Effects of ganaxolone on non-seizure outcomes in CDKL5 Deficiency Disorder: Double-blind placebo-controlled randomized trial.

CDKL5 deficiency disorder (CDD) is a rare developmental and epileptic encephalopathy. Ganaxolone, a neuroactive steroid, reduces the frequency of major motor seizures in children with CDD. This analysis explored the effect of ganaxolone on non-seizure outcomes. Children (2-19 years) with genetically confirmed CDD and ≥ 16 major motor seizures per month were enrolled in a double-blind randomized placebo-controlled trial. Ganaxolone or placebo was administered three times daily for 17 weeks. Behaviour was measured with the Anxiety, Depression and Mood Scale (ADAMS), daytime sleepiness with the Child Health Sleep Questionnaire, and quality of life with the Quality of Life Inventory-Disability (QI-Disability) scale. Scores were compared using ANOVA, adjusted for age, sex, number of anti-seizure mediations, baseline 28-day major motor seizure frequency, baseline developmental skills, and behaviour, sleep or quality of life scores. 101 children with CDD (39 clinical sites, 8 countries) were randomized. Median (IQR) age was 6 (3-10) years, 79.2 % were female, and 50 received ganaxolone. After 17 weeks of treatment, Manic/Hyperactive scores (mean difference 1.27, 95%CI -2.38,-0.16) and Compulsive Behaviour scores (mean difference 0.58, 95%CI -1.14,-0.01) were lower (improved) in the ganaxolone group compared with the placebo group. Daytime sleepiness scores were similar between groups. The total change in QOL score for children in the ganaxolone group was 2.6 points (95%CI -1.74,7.02) higher (improved) than in the placebo group but without statistical significance. Along with better seizure control, children who received ganaxolone had improved behavioural scores in select domains compared to placebo.

Diffraction properties of periodic lattices under free electron laser radiation.

In this Letter, we report the pioneering use of free electron laser radiation for the investigation of periodic crystalline structures. The diffraction properties of silver behenate single nanocrystals (5.8 nm periodicity) with the dimensions of 20 nm x 20 nm x 20 microm and as powder with grain sizes smaller than 200 nm were investigated with 8 nm free electron laser radiation in single-shot modus with 30 fs long free electron laser pulses. This work emphasizes the possibility of using soft x-ray free electron laser radiation for these crystallographic studies on a nanometer scale.

Aspects of the photodimerization mechanism of 2,4-dichlorocinnamic acid studied by kinetic photocrystallography.

Photoinduced structural variations in single crystals of 2,4-dichloro-trans-cinnamic acid (C9H6Cl2O2, DiClCA) have been investigated using X-ray diffraction (photocrystallography) and optical spectroscopic methods. During UV irradiation, which initiates the irreversible dimerization reaction, a loss of the long-range order of the reactant single crystal was found, i.e., that the dimerization is a heterogeneous one. This unexpected result emphasizes the still-existing problem of predicting changes or of remaining periodicity during chemical reactions in the solid state. On the basis of the experimental results, we propose a qualitative kinetic reaction scheme for DiClCA heterogeneous dimerization reaction.

Nonradiative relaxation of thiacarbocyanine dyes in binary mixtures.

It was found that preferential solvation of cyanine dyes in binary mixtures can strongly affect both their isomerization and aggregation; the comparison of absorption and fluorescence excitation spectra might be a useful tool for studying these nonradiative processes.

Nonlinear acoustic approach to material characterisation of polymers and composites in tensile tests.

The paper reports on experimental study of elastic nonlinearity of polymers and glass fibre-reinforced (GFR-) composites in a wide range of tensile stress applied (up to a fracture limit). Focused slanted transmission mode (FSTM) of air-coupled ultrasound is adapted for remote generation and detection of flexural waves in the samples of plastics. Local noncontact measurements of flexural wave velocity as a function of static strain are used to calculate the second-order nonlinearity parameters beta2 and study their behaviour through a loading cycle. Molecular untangling and crazing phenomena are identified, respectively, with maxima of positive and negative beta2 in thermoplastics. In composites, mechanics of fibre-matrix interaction is considered for brittle and plastic fractures. Hysteresis in velocity variation during loading-unloading cycle is used as an indicator of residual defect accumulation.

Nonlinear modulation technique for NDE with air-coupled ultrasound.

The present study is aimed at expanding flexibility and application area of nonlinear acoustic modulation (NAM-) technique by combining the benefits of noncontact ultrasound excitation (remote locating and imaging of defects) with sensitivity of nonlinear methods in a new air-coupled NAM-version. A pair of focused air-coupled transducers was used to generate and receive (high-frequency) longitudinal or flexural waves in plate-like samples. Low-frequency (LF-) vibrations were excited with a shaker or a loudspeaker. Temporal and spectral analysis of the output signal revealed an extremely efficient nonlinear amplitude modulation and multiple frequency side-bands for sound transmission and flexural wave propagation through cracked defects. On the contrary, a negligible modulation was observed for large and medium scale inclusions and material inhomogeneities (linear defects). A new subharmonic mode of the NAM was observed at high excitation levels. It was also shown for the first time that nonlinear vibrations of cracks resulted in radiation of a very high-order harmonics (well above 100) of the driving excitation in air that enabled imaging of cracks remotely by registration their highly nonlinear "acoustic emission" with air-coupled transducers.

First investigations of the kinetics of the topochemical reaction of p-formyl-trans-cinnamic acid by time-resolved X-ray diffraction.

Under UV irradiation p-formyl-trans-cinnamic acid (p-FCA) crystals in the beta-phase dimerise irreversibly to solid 4,4'-diformyl-beta-truxinic acid. The experimental conditions were chosen in such a way (non-aqueous environment and room temperature) that the product formed is amorphous. The kinetics of this bimolecular reaction, which has not yet been characterised, was investigated by picosecond time-resolved X-ray diffraction. From the experimental results a mechanism for this topochemical reaction is proposed including two observed time constants, one less than 100 ps and another of several seconds. The feasibility of investigating this class of substances by time-resolved X-ray diffraction from third generation synchrotron sources and future free-electron lasers is discussed.

Air-coupled ultrasound inspection of various materials.

Conventional ultrasound inspection, a standard non-destructive testing method, uses a coupling medium (e.g. water) because of impedance mismatch. This liquid contact is a drawback because it prevents inspection of many materials. There is a need, then, for air-coupled ultrasound testing, which is now feasible because of low impedance focused narrow band transducers and sensitive electronics, both of which improve the signal-to-noise ratio. We present results obtained on fibre-reinforced plastics, water sensitive materials (e.g. reinforced ceramics), and "shape adaptive" structures to reveal delaminations, impacts, and growth of internal defects. Actuators embedded in "adaptive" structures are used as transmitters while the receiver records the signals. Thus it is possible to image defect areas and non-linear behaviour of potential defects.

CAN: an example of nonclassical acoustic nonlinearity in solids.

A new class of nonlinear acoustic phenomena has been observed for acoustic wave interaction with simulated and realistic nonbonded contact interfaces (cracked defects) in solids. "Nonclassical" effects are due to substantially asymmetric stiffness characteristics of the interface for normal stress that results in specific contact acoustic nonlinearity (CAN). The asymmetry in the contact restoring forces causes the stiffness parametric modulation and instability of oscillations, which results in acoustic wave fractional subharmonic generation. The CAN subharmonics and higher harmonics reveal threshold dynamic behaviour, evident hysteresis, and instability effects.

Acoustic non-linearity for defect selective imaging.

Non-linear acoustic effects are of increasing interest in close-to-application research in which mostly ultrasonic frequencies above 1 MHz are used. If the excitation frequency is reduced, one can use high power excitation performed locally by a piezoceramic stack actuator that provides much higher vibration amplitudes. The combination of this excitation with a scanning laser interferometer provides a system for rapidly imaging non-linearities and thereby selectively detecting defects in most kinds of materials. This contribution presents various experimental results showing the potential of this new technique.

[The patient with respiratory problems]. / Der respiratorische Problempatient.

Despite improvements in operative and anesthesiological techniques, respiratory problems in surgical patients have been minimized but not eliminated. In addition to risks which are typical for the individual patient, the perioperative respiratory morbidity is affected by anesthesiological manipulations as well as the operation and the nature of the operation (elective versus emergency). In this paper, after describing anesthesia-associated disturbances of the respiratory situation together with worsening due to the disease in patients with COLD, techniques and methods for therapy, prophylaxis, and prognostic assessment are delineated. Two examples are given for patients with respiratory problems (abdomino-thoracic esophageal resection as a example of local trauma in patients with numerous preoperative risk factors and acute necrotizing pancreatitis to describe the sequelae of a toxic process). The essence of our discussion is that, prognostically, preoperative diagnosis is of reduced value. Only a synopsis of clinical findings together with spirometry and blood gas analysis appears to be relevant. Early mobilization in conjunction with excellent postoperative pain therapy is of utmost importance, which is equivalent to the almost routine placement of a patient controllable epidural analgesia technique. These concepts have shown in the two patient groups described that respiratory morbidity may be reduced significantly. Cooperation between surgeons and anesthesiologists, which is characterized by complete and mutually high competence on both sides, is essential for successfully managing patients at increased respiratory risk.

Investigations into the polymorphism of lipid A from lipopolysaccharides of Escherichia coli and Salmonella minnesota by Fourier-transform infrared spectroscopy.

The polymorphism of lipid A, the endotoxic principle of the lipopolysaccharides of gram-negative bacteria, has been investigated in the fully hydrated state at temperatures between 5 degrees and 58 degrees C via Fourier-transform infrared spectroscopy. These measurements were supplemented by X-ray diffraction, fluorescence intensity techniques and differential thermal analysis. Up to three distinct phase transitions could be detected, with the main transition temperatures lying at approximately 41 degrees, 46 degrees, 44 degrees and 47 degrees C for Escherichia coli lipid A, Salmonella minnesota lipid A, and the synthetic lipid A compounds 506 and 516, respectively. 4'-Monophosphoryl-lipid A samples exhibited their main transition temperatures at considerably higher temperatures (about 52 degrees C for E. coli lipid A). The analysis of greater than CH2 stretching absorption bands as well as the wide-angle scattering behaviour of the lipid A samples showed that the main transition apparently involved the completion of hydrocarbon chain melting of lipid A, as typically observed for phospholipids. However, the phase transition behaviour was found to be much more complex than that usually observed for model phospholipid systems. Even below the main transition temperature, considerable amounts of the methylene segments of the acyl chains of lipid A were found to assume gauche conformations. These conformational changes might be related to the occurrence of up to two further transitions located at about 22 degrees, 30 degrees, 27 degrees and 25.5 degrees C (first transition) and at about 34 degrees, 42 degrees, 38.5 degrees and 40.5 degrees C (second transition) for E. coli lipid A, S. minnesota lipid A and the synthetic lipid A compounds 506 and 516, respectively. Furthermore, by the analysis of some characteristic infrared absorption bands related to the hydrophilic backbone, it could be demonstrated that the temperature-induced conformational changes occurring within the hydrocarbon chains were constantly and simultaneously accompanied by detectable rearrangements within the interfacial region and the polar head group of lipid A. The following conclusions were drawn: Up to about 30 degrees C the lipid A assemblies were supposed to adopt virtually bilayered, true lamellar arrangements, as revealed by the analysis of greater than CH2 scissoring vibrations and X-ray diffraction pattern. However, as indicated by fluorometric techniques, no stable closed vesicles seemed to be formed even under these conditions.(ABSTRACT TRUNCATED AT 400 WORDS)

Optoacoustic and photothermal material inspection techniques.

Infrared photothermal material inspection in a transmission arrangement is compared to optoacoustic imaging with respect to depth range, resolution, and interpretation of results. The photothermal method seems to be advantageous, but depth information is not obtained.