302 research outputs found
The Molecular Structure of ortho- and meta-Iodonitrobenzene in the Gaseous State as Determined by the Electron Diffraction Method. General Trends in the Bond Lengths and STO-3G* Ab Initio Calculations on Iodonitrobenzenes.
ALA and ALA hexyl ester induction of porphyrins after their systemic administration to tumour bearing mice
The use of synthetic lipophilic molecules derived from 5-aminolevulinic acid (ALA) is currently under investigation to enhance cellular ALA penetration. In this work we studied the effect of systemic administration to mice of the hexyl ester of ALA (He-ALA) on porphyrin tissue synthesis as compared to ALA. In most normal tissues as well as in tumour, He-ALA induced less porphyrin synthesis than ALA after its systemic administration either intravenous or intraperitoneal, although explant organ cultures exposed to either ALA or He-ALA revealed equally active esterases. The only tissue that accumulated higher porphyrin levels from He-ALA (seven times more than ALA) was the brain, and this correlated well with a rapid increase in ALA/He-ALA content in brain after administration of He-ALA. This may be ascribed to a differential permeability to lipophilic substances controlled by the blood–brain barrier, a feature which could be further exploited to treat brain tumours
Participation in medical decision-making across Europe: an international longitudinal multicenter study
Background: The purpose of this paper was to examine national differences in the desire to participate in decision-making of people with severe mental illness in six European countries.
Methods: The data was taken from a European longitudinal observational study (CEDAR; ISRCTN75841675). A sample of 514 patients with severe mental illness from the study centers in Ulm, Germany, London, England, Naples, Italy, Debrecen, Hungary, Aalborg, Denmark and Zurich, Switzerland were assessed as to desire to participate in medical decision-making. Associations between desire for participation in decision-making and center location were analyzed with generalized estimating equations.
Results: We found large cross-national differences in patients’ desire to participate in decision-making, with the center explaining 40% of total variance in the desire for participation (p<0.001). Averaged over time and independent of patient characteristics, London (mean=2.27), Ulm (mean=2.13) and Zurich (mean=2.14) showed significantly higher scores in desire for participation, followed by Aalborg (mean=1.97), where scores were in turn significantly higher than in Debrecen (mean=1.56). The lowest scores were reported in Naples (mean=1.14). Over time, desire for participation in decision-making increased significantly in Zurich (b=0.23) and decreased in Naples (b=-0.14). In all other centers, values remained stable.
Conclusions: This study demonstrates that patients’ desire for participation in decisionmaking varies by location. We suggest that more research attention be focused on identifying specific cultural and social factors in each country to further explain observed differences across Europe
Structural basis of subtype-selective competitive antagonism for GluN2C/2D-containing NMDA receptors.
N-Methyl-D-aspartate receptors (NMDARs) play critical roles in the central nervous system. Their heterotetrameric composition generates subtypes with distinct functional properties and spatio-temporal distribution in the brain, raising the possibility for subtype-specific targeting by pharmacological means for treatment of neurological diseases. While specific compounds for GluN2A and GluN2B-containing NMDARs are well established, those that target GluN2C and GluN2D are currently underdeveloped with low potency and uncharacterized binding modes. Here, using electrophysiology and X-ray crystallography, we show that UBP791 ((2S*,3R*)-1-(7-(2-carboxyethyl)phenanthrene-2-carbonyl)piperazine-2,3-dicarboxylic acid) inhibits GluN2C/2D with 40-fold selectivity over GluN2A-containing receptors, and that a methionine and a lysine residue in the ligand binding pocket (GluN2D-Met763/Lys766, GluN2C-Met736/Lys739) are the critical molecular elements for the subtype-specific binding. These findings led to development of UBP1700 ((2S*,3R*)-1-(7-(2-carboxyvinyl)phenanthrene-2-carbonyl)piperazine-2,3-dicarboxylic acid) which shows over 50-fold GluN2C/2D-selectivity over GluN2A with potencies in the low nanomolar range. Our study shows that the L-glutamate binding site can be targeted for GluN2C/2D-specific inhibition
A Unified Model of the GABA(A) Receptor Comprising Agonist and Benzodiazepine Binding Sites
We present a full-length α(1)β(2)γ(2) GABA receptor model optimized for agonists and benzodiazepine (BZD) allosteric modulators. We propose binding hypotheses for the agonists GABA, muscimol and THIP and for the allosteric modulator diazepam (DZP). The receptor model is primarily based on the glutamate-gated chloride channel (GluCl) from C. elegans and includes additional structural information from the prokaryotic ligand-gated ion channel ELIC in a few regions. Available mutational data of the binding sites are well explained by the model and the proposed ligand binding poses. We suggest a GABA binding mode similar to the binding mode of glutamate in the GluCl X-ray structure. Key interactions are predicted with residues α(1)R66, β(2)T202, α(1)T129, β(2)E155, β(2)Y205 and the backbone of β(2)S156. Muscimol is predicted to bind similarly, however, with minor differences rationalized with quantum mechanical energy calculations. Muscimol key interactions are predicted to be α(1)R66, β(2)T202, α(1)T129, β(2)E155, β(2)Y205 and β(2)F200. Furthermore, we argue that a water molecule could mediate further interactions between muscimol and the backbone of β(2)S156 and β(2)Y157. DZP is predicted to bind with interactions comparable to those of the agonists in the orthosteric site. The carbonyl group of DZP is predicted to interact with two threonines α(1)T206 and γ(2)T142, similar to the acidic moiety of GABA. The chlorine atom of DZP is placed near the important α(1)H101 and the N-methyl group near α(1)Y159, α(1)T206, and α(1)Y209. We present a binding mode of DZP in which the pending phenyl moiety of DZP is buried in the binding pocket and thus shielded from solvent exposure. Our full length GABA(A) receptor is made available as Model S1
The development and evaluation of a five-language multi-perspective standardised measure: clinical decision-making involvement and satisfaction (CDIS).
BACKGROUND: The aim of this study was to develop and evaluate a brief quantitative five-language measure of involvement and satisfaction in clinical decision-making (CDIS) - with versions for patients (CDIS-P) and staff (CDIS-S) - for use in mental health services. METHODS: An English CDIS was developed by reviewing existing measures, focus groups, semistructured interviews and piloting. Translations into Danish, German, Hungarian and Italian followed the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) Task Force principles of good practice for translation and cultural adaptation. Psychometricevaluation involved testing the measure in secondary mental health services in Aalborg, Debrecen, London, Naples, Ulm and Zurich. RESULTS: After appraising 14 measures, the Control Preference Scale and Satisfaction With Decision-making English-language scales were modified and evaluated in interviews (n = 9), focus groups (n = 22) and piloting (n = 16). Translations were validated through focus groups (n = 38) and piloting (n = 61). A total of 443 service users and 403 paired staff completed CDIS. The Satisfaction sub-scale had internal consistency of 0.89 (0.86-0.89 after item-level deletion) for staff and 0.90 (0.87-0.90) for service users, both continuous and categorical (utility) versions were associated with symptomatology and both staff-rated and service userrated therapeutic alliance (showing convergent validity), and not with social disability (showing divergent validity), and satisfaction predicted staff-rated (OR 2.43, 95%CI 1.54- 3.83 continuous, OR 5.77, 95%CI 1.90-17.53 utility) and service user-rated (OR 2.21, 95%CI 1.51-3.23 continuous, OR 3.13, 95%CI 1.10-8.94 utility) decision implementation two months later. The Involvement sub-scale had appropriate distribution and no floor or ceiling effects, was associated with stage of recovery, functioning and quality of life (staff only) (showing convergent validity), and not with symptomatology or social disability (showing divergent validity), and staff-rated passive involvement by the service user predicted implementation (OR 3.55, 95%CI 1.53-8.24). Relationships remained after adjusting for clustering by staff. CONCLUSIONS: CDIS demonstrates adequate internal consistency, no evidence of item redundancy, appropriate distribution, and face, content, convergent, divergent and predictive validity. It can be recommended for research and clinical use. CDIS-P and CDIS-S in all 3 five languages can be downloaded at http://www.cedar-net.eu/instruments. TRIAL REGISTRATION: ISRCTN75841675.CEDAR study is funded by a grant from the Seventh Framework
Programme (Research Area HEALTH-2007-3.1-4 Improving clinical decision
making) of the European Union (Grant no. 223290)
Taxonomic studies of Amanita muscaria (L.) Lam (Amanitaceae, Agaricomycetes) and its infraspecific taxa in Brazil
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