All optical control of comb-like coherent acoustic phonons in multiple quantum well structures through double-pump-pulse pump-probe experiments.

We present an advancement in applications of ultrafast optics in picosecond laser ultrasonics - laser-induced comb-like coherent acoustic phonons are optically controlled in a In0.27Ga0.73As/GaAs multiple quantum well (MQW) structure by a high-speed asynchronous optical sampling (ASOPS) system based on two GHz Yb:KYW lasers. Two successive pulses from the same pump laser are used to excite the MQW structure. The second pump light pulse has a tunable time delay with respect to the first one and can be also tuned in intensity, which enables the amplitude and phase modulation of acoustic phonons. This yields rich temporal acoustic patterns with suppressed or enhanced amplitudes, various wave-packet shapes, varied wave-packet widths, reduced wave-packet periods and varied phase shifts of single-period oscillations within a wave-packet. In the frequency domain, the amplitude and phase shift of the individual comb component present a second-pump-delay-dependent cosine-wave-like and sawtooth-wave-like variation, respectively, with a modulation frequency equal to the comb component frequency itself. The variations of the individual component amplitude and phase shift by tuning the second pump intensity exhibit an amplitude valley and an abrupt phase jump at the ratio around 1:1 of the two pump pulse intensities for certain time delays. A simplified model, where both generation and detection functions are assumed as a cosine stress wave enveloped by Gaussian or rectangular shapes in an infinite periodic MQW structure, is developed in order to interpret acoustic manipulation in the MQW sample. The modelling agrees well with the experiment in a wide range of time delays and intensity ratios. Moreover, by applying a heuristic-analytical approach and nonlinear corrections, the improved calculations reach an excellent agreement with experimental results and thus enable to predict and synthesize coherent acoustic wave patterns in MQW structures.

High-speed asynchronous optical sampling based on GHz Yb:KYW oscillators.

A low-cost scheme of high-speed asynchronous optical sampling based on Yb:KYW oscillators is reported. Two GHz diode-pumped oscillators with a slight pulse repetition rate offset serve as pump and probe source, respectively. The temporal resolution of this system is limited to 500 fs mainly by the pulse duration of the oscillators and also by relative timing jitter between the oscillators. A near-shot-noise noise floor around 10-6 (∆R/R) is obtained within a data acquisition time of a few seconds. The performance of the system is demonstrated by measurements of coherent acoustic phonons in a semiconductor sample that resembles a semiconductor saturable absorber mirror or an optically pumped semiconductor chip.

Collective Modes and Structural Modulation in Ni-Mn-Ga(Co) Martensite Thin Films Probed by Femtosecond Spectroscopy and Scanning Tunneling Microscopy.

The origin of the martensitic transition in the magnetic shape memory alloy Ni-Mn-Ga has been widely discussed. While several studies suggest it is electronically driven, the adaptive martensite model reproduced the peculiar nonharmonic lattice modulation. We used femtosecond spectroscopy to probe the temperature and doping dependence of collective modes, and scanning tunneling microscopy revealed the corresponding static modulations. We show that the martensitic phase can be described by a complex charge-density wave tuned by magnetic ordering and strong electron-lattice coupling.

Lifetimes of confined acoustic phonons in ultrathin silicon membranes.

We study the relaxation of coherent acoustic phonon modes with frequencies up to 500 GHz in ultrathin free-standing silicon membranes. Using an ultrafast pump-probe technique of asynchronous optical sampling, we observe that the decay time of the first-order dilatational mode decreases significantly from ~4.7 ns to 5 ps with decreasing membrane thickness from ~194 to 8 nm. The experimental results are compared with theories considering both intrinsic phonon-phonon interactions and extrinsic surface roughness scattering including a wavelength-dependent specularity. Our results provide insight to understand some of the limits of nanomechanical resonators and thermal transport in nanostructures.

Surface plasmon-based detection for picosecond ultrasonics in planar gold-dielectric layer geometries.

Longitudinal acoustic modes in planar thin gold films are excited and detected by a combination of ultrafast pump-probe photoacoustic spectroscopy and a surface plasmon resonance (SPR) technique. The resulting high sensitivity allows the detection of acoustic modes up to the 7th harmonic (258 GHz) with sub-pm amplitude sensing capabilities. This makes a comparison of damping times of individual modes possible. Further, the dynamics of the real and imaginary part of the dielectric function and the film's thickness variation are separated by using the dependence of the amplitudes of the acoustic modes on the detection angle and the surface plasmon resonance. We find that longitudinal acoustic modes in the gold films mainly affect the real part of the dielectric function and highlight the importance to consider thickness related effects in acousto-plasmonic sensing.

Neuron-specific deletion of a single copy of the insulin-like growth factor-1 receptor gene reduces fat accumulation during aging.

Insulin, insulin-like growth factor-1 (IGF-1), and leptin signaling have been proposed to play an important role in regulating energy homeostasis. In order to specifically address the role of neuronal IGF-1 receptor (IGF-1R) signaling for energy expenditure and metabolism we used conditional mutagenesis. Deletion of one copy of the IGF-1R specifically in post-mitotic neurons (nIGF-1R(+/-) ) does not result in growth retardation or skeletal abnormalities. Interestingly, male nIGF-1R(+/-) mice accumulate less fat mass during aging accompanied with decreased leptin levels compared to wild-type littermates. Furthermore, male nIGF-1R(+/-) mice present with increased locomotor activity and energy expenditure. In contrast, female nIGF-1R(+/-) mice remained nearly unaffected. Circadian pattern of locomotor activity and energy expenditure as well as food and water intake did not change. Consistent with increased locomotor activity, the respiratory quotient was shifted to increased fat oxidation in nIGF-1R(+/-) mice. Surprisingly, serum IGF-1 and IGF-1 binding protein 3 (IGF-BP3) concentrations were decreased in nIGF-1R(+/-) mice despite the presence of normal pituitaries suggesting a functional feedback mechanism via neuronal IGF-1Rs, which regulate serum IGF-1 levels. Thus, we show that neuron-specific IGF-1R deletion in male mice decreases body fat accumulation and increases energy expenditure during aging.

Glass transition of nanometric polymer films probed by picosecond ultrasonics.

The possibility to measure the glass transition temperature in poly(methyl methacrylate) (PMMA) films by picosecond ultrasonics with thicknesses ranging from 458 nm to 32 nm is demonstrated. A shift of the longitudinal acoustic eigenmodes towards lower frequencies with temperature is observed accompanied by a change in the temperature-frequency slopes at the glass transition temperature. The contributions to the frequency shift from changes in film thickness and sound velocity are discussed and the latter is extracted below the glass transition temperature. Finally, the advantages and disadvantages of the current approach in a comparison to other methods based on acoustic measurements in the GHz regime are reviewed.

Beyond checkpoint inhibition - Immunotherapeutical strategies in combination with radiation.

The revival of cancer immunotherapy has taken place with the clinical success of immune checkpoint inhibition. However, the spectrum of immunotherapeutic approaches is much broader encompassing T cell engaging strategies, tumour-specific vaccination, antibodies or immunocytokines. This review focuses on the immunological effects of irradiation and the evidence available on combination strategies with immunotherapy. The available data suggest great potential of combined treatments, yet also poses questions about dose, fractionation, timing and most promising multimodal strategies.

Interface Adhesion and Structural Characterization of Rolled-up GaAs/In0.2Ga0.8As Multilayer Tubes by Coherent Phonon Spectroscopy.

We present a detailed experimental and theoretical study of the acoustic phonon modes in rolled-up multilayers with thickness of the layers in the nanometre and diameters in the micrometre range. We compare our results to planar, unrolled multilayers grown by molecular beam epitaxy. For the planar multilayers the experimentally obtained acoustic modes exhibit properties of a superlattice and match well to calculations obtained by the Rytov model. The rolled-up superlattice tubes show intriguing differences compared to the planar structures which can be attributed to the imperfect adhesion between individual tube windings. A transfer matrix method including a massless spring accounting for the imperfect adhesion between the layers yields good agreement between experiment and calculations for up to five windings. Areas with sufficient mechanical coupling between all windings can be distinguished by their acoustic mode spectrum from areas where individual windings are only partially in contact. This allows the spatially resolved characterization of individual tubes with micrometre spatial resolution where areas with varying interface adhesion can be identified.

Efficacy and tolerability of intramuscular and oral meloxicam in patients with acute lumbago: a comparison with intramuscular and oral piroxicam.

In this controlled, randomised, parallel-group, multicentre study, the efficacy and tolerability of an intramuscular (i.m.) dose of meloxicam (15 mg) on Day 1 followed by seven days of oral meloxicam (15 mg/day) were compared with those of an i.m. dose of piroxicam (20 mg) on Day 1 followed by seven days of oral piroxicam (20 mg/day) therapy in a total of 169 outpatients with acute lumbago. Time to onset of analgesic action after i.m. injection was determined, and overall efficacy, pain on movement, limitation of daily activities, local tolerability at the injection site and overall tolerability were assessed by investigators and patients on verbal rating scales (VRSs). Adverse events and laboratory assessments were documented. Meloxicam and piroxicam showed a rapid onset of action after i.m. injection (40 and 45 minutes median time, respectively), overall efficacy of both therapies was highly rated, and limitations to daily life were greatly reduced in the majority of patients in both groups. There were no statistically significant differences in efficacy between meloxicam and piroxicam. Local and overall tolerabilities were equally good for the two drugs, but there were fewer gastrointestinal (GI) adverse events among meloxicam patients (1.2% of patients) than piroxicam patients (7.0% of patients). The improved tolerability profile of meloxicam may be explained by its selectivity towards cyclooxygenase-2.

The efficacy and tolerability of an 8-day administration of intravenous and oral meloxicam: a comparison with intramuscular and oral diclofenac in patients with acute lumbago. German Meloxicam Ampoule Study Group.

In this controlled, randomized, parallel and open multicentre study, the efficacy and tolerability of a regimen comprising intravenous (i.v.) meloxicam followed by oral therapy was compared with a standard regimen of intramuscular (i.m.) diclofenac followed by oral dosing in patients with acute lumbago. Of a total of 183 patients, 92 were randomized to receive meloxicam 15 mg i.v. on day 1 followed by 7 days oral treatment with one 15 mg tablet daily, and 91 patients received diclofenac 75 mg i.m. on day 1 followed by 7 days treatment with one 100 mg slow release tablet daily. Pain on movement and limitation of activities were assessed by patients and physicians using questionnaires. Meloxicam i.v. demonstrated a significantly faster median time of onset of analgesic action (30 minutes), compared with diclofenac i.m. (60 minutes). The reduction in pain during movement 30 minutes after injection was also significantly in favour of meloxicam. Assessments of global efficacy indicated that meloxicam was significantly better than diclofenac as rated by investigators (p = 0.02) and patients (p = 0.01). Moreover, the rating of investigators and patients for local and global tolerance was significantly in favour of meloxicam (p < 0.05) and improvements in the quality of life were almost significant (p = 0.053). Fewer adverse events, particularly of a gastrointestinal (GI) nature, occurred in the meloxicam group compared with the diclofenac group. This study therefore demonstrates that meloxicam 15 mg i.v. followed by oral therapy is both efficacious and well tolerated in the treatment of acute lumbago, and compares favourably with the standard NSAID, diclofenac, in this indication.

Metformin lowers Ser-129 phosphorylated α-synuclein levels via mTOR-dependent protein phosphatase 2A activation.

Phospho-Ser129 α-synuclein is the modified form of α-synuclein that occurs most frequently within Parkinson's disease pathological inclusions. Here we demonstrate that the antidiabetic drug metformin significantly reduces levels of phospho-Ser129 α-synuclein and the ratio of phospho-Ser129 α-synuclein to total α-synuclein. This effect was documented in vitro in SH-SY5Y and HeLa cells as well as in primary cultures of hippocampal neurons. In vitro work also elucidated the mechanisms underlying metformin's action. Following metformin exposure, decreased phospho-Ser129 α-synuclein was not strictly dependent on induction of AMP-activated protein kinase, a primary target of the drug. On the other hand, metformin-induced phospho-Ser129 α-synuclein reduction was consistently associated with inhibition of mammalian target of rapamycin (mTOR) and activation of protein phosphatase 2A (PP2A). Evidence supporting a key role of mTOR/PP2A signaling included the finding that, similar to metformin, the canonical mTOR inhibitor rapamycin was capable of lowering the ratio of phospho-Ser129 α-synuclein to total α-synuclein. Furthermore, no decrease in phosphorylated α-synuclein occurred with either metformin or rapamycin when phosphatase activity was inhibited, supporting a direct relationship between mTOR inhibition, PP2A activation and protein dephosphorylation. A final set of experiments confirmed the effectiveness of metformin in vivo in wild-type C57BL/6 mice. Addition of the drug to food or drinking water lowered levels of phospho-Ser129 α-synuclein in the brain of treated animals. These data reveal a new mechanism leading to α-synuclein dephosphorylation that could be targeted for therapeutic intervention by drugs like metformin and rapamycin.

Identification of a region in the human IRS2 promoter essential for stress induced transcription depending on SP1, NFI binding and ERK activation in HepG2 cells.

Recent studies have discovered changes in the insulin-/IGF1 signaling affecting glucose metabolism and the molecular pathogenesis of human hepatocellular cancer. Insulin/IGF1 receptor mediates its intracellular effects by recruitment of one out of the four different insulin receptor substrates (IRS). To investigate mechanisms of IRS2 expression, we analyzed transcriptional regulation of IRS2 in human HepG2 cells. We identified a region 688 bp upstream of the translation start codon responsible for approximately 90% of basal human IRS2 promoter activity in HepG2 cells, and confirmed binding of specificity protein 1 (also called Sp1 transcription factor, SP1) and nuclear factor 1 (NFI) in this region. Mutation of both SP1 and NFI binding sites or inhibition of extracellular signal regulated kinase (ERK) suppressed IRS2 promoter activity almost completely, revealing a major role of MAP kinases (MAPK) for IRS2 transcription. Activating this cascade with oxidative stress increased IRS2 promoter activity and endogenous IRS2 expression substantially. IRS2 promoter activity rose even more after additional inhibition of p38MAPK indicating an inhibitory effect of p38MAPK on ERK mediated IRS2 transcription. Activation of the MAPK pathway using interleukin 1, beta (IL1B) increased IRS2 promoter activity similar to oxidative stress. In contrast IL1B decreases and inhibition of the MAPK pathway increases IRS1 promoter activity revealing opposed effects of IL1B and ERK on the expression of different IRS proteins. In conclusion we discovered a specific region (-688 to -611 bp) in the IRS2 promoter essential for basal promoter activity and oxidative stress induced transcription depending on ERK activation and SP1 and NFI binding in human hepatocytes.

[Effect and effectiveness of hyperbaric oxygen therapy in chronic hearing disorders. Report of 557 cases 1989]. / Zur Wirkung und Wirksamkeit der hyperbaren Sauerstofftherapie bei alten Hörstörungen. Bericht über 557 Fälle aus dem Jahre 1989.

After ten applications of hyperbaric oxygen therapy to 557 patients with hearing loss, 27.8% of the patients experienced a hearing improvement of more than 10 dB. Tinnitus improved in 62.2% of all cases. Hyperbaric oxygen therapy should be used for all cases of extreme hearing loss or severe tinnitus that is resistant to the usual therapy.

A comparison of the efficacy and tolerability of meloxicam and diclofenac in the treatment of patients with osteoarthritis of the lumbar spine.

OBJECTIVE: The aim of this study was to evaluate the efficacy and tolerability of meloxicam compared with diclofenac in patients with osteoarthritis of the lumbar spine. SUBJECTS: 229 patients with radiologically confirmed osteoarthritis of the lumbar spine. TREATMENT AND METHODS: Once-daily meloxicam 7.5 mg tablet or diclofenac 100 mg slow release tablet. Efficacy and tolerability parameters were assessed at baseline and after 3, 7 and 14 days of treatment. RESULTS: The two drugs had equal short-term efficacy, with pain on motion of lumbar spine significantly (p<0.05) decreased at Day 3. Secondary efficacy variables were also significantly improved at Days 3, 7 and 14. There were no statistically significant differences between the two drugs, although the global tolerability of meloxicam was significantly better than for diclofenac, as assessed by the investigators (p = 0.0072) and the patients (p = 0.049). CONCLUSIONS: Meloxicam and diclofenac were equivalent in relieving the acute pain associated with osteoarthritis of the lumbar spine. However, meloxicam was much better tolerated.

Arteria ulnar superficial: importancia anátomo clínica / Superficial ulnar artery: anatomoclinical importancy

La arteria ulnar se origina normalmente de la arteria braquial a nivel de la fosa cubital. Algunas veces tiene un origen más alto pero su trayecto y relaciones a nivel del antebrazo son normales. En otras ocaciones, un origen alto de la arteria ulnar va acompañado de un trayecto distinto, anterior a la musculatura antebraquial, pasando a denominarse arteria ulnar superficial. Sin embargo, raramente ha sido descrita superficial a la fascia profunda, de tal modo que su trayecto es próximo a la superficie pero subfascial. Describimos un caso de arteria ulnar superficial, unilateral, encontrada en la disección de un cadáver de un individuo adulto de sexo masculino, en la Disciplina de Anatomía Humana, Facultad de Medicina de la Universidad de La Frontera, Temuco, Chile. La arteria ulnar superficial se originaba de la arteria braquial en la parte distal del brazo. Acompañada de sus dos venas satélites era cruzada anteriormente por la vena intermedia basílica. Descendía anteriormente a los músculos pronador redondo, flexor radial del carpo y palmar largo, colocándose en el tercio medio del antebrazo, anteromedialmente al músculo flexor ulnar del carpo, aproximándose a la vena basílica del antebrazo. Las variaciones anatómicas arteriales adquieren importancia en los procedimientos de rutina que se efectúan tanto a nivel de la fosa cubital como de la región antebraquial anterior, en especial para los cirujanos plásticos y vasculares, radiólogos y otros profesionales que deben intervenir las venas superficiales de la región