrate that the ionization front produced by a flying focus can frequency upshift an ultrashort optical pulse to the extreme ultraviolet over a centimeter of propagation. An analytic model of the upshift predicts that this scheme could be scaled to a novel tabletop source of spatially coherent x rays.

Ionization Waves of Arbitrary Velocity.

Flying focus is a technique that uses a chirped laser beam focused by a highly chromatic lens to produce an extended focal region within which the peak laser intensity can propagate at any velocity. When that intensity is high enough to ionize a background gas, an ionization wave will track the intensity isosurface corresponding to the ionization threshold. We report on the demonstration of such ionization waves of arbitrary velocity. Subluminal and superluminal ionization fronts were produced that propagated both forward and backward relative to the ionizing laser. All backward and all superluminal cases mitigated the issue of ionization-induced refraction that typically inhibits the formation of long, contiguous plasma channels.

Nonlinear Thomson scattering with ponderomotive control.

In nonlinear Thomson scattering, a relativistic electron reradiates the photons of a laser pulse, converting optical light to x rays or beyond. While this extreme frequency conversion offers a promising source for probing high-energy-density materials and driving uncharted regimes of nonlinear quantum electrodynamics, conventional nonlinear Thomson scattering has inherent trade-offs in its scaling with laser intensity. Here we discover that the ponderomotive control afforded by spatiotemporal pulse shaping enables regimes of nonlinear Thomson scattering that substantially enhance the scaling of the radiated power, emission angle, and frequency with laser intensity. By appropriately setting the velocity of the intensity peak, a spatiotemporally shaped pulse can increase the power radiated by orders of magnitude. The enhanced scaling with laser intensity allows for operation at significantly lower electron energies or intensities.

Vacuum acceleration of electrons in a dynamic laser pulse.

A planar laser pulse propagating in vacuum can exhibit an extremely large ponderomotive force. This force, however, cannot impart net energy to an electron: As the pulse overtakes the electron, the initial impulse from its rising edge is completely undone by an equal and opposite impulse from its trailing edge. Here we show that planarlike "flying focus" pulses can break this symmetry, imparting relativistic energies to electrons. The intensity peak of a flying focus-a moving focal point resulting from a chirped laser pulse focused by a chromatic lens-can travel at any subluminal velocity, forward or backward. As a result, an electron can gain enough momentum in the rising edge of the intensity peak to outrun and avoid the trailing edge. Accelerating the intensity peak can further boost the momentum gain. Theory and simulations demonstrate that these dynamic intensity peaks can backwards accelerate electrons to the MeV energies required for radiation and electron diffraction probes of high energy density materials.

Tobramycin once- vs thrice-daily for elective intravenous antipseudomonal therapy in pediatric cystic fibrosis patients.

PURPOSE: We hypothesized that a single intravenous (iv) tobramycine infusion (treatment B) would have equivalent anti-infectious efficacy in chronic Pseudomonas aeruginosa (PA) infection in cystic fibrosis (CF) as the commonly performed treatment of three doses (treatment A) . Toxicity and practicability may even be improved in the single-dose regimen. METHODS: This was a randomized crossover study comparing outcome after 14 and 35 days. The primary end-point was a decrease in the leukocyte count, and the secondary end-points were clinical and lung function parameters, Pseudomonas quantification in sputum, and inflammation markers (immunoglobulin G, C-reactive protein) in serum. 30 patients (20 female, mean age 11.2 years, mean age range 1.7-18.1 years) received elective 14-day courses of treatments A or B, followed by the alternative treatment after a mean interval of 37 (+/- 21) weeks. RESULTS: With the exception of PA density, there were no significant differences between both treatment strategies after 14 days of treatment. After 35 days of treatment, there were no significant changes in the leukocyte count and inflammation markers. Both treatment strategies reduced the bacterial load in the airways, as reflected by a decreased PA density in sputum. Nephrotoxicity was equal in both groups, with a transient slight elevation of urinary N-acetyl-beta-glucosaminidase concentrations. Standard audiometry tests revealed no evidence of a hearing impairment in any patient following therapy. Mean body weight increased during the study period by 0.5 kg. Forced expiratory volume increased by approximately 5% of the predicted volume, forced vital capacity increased by 2% of predicted capacity, and forced mid expiratory flow rate increased by 7% (A) or 4% (B) of the predicted normal value, although these changes were not statistically significant. CONCLUSION: We conclude that tobramycin given in a daily single dose (with the advantage of being more practical in a home environment) has an efficacy equal to that of three daily doses in terms of elective antipseudomonal therapy in clinically stable patients with CF.

Continuous vs thrice-daily ceftazidime for elective intravenous antipseudomonal therapy in cystic fibrosis.

BACKGROUND/AIM: We hypothesized that a continuous 24-h infusion of 100 mg/kg per day ceftazidime (treatment C) would result in equivalent or even superior anti-infectious efficacy in chronic Pseudomonus aeruginosa (PA) infection in patients with cystic fibrosis (CF) in comparison to the usual application of 200 mg/kg per day ceftazidime in three doses (treatment T). METHODS: This was a randomized crossover study comparing outcome after 14 days and 35 days. Tobramycin administered once daily (10 mg/kg per day) was administered concomitantly in both groups. The primary end-point was a decrease in the leukocyte count, and the secondary endpoints were clinical and lung function parameters, Pseudomonas quantification in sputum, and inflammation markers (immunogloblulin [Ig] G, C-reactive protein [CRP]) in serum. All patients received antibiotics electively as 14-day courses on a regular basis, not for acute exacerbations. RESULTS: Fifty-six patients (29 females, mean patient age 14.4 years, age range 5-37) initially received treatments C or T, followed by the alternative treatment after a mean interval of 37 (+/- 21) weeks. After 2 weeks of antibiotic treatment, the overall study group showed significant improvements compared to baseline for body weight, leukocyte counts, CRP, forced expiratory volume in 1 s (FEV(1)), FVC (forced vital capacity), and bacterial load in the airways, with no significant differences between treatment groups. Both regimens were well tolerated. Three weeks after cessation of antimicrobial therapy, leukocytes and PA density had returned to pre-treatment values. CONCLUSION: We conclude that continuous or thrice-daily dosing of intravenous ceftazidime, both combined with once-daily tobramycin, are equally effective application regimens for elective antipseudomonal therapy in clinically stable patients with CF.

Experimental investigation of nasal airflow.

The airway geometry of the nasal cavity is manifestly complex, and the manner in which it controls the airflow to accomplish its various physiological functions is not fully understood. Since the complex morphology and inaccessibility of the nasal passageways precludes detailed in-vivo measurements, either computational simulation or in-vitro experiments are needed to determine how anatomical form and function are related. The fabrication of a replica model of the nasal cavity, of a high optical clarity and derived from in-vivo scan data is described here, together with characteristics of the flow field investigated using particle image velocimetry (PIV) and flow visualization. Flow visualization is shown to be a capable and convenient technique for identifying key phenomena. Specifically the emergence of the jet from the internal nasal valve into the main cavity, how it impacts on the middle turbinate, and the large enhancement of dispersion that accompanies the initial appearance of flow instability are revealed as particularly significant features. The findings from the visualization experiments are complemented by PIV imaging, which provides quantitative detail on the variations in velocity in different regions of the nasal cavity. These results demonstrate the effectiveness of the cavity geometry in partitioning the flow into high shear zones, which facilitate rapid heat transfer and humidification from the nasal mucosa, and slower zones affording greater residence times to facilitate olfactory sensing. The experimental results not only provide a basis for comparison with other computational modelling but also demonstrate an alternative and flexible means to investigate complex flows, relevant to studies in different parts of the respiratory or cardiovascular systems.

Renal Pseudoaneurysms and Arteriovenous Fistulas as a Complication of Nephron-Sparing Partial Nephrectomy: Technical and Functional Outcomes of Patients Treated With Selective Microcoil Embolization During a Ten-Year Period.

PURPOSE: The aim of this study was to evaluate the clinical and functional outcomes in patients who underwent selective interventional embolization of renal pseudoaneurysms or arteriovenous fistulas at our center. MATERIALS AND METHODS: Our retrospective analysis included all consecutive patients who received selective transcatheter embolization of renal pseudoaneurysms or arteriovenous fistulas after partial nephrectomy in our department from January, 2003 to September, 2013. The technical and clinical success rate and functional outcome of every procedure was collected and analyzed. Furthermore, the change in renal parenchymal volume before and after embolization was determined in a subgroup. RESULTS: A total of 1425 patients underwent partial nephrectomy at our hospital. Of these, 39 (2.7 %) were identified with a pseudoaneurysm or an arteriovenous fistula after partial nephrectomy. The diagnosis of the vascular lesions was made by means of biphasic CT or CEUS. Technical success by means of selective microcoil embolization was achieved in all 39 patients (100 %). Clinical success, defined as no need for further operation or nephrectomy during follow-up, was achieved in 35 of 39 patients (85.7 %). Renal function, as measured by eGFR before and after the intervention, did not change significantly. However, a mean loss of parenchymal volume of 25.2 % was observed in a subgroup. No major or minor complications were attributable to the embolization procedure. CONCLUSION: Transcatheter embolization is a promising method for treating vascular complications which may occur after partial nephrectomy. We confirm the high success rate of this technique while discussing renal functional outcomes and potential safety aspects. KEY POINTS: Arterial pseudoaneurysms and arteriovenous fistulas are rare but severe complications after partial nephrectomy. Selective microcoil embolization is a safe and effective kidney-preserving procedure for treating these complications. Embolization leads to a significant loss of renal parenchymal volume but not to a loss of renal function.

Intra- and interhemispheric electroencephalogram coherence in siblings discordant for schizophrenia and healthy volunteers.

Former studies had pointed to an increased electroencephalogram (EEG) coherence in schizophrenics, but it remained unsolved whether this deviation represents the premorbid state or is only a consequence of the current or previous schizophrenic episodes. To clarify this question, we tested the hypothesis that subjects at elevated risk also reveal higher coherences compared to healthy controls. For that, intra- and interhemispheric EEG coherences were investigated in untreated schizophrenics, their healthy siblings, and healthy controls. Differences were only found regarding the intrahemispheric coherences. Both in schizophrenics and, even though to a lesser degree, in their siblings significantly higher coherence estimates were found compared to the control group. The results are in accordance with the assumption that schizophrenia is predominantly a neurodevelopmental disease. Increased coherence might be assumed to be a vulnerability marker for schizophrenia reflecting maldevelopment of the brain before onset of the disorder.

DAT1 gene polymorphism in alcoholism: a family-based association study.

BACKGROUND: The present study tests the hypothesis that the 9-repeat allele of the dopamine transporter gene (DAT1; SLC6A3) is more frequent in alcohol-dependent probands--and in particular those with severe withdrawal symptoms (seizures and/or delirium)--compared to nonalcoholics. METHODS: To avoid stratification effects, the family-based association approach of Falk and Rubinstein was used in our sample of 87 alcohol-dependent probands and their biological parents. RESULTS: By applying a family-based association approach, we were not able to detect significant association between allele 9 at DAT1 (SLC6A3) and alcoholism as well as between patients with or without severe withdrawal symptoms. CONCLUSIONS: Based on our data, the impact of the 9-repeat allele of the dopamine transporter gene in alcoholism and the severity of alcohol withdrawal symptoms is putatively not substantial.

Support for allelic association of a polymorphic site in the promoter region of the serotonin transporter gene with risk for alcohol dependence.

OBJECTIVE: An association between the 5-HTTLPR short variant polymorphism in the promoter region of the serotonin transporter gene and risk for alcohol dependence has been reported from case-control studies that are, however, prone to chance findings related to artifacts of population structure. The authors sought additional evidence for this association from a family-based study. METHOD: Ninety-two alcohol-dependent probands and their parents were tested for nonrandom transmission of alleles from heterozygous parents to affected probands. RESULTS: Preferential transmission of the short allele was found (65 of 102 transmissions from heterozygous parents). CONCLUSIONS: The results suggest allelic association between a variant in the promoter region of the serotonin transporter gene and the risk for alcohol dependence. However, it remains to be seen whether the functional properties of this variant are directly responsible for the increased risk to alcohol dependence.

Subcortical correlates of craving in recently abstinent alcoholic patients.

OBJECTIVE: This study investigated functional cerebral correlates of craving in alcoholic patients and examined the state/trait characteristics of the regional cerebral network implicated in craving. METHOD: Functional magnetic resonance imaging (fMRI) was used to map cerebral response elicited by ethanol odor in 10 male patients with alcohol dependence who had undergone detoxification and 10 matched nonpatients. After 3 weeks, during which the patients underwent standardized behavioral therapy with psychopharmacological intervention, all subjects were studied a second time with fMRI to evaluate the effects of therapy on the functional cerebral correlates of craving. RESULTS: In the alcoholic patients, cue-induced craving before treatment elicited activation primarily in the subcortical-limbic region of the right amygdala/hippocampal area and in the cerebellum. After treatment, activation was found in the superior temporal sulcus, while subcortical or cerebellar participation was no longer present. Comparison subjects showed no comparable amygdala or cerebellar activation during ethanol stimulation and demonstrated no change in activation pattern between measurements. CONCLUSIONS: This investigation points to state-dependent neurobiological correlates of cue-induced craving in alcoholic patients and suggests that these correlates can be influenced by therapeutic interventions. The presence of emotional aspects of craving is suggested by amygdala activation.

Detection of 4'-phosphopantetheine at the thioester binding site for L-valine of gramicidinS synthetase 2.

Biosynthesis of gramicidinS in Bacillus brevis is catalysed by a multienzyme system consisting of two multifunctional proteins, gramicidinS synthetase 1 and 2 codified by the grsA and grsB genes, respectively. GramicidinS synthetase 2 shows a modular architecture of four amino acid-activating domains each containing a thioester binding motif LGG H/D S L/I highly conserved in its C-terminal region, as demonstrated by sequence analysis of the grsB gene [W. Schlumbohm et al. (1991) J. Biol. Chem. 266, 23135-23141]. This multienzyme was specifically labeled at the thioester binding site of L-valine with [3H]N-ethylmaleimide using a substrate protection technique. After enzymatic digestion a labeled active site peptide was isolated in pure form by multistep methodology. This fragment was identified by gas-phase sequencing as the active site peptide of the thiotemplate site for L-Val by comparison with the grsB gene sequence. By mass spectrometry in combination with amino acid analysis it was demonstrated that a 4'-phosphopantetheine carrier was attached to the active serine in this motif. Our results give evidence that multiple peripheral 4'-phosphopantetheine carriers are involved in the formation of gramicidinS in contrast to a central carrier arm as assumed in the original version of the thiotemplate mechanism. A 'Multiple Carrier Model' of nonribosomal peptide biosynthesis is proposed.

Neuronal nicotinic acetylcholine receptor alpha 4 subunit (CHRNA4) and panic disorder: an association study.

Anxiety disorders have been reported to be associated with low-voltage EEG (LVEEG). Some cases with LVEEG (approximately 1/3) have been linked to chromosome 20q13.2q13.3. In the same chromosomal region, the gene for the neuronal nicotinic acetylcholine receptor alpha 4 subunit (CHRNA4) has been located. We therefore tested the hypothesis that polymorphisms in the CHRNA4 gene show an allelic association with panic disorder. We examined the allele frequencies of three different CHRNA4 polymorphisms in patients with panic disorder and in healthy controls. No significant differences in the allele frequencies of these three polymorphisms were noted. This study does not support an association between panic disorder and the CHRNA4 gene.

Fragile-X carrier females: evidence for a distinct psychopathological phenotype?

The present study examined 35 mothers (29 premutation carriers) of children with fragile-X syndrome in measures of intelligence and psychiatric disorders by comparing them with two control groups: a) 30 mothers of children in the general population and b) 17 mothers of non-fra-X retarded children with autism. Premutation carriers had a higher frequency of affective disorders than mothers from the general population. Preliminary data indicate that normally intelligent premutation carriers of the fra-X genetic abnormality have a similar frequency of affective disorders (DSM-III-R criteria [APA, 1987]) than mothers of autistic children. Neither carriers of the premutation nor carriers of the full mutation in the fra-X group obtained a diagnosis of the schizophrenia-spectrum (schizophrenia, schizophreniform disorder, and schizoaffective disorder). Carriers of the fra-X full mutation had considerably lower IQ than carriers of the fra-X premutation. There was a negative correlation between length of CGG repeats and IQ which failed to reach significance in both groups of fra-X carriers. Psychiatric morbidity was not restricted to carriers of the fra-X full mutation only but was also present in normal intelligent premutation carriers. Furthermore the age of onset of psychiatric morbidity in both groups of mothers of fra-X children as well as the group of mothers with autistic children was much earlier than the age when mental retardation had been diagnosed in their children. Increased psychosocial burden of raising a developmentally retarded child and/or feelings of guilt of being a fra-X carrier can therefore not fully explain our findings (three-fold higher frequencies of affective disorders compared to mothers from the general population).

Human delta-opioid receptor gene and susceptibility to heroin and alcohol dependence.

In the present study, we tested the hypothesis that addictive behavior may be influenced by genetic variation in the human delta-opioid receptor gene. We investigated the contribution of a silent T to C change in the coding region to the development of heroin and alcohol dependence using large case-control and family-based association samples. Presence of the C allele was previously reported to significantly increase the risk for heroin dependence. In the present study, however, we did not find statistically significant differences between patients and controls nor did we find preferential transmission of the C allele from parents to affected offspring. Our results, therefore, do not support an association between genetic variation of the delta-opioid receptor and addictive behavior in man.