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Experiments on ASDEX Upgrade (AUG) in 2021 and 2022 have addressed a number of critical issues for ITER and EU DEMO. A major objective of the AUG programme is to shed light on the underlying physics of confinement, stability, and plasma exhaust in order to allow reliable extrapolation of results obtained on present day machines to these reactor-grade devices. Concerning pedestal physics, the mitigation of edge localised modes (ELMs) using resonant magnetic perturbations (RMPs) was found to be consistent with a reduction of the linear peeling-ballooning stability threshold due to the helical deformation of the plasma. Conversely, ELM suppression by RMPs is ascribed to an increased pedestal transport that keeps the plasma away from this boundary. Candidates for this increased transport are locally enhanced turbulence and a locked magnetic island in the pedestal. The enhanced D-alpha (EDA) and quasi-continuous exhaust (QCE) regimes have been established as promising ELM-free scenarios. Here, the pressure gradient at the foot of the H-mode pedestal is reduced by a quasi-coherent mode, consistent with violation of the high-n ballooning mode stability limit there. This is suggestive that the EDA and QCE regimes have a common underlying physics origin. In the area of transport physics, full radius models for both L- and H-modes have been developed. These models predict energy confinement in AUG better than the commonly used global scaling laws, representing a large step towards the goal of predictive capability. A new momentum transport analysis framework has been developed that provides access to the intrinsic torque in the plasma core. In the field of exhaust, the X-Point Radiator (XPR), a cold and dense plasma region on closed flux surfaces close to the X-point, was described by an analytical model that provides an understanding of its formation as well as its stability, i.e., the conditions under which it transitions into a deleterious MARFE with the potential to result in a disruptive termination. With the XPR close to the divertor target, a new detached divertor concept, the compact radiative divertor, was developed. Here, the exhaust power is radiated before reaching the target, allowing close proximity of the X-point to the target. No limitations by the shallow field line angle due to the large flux expansion were observed, and sufficient compression of neutral density was demonstrated. With respect to the pumping of non-recycling impurities, the divertor enrichment was found to mainly depend on the ionisation energy of the impurity under consideration. In the area of MHD physics, analysis of the hot plasma core motion in sawtooth crashes showed good agreement with nonlinear 2-fluid simulations. This indicates that the fast reconnection observed in these events is adequately described including the pressure gradient and the electron inertia in the parallel Ohm’s law. Concerning disruption physics, a shattered pellet injection system was installed in collaboration with the ITER International Organisation. Thanks to the ability to vary the shard size distribution independently of the injection velocity, as well as its impurity admixture, it was possible to tailor the current quench rate, which is an important requirement for future large devices such as ITER. Progress was also made modelling the force reduction of VDEs induced by massive gas injection on AUG. The H-mode density limit was characterised in terms of safe operational space with a newly developed active feedback control method that allowed the stability boundary to be probed several times within a single discharge without inducing a disruptive termination. Regarding integrated operation scenarios, the role of density peaking in the confinement of the ITER baseline scenario (high plasma current) was clarified. The usual energy confinement scaling ITER98( p,y ) does not capture this effect, but the more recent H20 scaling does, highlighting again the importance of developing adequate physics based models. Advanced tokamak scenarios, aiming at large non-inductive current fraction due to non-standard profiles of the safety factor in combination with high normalised plasma pressure were studied with a focus on their access conditions. A method to guide the approach of the targeted safety factor profiles was developed, and the conditions for achieving good confinement were clarified. Based on this, two types of advanced scenarios (‘hybrid’ and ‘elevated’ q -profile) were established on AUG and characterised concerning their plasma performance.

Within the 9th European Framework programme, since 2021 EUROfusion is operating five tokamaks under the auspices of a single Task Force called ‘Tokamak Exploitation’. The goal is to benefit from the complementary capabilities of each machine in a coordinated way and help in developing a scientific output scalable to future largre machines. The programme of this Task Force ensures that ASDEX Upgrade, MAST-U, TCV, WEST and JET (since 2022) work together to achieve the objectives of Missions 1 and 2 of the EUROfusion Roadmap: i) demonstrate plasma scenarios that increase the success margin of ITER and satisfy the requirements of DEMO and, ii) demonstrate an integrated approach that can handle the large power leaving ITER and DEMO plasmas. The Tokamak Exploitation task force has therefore organized experiments on these two missions with the goal to strengthen the physics and operational basis for the ITER baseline scenario and for exploiting the recent plasma exhaust enhancements in all four devices (PEX: Plasma EXhaust) for exploring the solution for handling heat and particle exhaust in ITER and develop the conceptual solutions for DEMO. The ITER Baseline scenario has been developed in a similar way in ASDEX Upgrade, TCV and JET. Key risks for ITER such as disruptions and run-aways have been also investigated in TCV, ASDEX Upgrade and JET. Experiments have explored successfully different divertor configurations (standard, super-X, snowflakes) in MAST-U and TCV and studied tungsten melting in WEST and ASDEX Upgrade. The input from the smaller devices to JET has also been proven successful to set-up novel control schemes on disruption avoidance and detachment.

In 2021 JET exploited its unique capabilities to operate with T and D–T fuel with an ITER-like Be/W wall (JET-ILW). This second major JET D–T campaign (DTE2), after DTE1 in 1997, represented the culmination of a series of JET enhancements—new fusion diagnostics, new T injection capabilities, refurbishment of the T plant, increased auxiliary heating, in-vessel calibration of 14 MeV neutron yield monitors—as well as significant advances in plasma theory and modelling in the fusion community. DTE2 was complemented by a sequence of isotope physics campaigns encompassing operation in pure tritium at high T-NBI power. Carefully conducted for safe operation with tritium, the new T and D–T experiments used 1 kg of T (vs 100 g in DTE1), yielding the most fusion reactor relevant D–T plasmas to date and expanding our understanding of isotopes and D–T mixture physics. Furthermore, since the JET T and DTE2 campaigns occurred almost 25 years after the last major D–T tokamak experiment, it was also a strategic goal of the European fusion programme to refresh operational experience of a nuclear tokamak to prepare staff for ITER operation. The key physics results of the JET T and DTE2 experiments, carried out within the EUROfusion JET1 work package, are reported in this paper. Progress in the technological exploitation of JET D–T operations, development and validation of nuclear codes, neutronic tools and techniques for ITER operations carried out by EUROfusion (started within the Horizon 2020 Framework Programme and continuing under the Horizon Europe FP) are reported in (Litaudon et al Nucl. Fusion accepted), while JET experience on T and D–T operations is presented in (King et al Nucl. Fusion submitted).

In high- β scenarios with on-axis co-current electron cyclotron current drive, which normally lowers q _0 below unity, the absence of sawteeth suggests the involvement of an additional current redistribution mechanism beyond neoclassical current diffusion. This is supported by imaging motional Stark effect diagnostic measurements, which indicate that q _0 remains consistently around 1. This phenomenon is observed in the presence of a 1/1 mode, indicating its potential role in the current redistribution. It is shown that the mode’s ability to modify the central current and suppress sawteeth increases with plasma pressure. These findings align with a recent theoretical model, which predicts a pressure threshold for sawtooth avoidance by a 1/1 quasi-interchange mode and where this threshold increases with the strength of inward current diffusion. Moreover, the advantages of the flux pumping scenario for future machines are highlighted.

The plasma response to resonant magnetic perturbations (RMPs) in ASDEX Upgrade is modeled with the non-linear resistive MHD code JOREK, using input profiles that match those of the experiments as closely as possible. The RMP configuration for which edge localized modes are best mitigated in experiments is related to the largest edge kink response observed near the X-point in modeling. On the edge resonant surfaces q  =  m/n, the coupling between the kink component (m  >  nq) and the m resonant component is found to induce the amplification of the resonant magnetic perturbation. The ergodicity and the 3D-displacement near the X-point induced by the resonant amplification can only partly explain the density pumpout observed in experiments. [ABSTRACT FROM AUTHOR]

The murine embryonic diaphragm is a primary model for studying myogenesis and neuro-muscular synaptogenesis, both representing processes regulated by spatially organized genetic programs of myonuclei located in distinct myodomains. However, a spatial gene expression pattern of embryonic mouse diaphragm has not been reported. Here, we provide spatially resolved gene expression data for horizontally sectioned embryonic mouse diaphragms at embryonic days E14.5 and E18.5. These data reveal gene signatures for specific muscle regions with distinct maturity and fiber type composition, as well as for a central neuromuscular junction (NMJ) and a peripheral myotendinous junction (MTJ) compartment. Comparing spatial expression patterns of wild-type mice with those of transgenic mice lacking either the skeletal muscle calcium channel Ca V 1.1 or β-catenin, reveals curtailed muscle development and dysregulated expression of genes potentially involved in NMJ formation. Altogether, these datasets provide a powerful resource for further studies of muscle development and NMJ formation in the mouse., Competing Interests: The authors declare no competing interests., (© 2024 The Author(s).)

Purpose: It is still in question whether head oscillation damping during walking forms a part of the vestibular function. The anatomical pathway from the vestibular system to the neck muscles via the medial vestibulospinal tract (MVST) is well known but there is a lack of knowledge of the exact influence and modulation of each other in daily life activities., Methods: (I) We fixed a head-neck unit of a human cadaver specimen in a steal frame to determine the required pitch-torque for a horizontal head position. The mean value of the acquired pitch-torque was 0.54 Nm. (II) On a motorized treadmill we acquired kinematic data of the head, the sternum and both feet by wireless 3D IMUs for seven asymptomatic volunteers. Subsequently three randomized task conditions were performed. Condition 1 was walking without any irritation. Condition 2 imitated a sacculus irritation using a standardized cVEMP signal. The third condition used an electric neck muscle-irritation (TENS). The data were analyzed by the simulation environment software OpenSim 4.0., Results: 8 neck muscle pairs were identified. By performing three different conditions we observed some highly significant deviations of the neck muscle peak torques. Analysing Euler angles, we found during walking a LARP and RALP head pendulum, which also was strongly perturbated., Conclusion: Particularly the pitch-down head oscillation damping is the most challenging one for neck muscles, especially under biomechanical concerns. Mainly via MVST motor activity of neck muscles  might be modulated by vestibular motor signals. Two simultaneous proprioceptor effects might optimize head oscillation damping. One might be a proprioceptive feedback loop to the vestibular nucleus. Another might trigger the cervicocollic reflex (CCR)., (© 2020. The Author(s).)

Objective : Nonrestorative sleep and sleep disorders are commonly reported in patients suffering from craniomandibular (CMD) and craniocervical dysfunctions (CCD). This study aimed to investigate polysomnographic characteristics and the reduction of pain before and after treatment in these patients. Methods : Seventy-four patients with sleep disorders and evident CMD and CCD were included. Manual therapy and an Aqualizer® were used in the therapeutic group. Polysomnographic measurements were conducted pre- and post-therapy. Results : The number of sleep stage alterations and the sleep stage index differed significantly between pre- and post-therapeutic measurements. Between both groups, these parameters were significantly different, as well ( p  = .001 and p = .012). The subjective perception of sleep quality improved in 81.6% post-therapy ( p  < .001). Discussion : Manual therapy and the application of an Aqualizer® may improve sleep quality in patients suffering from CMD and CCD. Pain may not be the main cause for the sleep disorders in CMD and CCD.

This paper discusses otorhinolaryngological symptoms associated with functional disorders of the upper cervical spine. Hints aimed to avoid misdiagnoses of cross-organ otorhinolaryngological symptoms as phobic or psychogenic disorders are presented. Clinically relevant neuroanatomical convergence of the upper cervical spine (occiput to C3) is fundamental for the interpretation of functional otorhinolaryngological symptoms. Based thereon, evidence for the most common cervical differential diagnoses of dizziness, tinnitus, dysphagia, and craniomandibular dysfunction is presented separately. The corresponding therapeutic options and their contraindications are discussed in the concluding chapter. The importance of interdisciplinary cooperation in related fields is emphasized.

Introduction  Interdisciplinary research has contributed greatly to an improved understanding of the vestibular system. To date, however, very little research has focused on the vestibular system's somatosensory afferents. To ensure the diagnostic quality of vestibular somatosensory afferent data, especially the extra cranial afferents, stimulation of the vestibular balance system has to be precluded. Objective  Sophisticated movements require intra- and extra cranial vestibular receptors. The study's objective is to evaluate an investigation concept for cervico-vestibular afferents with respect to clinical feasibility. Methods  A dedicated chair was constructed, permitting three-dimensional trunk excursions, during which the volunteer's head remains fixed. Whether or not a cervicotonic provocation nystagmus (c-PN) can be induced with static trunk excursion is to be evaluated and if this can be influenced by cervical monophasic transcutaneous electrical nerve stimulation (c-TENS) with a randomized test group. 3D-video-oculography (VOG) was used to record any change in cervico-ocular examination parameters. The occurring nystagmuses were evaluated visually due to the small caliber of nystagmus amplitudes in healthy volunteers. Results  The results demonstrate: no influence of placebo-controlled c-TENS on the spontaneous nystagmus; a significant increase of the vertical nystagmus on the 3D-trunk-excursion chair in static trunk flexion with cervical provocation in all young healthy volunteers (n = 49); and a significant difference between vertical and horizontal nystagmuses during static trunk excursion after placebo-controlled c-TENS, except for the horizontal nystagmus during trunk torsion. Conclusion  We hope this cervicotonic investigation concept on the 3D trunk-excursion chair will contribute to new diagnostic and therapeutic perspectives on cervical pathologies in vestibular head-to-trunk alignment.

Introduction: Noise is one of the factors that can seriously disturb sleep, and sound volume is an important factor in this context. One strategy involves avoiding exposure to sounds in the night, while entail the minimization of background noise in a bedroom. The goal of this study was to investigate the effect of systematic sound attenuation on nocturnal sleep by influencing sound volume and reverberation within the context of room acoustics., Materials and Methods: On this basis, we designed a randomized, controlled crossover trial investigating 24 healthy sleepers (15 men and 9 women, aged 24.9 ± 4.1 years) with a body mass index (BMI) of 21.9 ± 1.6 kg/m2. Each participant slept for three consecutive nights at three different locations: (a) at our sleep lab, (b) at the participant's home, and (c) at an acoustically isolated room. In addition to conduct of polysomnography (PSG), subjective sleep quality and nocturnal noise level were measured at each location. We likewise measured room temperature and relative humidity., Results: Under conditions of equal sleep efficiency, a significant increase in deep sleep, by 16-34 min, was determined in an acoustically isolated room in comparison to the two other sleep locations. Fewer arousal events and an increase in rapid eye movement (REM) latency became evident in an acoustically isolated environment. Sleep in a domestic environment was subjectively better than sleep under the two test conditions., Discussion: For healthy sleepers, room acoustics influence the microstructure of sleep, without subjective morning benefit. Reduction of noise level and of reverberation leads to an increase in the amount of deep sleep and to reduction of nocturnal arousal events, which is especially important for poor sleepers., Competing Interests: There are no conflicts of interest.

Transplantation of xenogeneic thymus tissue allows xenograft tolerance induction in the highly disparate pig-to-mouse model. Fetal swine thymus (SW THY) can support the generation of a diverse human T cell repertoire that is tolerant of the pig in vitro. We demonstrate that SW THY generates all human T cell subsets, including regulatory T cells (Tregs), in similar numbers as fetal human thymus (HU THY) grafts in immunodeficient mice receiving the same human CD34(+) cells. Peripheral T cells are specifically tolerant to the mouse and to the human and porcine donors, with robust responses to nondonor human and pig Ags. Specific tolerance is observed to pig skin grafts sharing the THY donor MHC. SW THY-generated peripheral Tregs show similar function, but include lower percentages of naive-type Tregs compared with HU THY-generated Tregs. Tregs contribute to donor-pig specific tolerance. Peripheral human T cells generated in SW THY exhibit reduced proportions of CD8(+) T cells and reduced lymphopenia-driven proliferation and memory-type conversion, accelerated decay of memory-type cells, and reduced responses to protein Ags. Thus, SW thymus transplantation is a powerful xenotolerance approach for human T cells. However, immune function may be further enhanced by strategies to permit positive selection by autologous HLA molecules.

Immunosuppressive cytotoxic T lymphocyte associated antigen-4 immunoglobulin fusion proteins (CTLA4-Ig) block the CD28:CD80/86 costimulatory pathway. On a cellular level, CTLA4-Ig is understood to dampen T cell responses. As a mechanism, CTLA4-Ig has been reported to affect dendritic cell (DC) function via inducing the immunosuppressive indoleamine 2,3 dioxygenase (IDO) pathway and promoting a DC regulatory phenotype. We here probed cellular mechanisms of CTLA4-Ig immunoregulation in an allogeneic setting using C57BL/6 splenic or bone marrow derived DCs (BMDCs) as stimulators of allogeneic Balb/c derived T cells. To address whether CTLA4-Ig immunosuppression affected DCs, we pre-exposed C57BL/6 splenic or BMDCs to CTLA4-Ig and removed unbound CTLA4-Ig before co-culture with allogeneic T cells. CTLA4-Ig disappeared rapidly (within 4 h) from the cell membrane by combined internalization and dissociation. These CTLA4-Ig pre-exposed DCs were fully capable of stimulating allogeneic T cell proliferation, suggesting that CTLA4-Ig does not impair the DC stimulatory capacity. Only the presence of CTLA4-Ig during DC/T cell co-culture resulted in the expected inhibition of proliferation. C57BL/6 splenic or BMDCs exposed to CTLA4-Ig did not display IDO activity. We conclude that CTLA4-Ig immunosuppressive activity does not depend on a DC regulatory phenotype but on its presence during DC/T cell interaction., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Purpose: The purpose of the study was to determine whether the conditions during scuba diving without exercise (e.g., submersion, restricted breathing) stimulate the activities of the sympathoadrenergic system and the hypothalamic-pituitary-adrenal axis. This might facilitate panic reactions in dangerous situations., Methods: Fifteen experienced rescue divers participated in three experiments with two submersions each in a diving tower where ambient pressure could be varied. During submersion (duration = 15 min), they were breathing either pure oxygen (ambient pressure = 1.1 bar) or air (1.1 and 5.3 bar) or Heliox21 (21% O(2) and 79% He, 1.1 and 5.3 bar). The subjects stayed upright immediately below the water surface holding one hand with a cannulated radial artery out in the air. Noradrenaline, adrenaline, and dopamine concentrations in arterial blood and heart rate (HR) variability as indicators of sympathoadrenergic activity and cortisol and adrenocorticotropic hormone concentrations as strain indicators were measured., Results: [Noradrenaline] and [adrenaline] (initial values (mean ± SE) = 1616 ± 93 and 426 ± 38 pmol·L(-1)) decreased significantly by up to 30% and 50%, respectively, after 11 min of submersion, independent of pressure and inspired gas. HR variability showed roughly corresponding changes and also indications for parasympathetic stimulation, but artifacts by interference among HR monitors reduced the number of usable measurements. The other hormone concentrations did not change significantly., Conclusions: There was no increase of stress hormone concentrations in experienced subjects. The reduction of [noradrenaline] and [adrenaline] during scuba diving seems to be a reaction to orthostatic relief caused by external hydrostatic pressure on peripheral vasculature. The activity of the vegetative nervous system might be estimated from HR variability if interference among pulse watches can be avoided.

Optimal foraging strategies and food choice are influenced by various factors, e.g. availability, size and caloric content of the food type and predation risk. However, food choice criteria may change when food is not eaten immediately but has to be carried to a storage site for later use. For example, handling time in terms of harvesting and transport time should be optimized, particularly when the risk of predation is high. Thus, it is not clear whether food selected by hoarding animals reflects their food preference due to intrinsic features of the food type, e.g. size, caloric or lipid content, or whether the food type selected is a compromise that also considers the handling time required for harvesting and transport. We investigate this question in relation to food hoarding behaviour in mound-building mice. In autumn, mound-building mice Mus spicilegus collect seeds and other plant material and cover it with soil. Such above-ground storage is quite unusual for rodents. Here, we investigated whether there is a relationship between the seed species preferred as building materials and those preferred for food. We conducted a seed preference test using three most collected weed species for mound building. Controlling factors like food availability or predation risk, mice prefer Setaria spp. as food, although Amaranthus spp. and Chenopodium spp. were preferentially harvested and stored. By including the availability of the three species, our experimental results were confirmed, namely, a clear preference for Setaria spp. Also, handling time and seed size revealed to influence plant choice.

Background: Neutralizing antibodies (NABs) against interferon beta (IFNbeta) are associated with a loss of IFNbeta bioactivity and clinical effectiveness. To date, there are no anti-NAB strategies available. The primary objective of this trial was to investigate whether intravenous IFNbeta-1b can restore bioactivity in NAB-positive patients with MS., Methods: NAB-positive patients with MS were treated with 8 MIU IFNbeta-1b s.c., 8 MIU i.v., and 16 MIU i.v. Each application was preceded by a wash-out period of 1 week. Blood samples were collected before, 3, 12, and 24 h after each administration. Myxovirus protein A (MxA) RNA and protein levels were determined. The study has been approved by the local ethics committee., Results: Five patients completed the study. NAB titers ranged from 42 to 4482 neutralizing units. Median MxA protein (1821, range 12-3234) and RNA (2186, range 114-7525) area under the curve levels for the four measurements at each IFNbeta injection were significantly higher after i.v. application of 16 MIU as compared with both 8-MIU dosages, which were 743 (0-2709) for MxA protein after 8 MIU i.v. and 254 (0-1200) after s.c., and 1763 (25-7188) for MxA RNA after 8 MIU i.v., and 557 (5-2265) after s.c. applications. NAB titers decreased significantly and transiently after infusion of 16 MIU IFNbeta-1b but not after both forms of 8 MIU applications. Typical side effects could be controlled by paracetamol. No allergic reaction was observed., Discussion: The results indicate that i.v. administration of IFNbeta can restore bioavailability of IFNbeta in patients with NABs.

Previous studies assumed that specific audiometric measures like low-frequency biasing were noninvasive and inexpensive techniques for diagnosing endolymphatic hydrops (EH). The aim of this study was to compare the results of low-frequency DPOAE (LF-DPOAE) with those of transtympanic electrocochleography (ECoG) in patients with Menière's disease (MD). The prospective study included 50 patients, 22 to 72 years old, who were diagnosed with Menière's disease according to the criteria laid down by the American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) in 1995. LF-DPOAE and ECoG were performed on the same day after standard audiometry. Enlarged amplitude of summation potential to action potential ratio was used as the diagnostic criterion for EH. The results were compared to those of LF-DPOAE. In this audiometric examination we used the modulation index (MI) to detect EH if MI < 0.5. ECoG yielded a result in 46 of the 50 patients examined. An enlarged SP/AP ratio was found in 23 patients (50%). The results of 33 patients could be compared, i.e. assessable results in both tests. The two tests yielded the same results in 13 patients and different ones in 20 patients. ROC analysis and Mann-Whitney statistics showed no significant correlation between the two tests. With ECoG as the gold standard for verifying EH, we found that LF-DPOAE is not yet a suitable method for diagnosing EH.

Functionalization of atomic force microscope (AFM) tips with bioligands converts them into monomolecular biosensors which can detect complementary receptor molecules on the sample surface. Flexible PEG tethers are preferred because the bioligand can freely reorient and locally palpate the sample surface while the AFM tip is moved along. In a well-established coupling scheme [Hinterdorfer et al. (1996) Proc. Natl. Acad. Sci. U.S.A. 93, 3477-3481], a heterobifunctional PEG linker is used to tether thiol-containing bioligands to amino-functionalized AFM tips. Since antibodies contain no free thiol residues, prederivatization with N-succinimidyl 3-(acetylthio)propionate (SATP) is needed which causes a relatively high demand for antibody. The present study offers a convenient alternative with minimal protein consumption (e.g., 5 microg of protein in 50 microL of buffer) and no prederivatization, using a new heterobifunctional cross-linker that has two different amino-reactive functions. One end is an activated carboxyl (N-hydroxysuccinimide ester) which is much faster to react with the amino groups of the tips than the benzaldehyde function on its other end. The reactivity of the latter is sufficient, however, to covalently bind lysine residues of proteins via Schiff base formation. The method has been critically examined, using biotinylated IgG as bioligand on the tip and mica-bound avidin as complementary receptor. These experiments were well reproduced on amino-functionalized silicon nitride chips where the number of specifically bound IgG molecules (approximately 2000 per microm2) was estimated from the amount of specifically bound ExtrAvidin-peroxidase conjugate. For a bioscientific application, human rhinovirus particles were tethered to the tip, very-low-density lipoprotein receptor fragments were tethered to mica, and the specific interaction was studied by force microscopy.

In the present study, oligo(ethylene glycol) (OEG)-linked alkanethiols were synthesized which carry a vicinal diol on one end of the OEG chain. After self-assembled monolayer (SAM) formation on gold, the vicinal diols were converted into aldehyde functions by exposure to aqueous NaIO4, as previously used for SAMs with OEG chains buried in the center of the SAM [Jang et al. Nano Lett. 2003, 3, 691-694]. Mixed SAMs with latent aldehydes on 5% of the OEG termini showed high protein resistance, which greatly slowed the kinetics of protein coupling on the time scale of minutes. Small bioligands (such as biocytin hydrazide) or small heterobifunctional crosslinkers (maleimidopropionyl hydrazide, pyridyldithiopropionyl hydrazide) with hydrazide functions were efficiently bound to the aldehyde functions on the SAM, providing for specific capture of streptavidin or for fast covalent binding of proteins with free thiols or maleimide functions, respectively. In conclusion, OEG-terminated SAMs with latent aldehydes serve as protein-resistant sensor surfaces which are easily functionalized with small ligands or with heterobifunctional crosslinkers to which the bait molecule is attached in a subsequent step.

Background: The reasons for recurrent adenotonsillitis are poorly understood., Methods: The in situ composition of microbiota of nasal (5 children, 25 adults) and of hypertrophied adenoid and tonsillar tissue (50 children, 20 adults) was investigated using a broad range of fluorescent oligonucleotide probes targeted to bacterial rRNA. None of the patients had clinical signs of infection at the time of surgery., Results: Multiple foci of ongoing purulent infections were found within hypertrophied adenoid and tonsillar tissue in 83% of patients, including islands and lawns of bacteria adherent to the epithelium, with concomitant marked inflammatory response, fissures filled with bacteria and pus, and diffuse infiltration of the tonsils by bacteria, microabscesses, and macrophages containing phagocytosed microorganisms. Haemophilusinfluenzae mainly diffusely infiltrated the tissue, Streptococcus and Bacteroides were typically found in fissures, and Fusobacteria,Pseudomonas and Burkholderia were exclusively located within adherent bacterial layers and infiltrates. The microbiota were always polymicrobial., Conclusions: Purulent processes persist during asymptomatic periods of adenotonsillitis. Most bacteria involved in this process are covered by a thick inflammatory infiltrate, are deeply invading, or are located within macrophages. The distribution of the bacteria within tonsils may be responsible for the failure of antibiotic treatment.

Aldehyde functions are widely used for immobilization of biomolecules on glass surfaces but have found little attention for biofunctionalization of self-assembled monolayers (SAMs) on gold, due to interference between thiol and aldehyde functions. This problem was recently solved by synthesis of an alkanethiol that carried a vicinal diol group [Jang et al. (2003) Nano Lett. 3, 691-694]. The latter served as a latent aldehyde function that was unmasked by short exposure of the vicinal diol-terminated SAM to aqueous periodate. However, the synthesis of the new vicinal diol-terminated alkane thiol was time-consuming and had an overall yield of approximately 3.5%. In the present study, a general modular strategy was introduced by which SAM components with vicinal diol functions were rapidly synthesized with high yield: this was accomplished by amide bond formation between a SAM-forming carboxylic acid (exemplified by lipoic acid and 16-mercaptohexadecanoic acid) with 3-aminopropane-1,2-diol, using suitable protecting groups. The disulfide or free thiol group afforded SAM formation on gold and, after periodate oxidation of the vicinal diol functions, proteins were covalently bound via their lysine residues. At 1 mg/mL protein concentration, complete surface coverage was reached within minutes. No further protein was bound by nonspecific adsorption, but cognate proteins were specifically bound with high capacity. Pyrogallol-O-hexadecanoic acid and 10-undecenoic acid were also coupled with 3-aminopropane-1,2-diol by amide bond formation, thereby producing latent aldehyde-containing SAM components for metal oxides and hydrogen-terminated silicon, respectively, to show the general usefulness of the new synthetic design.

Habitual snoring without episodes of apnea or hypoventilation and without respiratory related arousals is considered to be annoying and without any need for treatment. However, studies seem to suggest an enormous psychosocial impact of annoyance for the bed partner. Apart from subjective questionnaires there still exists no generally accepted mode of measurement that can describe snoring objectively. We therefore adapted methods developed for environmental medicine and established a new snore score using psycho-acoustic parameters. For quantification of snoring noise we conducted nocturnal measurements in 19 habitual snorers. Free-field snore sounds were acquired with two low-cost non-contact microphones and transferred to a PC (sampling frequency 11 kHz). The data were recorded, analysed and stored automatically using a MATLAB script. Following the analysis of sound characteristics and levels, the score was computed from relevant parameters containing the rating level (L(R)), maximum level, two percentile levels for frequent maxima (L(5)S; L(1)) and snoring time. The determined values substantially exceeded the prescribed limits defined by WHO noise guidelines, and mainly affected the equivalent continuous sound exposure level, rating level and the immission standard values of brief noise peaks, whose maximum was exceeded by up to 32 dB(A). The Berlin snore score illustrated the objective acoustic annoyance on a scale from 0 to 100. It allows inter-individual comparison and objectifies the need for therapy. The clinical applicability of evaluating the reduction of snoring after surgical therapy is discussed exemplarily. The presented measuring method was found to be suitable for quantifying snoring noise and can be easily integrated into existing polysomnographic applications. In the case of habitual snoring with objective evidence of psychosocially disturbing acoustic annoyance, health fund providers should assume the costs of mandatory medical therapy.

Covalent binding of bioligands to atomic force microscope (AFM) tips converts them into monomolecular biosensors by which cognate receptors can be localized on the sample surface and fine details of ligand-receptor interaction can be studied. Tethering of the bioligand to the AFM tip via a approximately 6 nm long, flexible poly(ethylene glycol) linker (PEG) allows the bioligand to freely reorient and to rapidly "scan" a large surface area while the tip is at or near the sample surface. In the standard coupling scheme, amino groups are first generated on the AFM tip. In the second step, these amino groups react with the amino-reactive ends of heterobifunctional PEG linkers. In the third step, the 2-pyridyl-S-S groups on the free ends of the PEG chains react with protein thiol groups to give stable disulfide bonds. In the present study, this standard coupling scheme has been critically examined, using biotinylated IgG with free thiols as the bioligand. AFM tips with PEG-tethered biotin-IgG were specifically recognized by avidin molecules that had been adsorbed to mica surfaces. The unbinding force distribution showed three maxima that reflected simultaneous unbinding of 1, 2, or 3 IgG-linked biotin residues from the avidin monolayer. The coupling scheme was well-reproduced on amino-functionalized silicon nitride chips, and the number of covalently bound biotin-IgG per microm2 was estimated by the amount of specifically bound ExtrAvidin-peroxidase conjugate. Coupling was evidently via disulfide bonds, since only biotin-IgG with free thiol groups was bound to the chips. The mechanism of protein thiol coupling to 2-pyridyl-S-S-PEG linkers on AFM tips was further examined by staging the coupling step in bulk solution and monitoring turnover by release of 2-pyridyl-SH which tautomerizes to 2-thiopyridone and absorbs light at 343 nm. These experiments predicted 10(3)-fold slower rates for the disulfide coupling step than actually observed on AFM tips and silicon nitride chips. The discrepancy was reconciled by assuming 10(3)-fold enrichment of protein on AFM tips via preadsorption, as is known to occur on comparable inorganic surfaces.

A new synthesis method for preparation of thin films and powders consisting of zeolite beta nanocrystals embedded in ordered mesoporous silica matrix is described. The final structures possessing bimodal porosity, i.e., high degree of mesophase order and spatially defined microporous zeolite nanocrystals are obtained via simultaneous solvent evaporation of preformed silica/surfactant/ethanol/nanosized zeolite beta assemblies. The films were characterized with grazing-incident diffraction (GID), nitrogen sorption based on gravimetric measurements with quartz crystal microbalance (QCM) devices, and transmission electron microscopy (TEM). It is shown that the incorporation of beta nanocrystals in the mesoporous silica matrix and the mesophase order itself can be controlled through the variation of the fractional amounts of the zeolite nanoparticles and silica/surfactant solutions. The HR-TEM measurements showed that the nanosized Beta microporous crystals are separated and at the same time connected through an ordered mesostructured matrix.

In all, 55 eyes of 55 patients were examined prospectively in random order with the Humphrey field analyzer [central field 76 points, full threshold strategy, single-stimulus presentation, response-button control (HFA 1); central field 76 points, defect-depth strategy, response-button control (HFA 2)] and the Dicon TKS-4000 [central field 76 points, defect-depth strategy, multiple-stimulus presentation, response-button control (DIC 1); central field 76 points, defect-depth strategy, multiple-stimulus presentation, voice control (DIC 2)]. Some 26 patients (47%) had glaucomatous field defects, 7 patients (13%) had lesions of the visual pathway, 5 patients (9%) had normal fields. The other 17 patients (31%) had field defects due to vascular lesions of the retina or the optic nerve, retrobulbar neuritis, cataract, dysthyroid optic neuropathy, disorders of the macula, or human immunodeficiency virus (HIV) retinopathy. The mean testing time for the whole study population was 5.2 +/- 2.7 min for DIC 1. The difference from the mean testing time for HFA 2 (6.4 +/- 2.7 min) is statistically significant (p = 0.0013). DIC 2 reduces the mean testing time to 4.9 +/- 2.6 min. The difference from DIC 1 is not statistically significant (p = 0.8110). A multiple-stimulus presentation and voice control seem to be useful methods to reduce the testing time in automated perimetry without a loss of accuracy. Voice control, as used in the DICON TKS 4000, still has to be improved, however.

A semi-longitudinal study in 111 healthy school children, 11 years old, was started in May 1976 to evaluate age-related "normal-ranges" of two so-called "routine" blood parameters during adolescence. Follow-up examinations were performed at one-year intervals until 1982. In this paper growth velocity is described and results of estimations of alkaline phosphatase, inorganic phosphorus (Pi) and total calcium (Ca) are presented and compared with values in the literature. Peak growth velocity in girls (5.94 +/- 1.92 cm/year) occurred between 11 and 12 years, in boys (7.73 +/- 2.4 cm/year) between the age of 12 and 13 years; from the age of 14 years onwards boys were significantly taller than girls. A strong relationship (p less than 0.05) between growth and alkaline phosphatase could be shown throughout the period observed. Alkaline phosphatase activity varied within a wide range and reached mean peak values at the age of 11 years in girls (470.9 +/- 114.8 U/l) and the age of 13 in boys (514.4 +/- 135.7 U/l). Afterwards, alkaline phosphatase activity decreased towards adult levels. Inorganic phosphorus constantly decreased in both boys and girls until the age of 16, while from the age of 16 to 17 years a significant increase could be observed in both sexes. Total calcium values showed a significant increase between 12 and 13 years in boys and between 13 and 14 years in girls; after the age of 14 values decreased significantly in both sexes.(ABSTRACT TRUNCATED AT 250 WORDS)

Infusion of the beta 2-sympathomimetic agonist fenoterol into pregnant rabbits at a dose of 20 micrograms/kg/min + 2.5 or 30 ml/h isotonic solution significantly reduced urine excretion. Body weight changes of animals infused with 20 micrograms/kg/min fenoterol + 2.5 or 30 ml/h isotonic solution were inversely correlated to the reduction of urine excretion. The urinary potassium excretion per 24 h was not significantly altered after the infusion of fenoterol + 2.5 or 30 ml/h isotonic solution. On the other hand, the urinary sodium excretion per 24 h was significantly decreased in animals infused with 20 micrograms/kg/min fenoterol + 30 ml/h isotonic solution. Infusion of 20 micrograms/kg/min fenoterol + 2.5 ml/h isotonic solution did not significantly change hematocrit, hemoglobin or total protein values. In contrast, increasing the volume of isotonic solution to 30 ml/h resulted in significantly decreased hematocrit, hemoglobin and total protein levels at 6, 12 and 24 h after starting infusion. Serum potassium concentrations were reduced at 2-24 h after infusion of 20 micrograms/kg/min fenoterol + 2.5 or 30 ml/h isotonic solution was started. The serum sodium concentrations did not change significantly during the infusion of 20 micrograms/kg/min fenoterol + 2.5 or 30 ml/h isotonic solution. While in animals infused with isotonic solution alone or with 20 micrograms/kg/min fenoterol + 2.5 ml/h isotonic solution the central venous pressure did not change significantly, it was strongly increased in animals infused with 20 micrograms/kg/min fenoterol + 30 ml/h isotonic solution at 12-24 h after start of infusion. The results of this study are discussed with respect to those obtained from pregnant women under tocolytic therapy and to the possible pathomechanism of the development of pulmonary edema.

Infusion of an isotonic solution and increasing doses of the beta 2-sympathomimetic agonist fenoterol (0.6, 20, or 80 micrograms/kg/min) into female rabbits led to a reduction in urine excretion and a concomitant dose-dependent increase in body weight. Although an infusion at 2.5 ml/hr of an isotonic solution that contained 0.6 or 20 micrograms/kg/min of fenoterol did not significantly change the hematocrit, hemoglobin, or serum protein levels, they were significantly decreased by a similar infusion that contained 80 micrograms/kg/min of fenoterol and by giving 20 ml/hr of an isotonic solution that contained 0.6, 20 or 80 micrograms/kg/min of fenoterol. The central venous pressure remained unchanged in animals that received 2.5 ml/hr of an isotonic solution alone or in combination with 0.6 to 80 micrograms/kg/min of fenoterol. It was significantly elevated in animals treated with 30 ml/hr at similar doses. These data support our hypothesis that the development of pulmonary edema which has been reported with the use of tocolytic therapy is mainly due to hypervolemia related to the antidiuretic effect of the beta 2-sympathomimetics. The intravascular hypervolemia leads to an increased fluid content of the lung and may explain the development of pulmonary edema.

From May 1976 until June 1982 a longitudinal study in 54 apparently healthy Austrian schoolchildren with a mean age of 11.2 years at their first visit was performed. The aim of this study was to determine if there are any age-related changes in serum lipids, lipoproteins and alpha-tocopherol concentrations during adolescence and whether a permanent relationship between lipoproteins and alpha-tocopherol can be observed. Total cholesterol showed a significant decrease from age 11 to 14 years in boys (from 195.5 +/- 42.2 to 147.9 +/- 40.3 mg/dl) as well as in girls (from 181.9 +/- 29.7 to 144.1 +/- 23.4 mg/dl); thereafter, a slight increase could be shown. Similar changes could be observed for LDL cholesterol. No significant sex differences were found either in total or in LDL cholesterol, whereas in HDL cholesterol concentrations, a decrease in boys between 12 and 14 years (from 58.4 +/- 18.3 to 41.7 +/- 10.8 mg/dl) and an increase in girls from 13 years onwards led to significantly lower values in boys than in girls from the age of 16 years onwards. No consistent changes could be shown for alpha-tocopherol blood levels. Nevertheless, a close relationship between total cholesterol and alpha-tocopherol could be observed during all our investigations (0.4695 less than or equal to 0.7300, p less than 0.05) and, to a lesser degree, between LDL cholesterol and alpha-tocopherol. Significant correlations between alpha-tocopherol and HDL cholesterol and between alpha-tocopherol and triglycerides occurred only occasionally.