Oral bioavailability and drug/carrier particulate systems

The oral route remains the preferred route of administration to ensure patient satisfaction and compliance. However, new chemical entities may exhibit low bioavailability after oral administration because of poor stability within the gastrointestinal tract, poor solubility in gastrointestinal fluids, low mucosal permeability, and/or extensive first-pass metabolism. Consequently, these new drug substances cannot be further developed using conventional oral formulations. This issue is addressed by an innovative approach based on the entrapment of drug molecules in drug/carrier assembling systems. The carrier materials are lipids, naturally occurring polymers or synthetic polymers, which are considered as nontoxic and biocompatible materials. Drug entrapment is intended to protect drug substances against degradation by gastrointestinal fluids. Fine drug/carrier particle size ensures increased drug dissolution rates. Carriers and particle supramolecular organization can be designed to enhance drug absorption through the intestinal epithelium and lymphatic transport. Promising preclinical results have been obtained with model drugs like paclitaxel, insulin, calcitonin, or cyclosporin. Attention has focused on mucoadhesive carriers like chitosan that favor an intimate and extended contact between drugs and intestinal cells, thus enhancing absorption. Addition of ligands such as lectins improves intestinal drug absorption through specific binding of the carrier to intestinal cell carbohydrates. In conclusion, drug/carrier particulate systems are an attractive and exciting drug delivery strategy for highly potent drug substances unsuitable for oral use. Further evidence will determine whether this approach has marked therapeutic benefits over conventional drug formulations and is compatible with large-scale industrial production and stringent registration requirements. Producing highly effective particulate systems requiring low-complexity manufacturing processes is therefore an ongoing challenge

Fine Selmer Groups and Isogeny Invariance

We investigate fine Selmer groups for elliptic curves and for Galois representations over a number field. More specifically, we discuss Conjecture A, which states that the fine Selmer group of an elliptic curve over the cyclotomic extension is a finitely generated $\mathbb{Z}_p$-module. The relationship between this conjecture and Iwasawa's classical $\mu=0$ conjecture is clarified. We also present some partial results towards the question whether Conjecture A is invariant under isogenies.Comment: 20 page

VR/AR and hearing research: current examples and future challenges

A well-known issue in clinical audiology and hearing research is the level of abstraction of traditional experimental assessments and methods, which lack ecological validity and differ significantly from real-life experiences, often resulting in unreliable outcomes. Attempts to deal with this matter by, for example, performing experiments in real-life contexts, can be problematic due to the difficulty of accurately identifying control-specific parameters and events. Virtual and augmented reality (VR/AR) have the potential to provide dynamic and immersive audiovisual experiences that are at the same time realistic and highly controllable. Several successful attempts have been made to create and validate VR-based implementations of standard audiological and linguistic tests, as well as to design procedures and technologies to assess meaningful and ecologically-valid data. Similarly, new viewpoints on auditory perception have been provided by looking at hearing training and auditory sensory augmentation, aiming at improving perceptual skills in tasks such as speech understanding and sound-source localisation. In this contribution, we bring together researchers active in this domain. We briefly describe experiments they have designed, and jointly identify challenges that are still open and common approaches to tackle the

Synthesis and structural characterization of a mimetic membrane-anchored prion protein

During pathogenesis of transmissible spongiform encephalopathies (TSEs) an abnormal form (PrPSc) of the host encoded prion protein (PrPC) accumulates in insoluble fibrils and plaques. The two forms of PrP appear to have identical covalent structures, but differ in secondary and tertiary structure. Both PrPC and PrPSc have glycosylphospatidylinositol (GPI) anchors through which the protein is tethered to cell membranes. Membrane attachment has been suggested to play a role in the conversion of PrPC to PrPSc, but the majority of in vitro studies of the function, structure, folding and stability of PrP use recombinant protein lacking the GPI anchor. In order to study the effects of membranes on the structure of PrP, we synthesized a GPI anchor mimetic (GPIm), which we have covalently coupled to a genetically engineered cysteine residue at the C-terminus of recombinant PrP. The lipid anchor places the protein at the same distance from the membrane as does the naturally occurring GPI anchor. We demonstrate that PrP coupled to GPIm (PrP-GPIm) inserts into model lipid membranes and that structural information can be obtained from this membrane-anchored PrP. We show that the structure of PrP-GPIm reconstituted in phosphatidylcholine and raft membranes resembles that of PrP, without a GPI anchor, in solution. The results provide experimental evidence in support of previous suggestions that NMR structures of soluble, anchor-free forms of PrP represent the structure of cellular, membrane-anchored PrP. The availability of a lipid-anchored construct of PrP provides a unique model to investigate the effects of different lipid environments on the structure and conversion mechanisms of PrP

A randomized study evaluating cinacalcet to treat hypercalcemia in renal transplant recipients with persistent hyperparathyroidism

Persistent hyperparathyroidism (HPT) after kidney transplantation (KTx) is associated with hypercalcemia, hypophosphatemia and abnormally high levels of parathyroid hormone (PTH). In this randomized trial, cinacalcet was compared to placebo for the treatment of hypercalcemia in adult patients with persistent HPT after KTx. Subjects were randomized 1:1 to cinacalcet or placebo with randomization stratified by baseline corrected total serum calcium levels ( 6411.2 mg/dL [2.80 mmol/L] or >11.2 mg/dL [2.80 mmol/L]). The primary end point was achievement of a mean corrected total serum calcium value <10.2 mg/dL (2.55 mmol/L) during the efficacy period. The two key secondary end points were percent change in bone mineral density (BMD) at the femoral neck and absolute change in phosphorus; 78.9% cinacalcet- versus 3.5% placebo-treated subjects achieved the primary end point with a difference of 75.4% (95% confidence interval [CI]: 63.8, 87.1), p < 0.001. There was no statistical difference in the percent change in BMD at the femoral neck between cinacalcet and placebo groups, p = 0.266. The difference in the change in phosphorus between the two arms was 0.45 mg/dL (95% CI: 0.26, 0.64), p < 0.001 (nominal). No new safety signals were detected. In conclusion, hypercalcemia and hypophosphatemia were effectively corrected after treatment with cinacalcet in patients with persistent HPT after KTx. This randomized, placebo-controlled trial demonstrates that cinacalcet effectively and safely corrects hypercalcemia in adult patients with persistent hyperparathyroidism after successful kidney transplantation. See editorial by Coyne and Delos Santos on page 2446

Analysis of warm prestress data

Loading a cracked structure at elevated temperature, or warm prestressing (WPS), enhances its fracture resistance at a lower temperature. Five data sets, comprising 119 unclad pressure vessel steel specimens, were combined to derive correlations for WPS-enhanced fracture toughness (K{sub Ifrac}) in the absence of ductile tearing. New WPS test results for 27 surface flawed specimens, eight subclad flawed specimens, and five strain-aged specimens are discussed. K{sub Ifrac} exceeded non-WPS fracture toughness, K{sub Ic}, for all experiments. The WPS data showed that no specimens failed while K was decreasing, and that at least an additional seven percent additional reloading from the minimum value of applied K{sub I} took place prior to final fracture. The data included complete and partial unloading after WPS prior to final fracture. Crack tip 3-dimensional elastic-plastic finite element (3DEPFE) analysis was performed to support statistical analysis of the data. Regression models were compared with the Chell WPS model. Crack tip 3DEPFE analysis indicated that partially unloaded and completely unloaded data should be treated separately, and that the amount of unloading is unimportant for partially unloaded data. The regression models, which use K{sub I} at WPS (K{sub Iwps}) and K{sub Ic} as independent variables, better represented the WPS benefit than did the more complicated Chell model. An adequate accounting was made for constraint in the WPS experiments. The subclad flaw data support the use of the partial unload regression model, provided that some care is taken to represent the effect of intact cladding if present. The effect of strain aging at or below 260 C (500 F) on WPS benefit was of no consequence for the pressure vessel steels and WPS temperatures used to derive the regression models. The presence of ductile tearing precludes the use of the regression models. The regression model for partial unloading accurately predicted the behavior of full scale pressure vessel WPS experiments. All but one of the 174 experiments considered lie above the lower 2{sigma} estimate of the regressions. The experiments all supported Type I WPS, i.e., there was no fracture during cooling until reloading occurred. However, the regression equations apply to the reload, and are inapplicable to Type I WPS

Assessment and management of anxiety disorders in children and adolescents

Anxiety disorders in childhood and adolescence are extremely common and are often associated with lifelong psychiatric disturbance. Consistent with DSM-5 and the extant literature, this review concerns the assessment and treatment of specific phobias, separation anxiety disorder, generalised anxiety disorder, social anxiety disorder, panic disorder and agoraphobia. Evidence-based psychological treatments (cognitive behaviour therapy; CBT) for these disorders have been developed and investigated, and in recent years promising low-intensity versions of CBT interventions have been proposed that offer a means to increase access to evidence-based treatments. There is some evidence of effectiveness of pharmacological treatments for anxiety disorders in children and young people, however, routine prescription is not recommended due to concerns about potential harm

A quality metric for homology modeling: the H-factor

<p>Abstract</p> <p>Background</p> <p>The analysis of protein structures provides fundamental insight into most biochemical functions and consequently into the cause and possible treatment of diseases. As the structures of most known proteins cannot be solved experimentally for technical or sometimes simply for time constraints, <it>in silico </it>protein structure prediction is expected to step in and generate a more complete picture of the protein structure universe. Molecular modeling of protein structures is a fast growing field and tremendous works have been done since the publication of the very first model. The growth of modeling techniques and more specifically of those that rely on the existing experimental knowledge of protein structures is intimately linked to the developments of high resolution, experimental techniques such as NMR, X-ray crystallography and electron microscopy. This strong connection between experimental and <it>in silico </it>methods is however not devoid of criticisms and concerns among modelers as well as among experimentalists.</p> <p>Results</p> <p>In this paper, we focus on homology-modeling and more specifically, we review how it is perceived by the structural biology community and what can be done to impress on the experimentalists that it can be a valuable resource to them. We review the common practices and provide a set of guidelines for building better models. For that purpose, we introduce the H-factor, a new indicator for assessing the quality of homology models, mimicking the R-factor in X-ray crystallography. The methods for computing the H-factor is fully described and validated on a series of test cases.</p> <p>Conclusions</p> <p>We have developed a web service for computing the H-factor for models of a protein structure. This service is freely accessible at <url>http://koehllab.genomecenter.ucdavis.edu/toolkit/h-factor</url>.</p