Sleep-wake sensitive mechanisms of adenosine release in the basal forebrain of rodents : an in vitro study

Adenosine acting in the basal forebrain is a key mediator of sleep homeostasis. Extracellular adenosine concentrations increase during wakefulness, especially during prolonged wakefulness and lead to increased sleep pressure and subsequent rebound sleep. The release of endogenous adenosine during the sleep-wake cycle has mainly been studied in vivo with microdialysis techniques. The biochemical changes that accompany sleep-wake status may be preserved in vitro. We have therefore used adenosine-sensitive biosensors in slices of the basal forebrain (BFB) to study both depolarization-evoked adenosine release and the steady state adenosine tone in rats, mice and hamsters. Adenosine release was evoked by high K+, AMPA, NMDA and mGlu receptor agonists, but not by other transmitters associated with wakefulness such as orexin, histamine or neurotensin. Evoked and basal adenosine release in the BFB in vitro exhibited three key features: the magnitude of each varied systematically with the diurnal time at which the animal was sacrificed; sleep deprivation prior to sacrifice greatly increased both evoked adenosine release and the basal tone; and the enhancement of evoked adenosine release and basal tone resulting from sleep deprivation was reversed by the inducible nitric oxide synthase (iNOS) inhibitor, 1400 W. These data indicate that characteristics of adenosine release recorded in the BFB in vitro reflect those that have been linked in vivo to the homeostatic control of sleep. Our results provide methodologically independent support for a key role for induction of iNOS as a trigger for enhanced adenosine release following sleep deprivation and suggest that this induction may constitute a biochemical memory of this state

Discrepancy between prevalence and perceived effectiveness of treatment methods in myofascial pain syndrome: Results of a cross-sectional, nationwide survey

Background: Myofascial pain is a common dysfunction with a lifetime prevalence affecting up to 85% of the general population. Current guidelines for the management of myofascial pain are not available. In this study we investigated how physicians on the basis of prescription behaviour evaluate the effectiveness of treatment options in their management of myofascial pain. Methods: We conducted a cross-sectional, nationwide survey with a standardized questionnaire among 332 physicians (79.8% male, 25.6% female, 47.5 +/- 9.6 years) experienced in treating patients with myofascial pain. Recruitment of physicians took place at three German meetings of pain therapists, rheumatologists and orthopaedists, respectively. Physicians estimated the prevalence of myofascial pain amongst patients in their practices, stated what treatments they used routinely and then rated the perceived treatment effectiveness on a six-point scale (with 1 being excellent). Data are expressed as mean +/- standard deviation. Results: The estimated overall prevalence of active myofascial trigger points is 46.1 +/- 27.4%. Frequently prescribed treatments are analgesics, mainly metamizol/paracetamol (91.6%), non-steroidal anti-inflammatory drugs/coxibs (87.0%) or weak opioids (81.8%), and physical therapies, mainly manual therapy (81.1%), TENS (72.9%) or acupuncture (60.2%). Overall effectiveness ratings for analgesics (2.9 +/- 0.7) and physical therapies were moderate (2.5 +/- 0.8). Effectiveness ratings of the various treatment options between specialities were widely variant. 54.3% of all physicians characterized the available treatment options as insufficient. Conclusions: Myofascial pain was estimated a prevalent condition. Despite a variety of commonly prescribed treatments, the moderate effectiveness ratings and the frequent characterizations of the available treatments as insufficient suggest an urgent need for clinical research to establish evidence-based guidelines for the treatment of myofascial pain syndrome

Euclid preparation. TBD. Forecast impact of super-sample covariance on 3x2pt analysis with Euclid

Deviations from Gaussianity in the distribution of the fields probed by large-scale structure surveys generate additional terms in the data covariance matrix, increasing the uncertainties in the measurement of the cosmological parameters. Super-sample covariance (SSC) is among the largest of these non-Gaussian contributions, with the potential to significantly degrade constraints on some of the parameters of the cosmological model under study -- especially for weak lensing cosmic shear. We compute and validate the impact of SSC on the forecast uncertainties on the cosmological parameters for the Euclid photometric survey, obtained with a Fisher matrix analysis, both considering the Gaussian covariance alone and adding the SSC term -- computed through the public code PySSC. The photometric probes are considered in isolation and combined in the `3$\times$2pt' analysis. We find the SSC impact to be non-negligible -- halving the Figure of Merit of the dark energy parameters ($w_0$, $w_a$) in the 3$\times$2pt case and substantially increasing the uncertainties on $\Omega_{{\rm m},0}, w_0$, and $\sigma_8$ for cosmic shear; photometric galaxy clustering, on the other hand, is less affected due to the lower probe response. The relative impact of SSC does not show significant changes under variations of the redshift binning scheme, while it is smaller for weak lensing when marginalising over the multiplicative shear bias nuisance parameters, which also leads to poorer constraints on the cosmological parameters. Finally, we explore how the use of prior information on the shear and galaxy bias changes the SSC impact. Improving shear bias priors does not have a significant impact, while galaxy bias must be calibrated to sub-percent level to increase the Figure of Merit by the large amount needed to achieve the value when SSC is not included.Comment: 22 pages, 13 figure

Second Generation Steroidal 4-Aminoquinolines Are Potent, Dual-Target Inhibitors of the Botulinum Neurotoxin Serotype A Metalloprotease and P. falciparum Malaria

Significantly more potent second generation 4-amino-7-chloroquinoline (4,7-ACQ) based inhibitors of the botulinum neurotoxin serotype A (BoNT/A) light chain were synthesized. Introducing an amino group at the C(3) position of the cholate component markedly increased potency (IC50 values for such derivatives ranged from 0.81 to 2.27 mu M). Two additional subclasses were prepared: bis(steroidal)-4,7-ACQ derivatives and bis(4,7-ACQ)cholate derivatives; both classes provided inhibitors with nanomolar-range potencies (e.g., the K-i of compound 67 is 0.10 mu M). During BoNT/A challenge using primary neurons, select derivatives protected SNAP-25 by up to 89%. Docking simulations were performed to rationalize the compounds' in vitro potencies. In addition to specific residue contacts, coordination of the enzyme's catalytic zinc and expulsion of the enzyme's catalytic water were a consistent theme. With respect to antimalarial activity, the compounds provided better IC90 activities against chloroquine resistant (CQR) malaria than CQ, and seven compounds were more active than mefloquine against CQR strain W2

The role of geotechnical conditions in the foundation, expansion and preservation of the ancient town of Orvieto (Italy)

Orvieto rises on top of a mesa formed by a slab of weak pyroclastic rocks overlying an overconsolidated clay formation. The particular geotechnical conditions of the site en-hanced the erosive process that isolated the mesa and in turn favoured human settlement. These geotechnical conditions include the stiffness contrast between the slab and the clay, the low strength of the pyroclastics, and the susceptibility to degradation of the clay formation. These conditions have been found to be the source of a complex and time-dependent interaction between landslides and urbanization. In this paper the anthropic changes to the natural evolution of the landscape are reconstructed through archival and historic documents over the last eight centuries and interpreted from a geotechnical point of view. The types and characteristics of failures that occurred in the past are described by means of aerial photo analysis, field surveys and archival research, whilst geometry and kinematics of active movements are illustrated using present-day monitoring results. Based on a detailed interpretation of displacement and pore pressure monitoring in the clay slope and the results of numerical analysis of the erosional process and selected failures, a conceptual model of the instability mechanism of the hill is proposed. Finally, protection policies from the Renaissance period until the XX century, when comprehensive preservation projects started, are illustrated and their impact on the instability mechanism discussed

Input data: geotechnics

Reducing the risks associated with tunnel construction is the main purpose of geo-technical investigations and characterization. It is therefore essential that geotechni-cal investigation be carried out since the very beginning of the project. This requires collecting all existing information and data. At the same time, the relevant design parameters should be assessed from the collected data to: choose a suitable alignment for the tunnel, analyse the stability of the face, define the associated ground support and improvement, design the tunnel lining and carry out a pre-construction risk as-sessment on buildings adjacent to tunnelling works. On such basis, the geotechnical characterization should permit us to assess the feasibility of alternative schemes, to select the most appropriate construction method, to anticipate possible risks during construction and to undertake any possible mitigation. In this chapter, after recalling the main definitions of geotechnical properties, lab-oratory tests and site investigation for geotechnical characterization of tunnelling are presented and the geotechnical model is discussed

Input data: geotechnics

Reducing the risks associated with tunnel construction is the main purpose of geotechnical investigations and characterization. It is therefore essential that geotechnical investigation be carried out since the very beginning of the project. This requires collecting all existing information and data. At the same time, the relevant design parameters should be assessed from the collected data to: choose a suitable alignment for the tunnel, analyse the stability of the face, define the associated ground support and improvement, design the tunnel lining and carry out a pre-construction risk assessment on buildings adjacent to tunnelling works. On such basis, the geotechnical characterization should permit us to assess the feasibility of alternative schemes, to select the most appropriate construction method, to anticipate possible risks during construction and to undertake any possible mitigation. In this chapter, after recalling the main definitions of geotechnical properties, laboratory tests and site investigation for geotechnical characterization of tunnelling are presented and the geotechnical model is discussed