Factor structure of early smoking experiences and associations with smoking behavior: valence or sensitivity model?

The Early Smoking Experience (ESE) questionnaire is the most widely used questionnaire to assess initial subjective experiences of cigarette smoking. However, its factor structure is not clearly defined and can be perceived from two main standpoints: valence, or positive and negative experiences, and sensitivity to nicotine. This article explores the ESE's factor structure and determines which standpoint was more relevant. It compares two groups of young Swiss men (German- and French-speaking). We examined baseline data on 3,368 tobacco users from a representative sample in the ongoing Cohort Study on Substance Use Risk Factors (C-SURF). ESE, continued tobacco use, weekly smoking and nicotine dependence were assessed. Exploratory structural equation modeling (ESEM) and structural equation modeling (SEM) were performed. ESEM clearly distinguished positive experiences from negative experiences, but negative experiences were divided in experiences related to dizziness and experiences related to irritations. SEM underlined the reinforcing effects of positive experiences, but also of experiences related to dizziness on nicotine dependence and weekly smoking. The best ESE structure for predictive accuracy of experiences on smoking behavior was a compromise between the valence and sensitivity standpoints, which showed clinical relevance.

Siluro-Devonian graptolite stratigraphy of the Catalonian Coastal Ranges

Two facies characterize the Silurian and lower Devonian of the Catalonian Coastal Ranges, namely euxinic and pelagic carbonate facies. The first, is represented by black shales in which the atavus, acinaces, cyphus, triangulatus, convolutus, ?sedgwickii, ellesae and tumescens zones have been recognized. The graptolite succesion is far from complete on present evidence, but this is probably due to unfavorable environmental (taphonomic) conditions. This facies is similar to that prevailing throughout the Iberian massif and most of western Europe. The pelagic carbonate facies is peculiar to the Pridoli and lower Devonian and corresponds to the facies type prevailing in the Western Mediterranean Area. It is characterized by the nodular texture of limestones and marls, with all gradations between nodular limestones, marls and slates. Massive nodular limestone, occur in the lower part of the sequence (La Creu Formation) while the alternation of limestones, marls and slates charaterizes the upper part (Olorda Formation). Orthoconic cephalopds, crinoids, conodonts and tentaculites are the most common fossils present; graptolites occur in some shale horizons in the lower part of the Olorda Formation. These graptolites give strong indications of the uniformis and hercynicus zones (Lochkovian). The uppermost part of the sequence has not provided any graptolite fauna, but according their dacrioconarid fauna it corresponds probably to the Pragian.

Paleozoic stratigraphy of the Central and Northern part of the Catalonian Coastal Ranges (NE Spain)

The Paleozoic stratigraphic succession in the Catalonian Coastal Ranges spans the interval from Cambrian(?) to Carboniferous, with only one break, separating the pre-Carboniferous part of the sequence from the Carboniferous. The oldest rocks exposed form a sequence of schists, fine grained sandstones, gneisses (laminar pre-Hercynian intrusions), marbles, orto- and para-amphibolites and calcsilicate rocks. comparison with other localities iuggests an Early Cambrian age (or perhaps in part older). Upwards the sequence becomes more monotonous andconsists only of schists (or slates where themetamorphic grade is lower) and thin fine-grained sandstone layers (Cambrian-Ordovician). Still higher in the sequence, an altemation of greywackes and slates is found, with interlayered mud-supported conglomerates at its lower part and acid volcanic rocks which occur throughout the whole sequence. This part of the sequence has provided the oldest faunas known in the Catalonian Coastal Ranges, which indicate the Caradoc. Finally, in its uppermost part, the Ordovician sequence contains some thin limestone layers that contain Ashgill faunas. The Silurian, from Llandovery to Lower Ludlow, consists of black graptolitic shales with dolerite sills, whilst the upper Ludlow, Pridolian and Devonian consist of nodular limestones and marls withpelagic and hemipelagic faunas. The youngest Devonian faunas found correspond in general to the Emsian. The existence of a gap at this point of the sequence suggests the possibility that part of the Devonian could have been eroded. The Carboniferous is characterized by a thick culm sequence (Visean to Westphalian?), resting on thin chert and limestone layers (Tournaisian and Visean). A comparison with neighbouring areas shows a similarity regarding succession and facies with other Paleozoic massifs around the Western Mediterranean.

The Hercynian structure of the Catalonian Coastal Ranges (NE Spain)

In the Catalonian Coastal Ranges, Paleozoic sedimentary and meta-sedimentary rocks crop out in severa1 areas, intruded by late tectonic Hercynian granitoids and separated by Mesozoic and Tertiary cover sediments. Large structures are often difficult to recognize, although a general east-west trend can be observed on the geological map. Deformation was accompanied by the development of cleavages and regional metamorphism. Green-schist facies rocks are prominent throughout the Ranges, while amphibolite facies are restricted to small areas. In low-grade areas, the main deformation phase generated south-facing folds with an axial plane cleavage (slaty cleavage in metapelitic rocks). The intersection lineation (Ss/Sl) and the axes of minor folds trend cast-west, as do all mapable structures. Late deformations generated coarse crenulations, small chevrons and kink-bands, all intersecting the slaty cleavage at high angles. In medium- to high-grade areas no major folds have been observed. In these areas, the main foliation is a schistosity and is often folded, giving centimetric to decimetric, nearly isoclinal intrafolial folds. In schists, these folds aremuchmore common than inother lithologies, and can be associated with a crenulation cleavage. All these planar structures in high-grade rocks are roughly parallel. The late Hercynian deformational events, which gave rise to the crenulations and small chevrons, also produced large (often kilometric) open folds which fold the slaty cleavage and schistosity. As aconsequence, alternating belts with opposite dip (north and south) of the main foliation were formed. With respect to the Hercynian orogenic belt, the Paleozoic outcrops of the Catalonian Coastal Ranges are located within the northern branch of the Ibero-Armorican arc, and have a relatively frontal position within the belt. The Carboniferous of the Priorat-Prades area, together with other outcrops in the Castellón Province, the Montalbán massif (Iberian Chain) and the Cantabrian zone (specially the Pisuerga-Carrión Province) probably form part of a wide area of foreland Carboniferous deposition placed at the core of the arc.

Antigen binding to secretory immunoglobulin A results in decreased sensitivity to intestinal proteases and increased binding to cellular Fc receptors.

In intestinal secretions, secretory IgA (SIgA) plays an important sentinel and protective role in the recognition and clearance of enteric pathogens. In addition to serving as a first line of defense, SIgA and SIgA x antigen immune complexes are selectively transported across Peyer's patches to underlying dendritic cells in the mucosa-associated lymphoid tissue, contributing to immune surveillance and immunomodulation. To explain the unexpected transport of immune complexes in face of the large excess of free SIgA in secretions, we postulated that SIgA experiences structural modifications upon antigen binding. To address this issue, we associated specific polymeric IgA and SIgA with antigens of various sizes and complexity (protein toxin, virus, bacterium). Compared with free antibody, we found modified sensitivity of the three antigens assayed after exposure to proteases from intestinal washes. Antigen binding further impacted on the immunoreactivity toward polyclonal antisera specific for the heavy and light chains of the antibody, as a function of the antigen size. These conformational changes promoted binding of the SIgA-based immune complex compared with the free antibody to cellular receptors (Fc alphaRI and polymeric immunoglobulin receptor) expressed on the surface of premyelocytic and epithelial cell lines. These data reveal that antigen recognition by SIgA triggers structural changes that confer to the antibody enhanced receptor binding properties. This identifies immune complexes as particular structural entities integrating the presence of bound antigens and adds to the known function of immune exclusion and mucus anchoring by SIgA.

Cognate peptide-receptor ligand mapping by directed phage display

Background: A rapid phage display method for the elucidation of cognate peptide specific ligand for receptors is described. The approach may be readily integrated into the interface of genomic and proteomic studies to identify biologically relevant ligands.Methods: A gene fragment library from influenza coat protein haemagglutinin (HA) gene was constructed by treating HA cDNA with DNAse I to create 50 ¿ 100 bp fragments. These fragments were cloned into plasmid pORFES IV and in-frame inserts were selected. These in-frame fragment inserts were subsequently cloned into a filamentous phage display vector JC-M13-88 for surface display as fusions to a synthetic copy of gene VIII. Two well characterized antibodies, mAb 12CA5 and pAb 07431, directed against distinct known regions of HA were used to pan the library. Results: Two linear epitopes, HA peptide 112 ¿ 126 and 162¿173, recognized by mAb 12CA5 and pAb 07431, respectively, were identified as the cognate epitopes.Conclusion: This approach is a useful alternative to conventional methods such as screening of overlapping synthetic peptide libraries or gene fragment expression libraries when searching for precise peptide protein interactions, and may be applied to functional proteomics.

Predictive analysis and mapping of indoor radon concentrations in Switzerland

It is estimated that around 230 people die each year due to radon (222Rn) exposure in Switzerland. 222Rn occurs mainly in closed environments like buildings and originates primarily from the subjacent ground. Therefore it depends strongly on geology and shows substantial regional variations. Correct identification of these regional variations would lead to substantial reduction of 222Rn exposure of the population based on appropriate construction of new and mitigation of already existing buildings. Prediction of indoor 222Rn concentrations (IRC) and identification of 222Rn prone areas is however difficult since IRC depend on a variety of different variables like building characteristics, meteorology, geology and anthropogenic factors. The present work aims at the development of predictive models and the understanding of IRC in Switzerland, taking into account a maximum of information in order to minimize the prediction uncertainty. The predictive maps will be used as a decision-support tool for 222Rn risk management. The construction of these models is based on different data-driven statistical methods, in combination with geographical information systems (GIS). In a first phase we performed univariate analysis of IRC for different variables, namely the detector type, building category, foundation, year of construction, the average outdoor temperature during measurement, altitude and lithology. All variables showed significant associations to IRC. Buildings constructed after 1900 showed significantly lower IRC compared to earlier constructions. We observed a further drop of IRC after 1970. In addition to that, we found an association of IRC with altitude. With regard to lithology, we observed the lowest IRC in sedimentary rocks (excluding carbonates) and sediments and the highest IRC in the Jura carbonates and igneous rock. The IRC data was systematically analyzed for potential bias due to spatially unbalanced sampling of measurements. In order to facilitate the modeling and the interpretation of the influence of geology on IRC, we developed an algorithm based on k-medoids clustering which permits to define coherent geological classes in terms of IRC. We performed a soil gas 222Rn concentration (SRC) measurement campaign in order to determine the predictive power of SRC with respect to IRC. We found that the use of SRC is limited for IRC prediction. The second part of the project was dedicated to predictive mapping of IRC using models which take into account the multidimensionality of the process of 222Rn entry into buildings. We used kernel regression and ensemble regression tree for this purpose. We could explain up to 33% of the variance of the log transformed IRC all over Switzerland. This is a good performance compared to former attempts of IRC modeling in Switzerland. As predictor variables we considered geographical coordinates, altitude, outdoor temperature, building type, foundation, year of construction and detector type. Ensemble regression trees like random forests allow to determine the role of each IRC predictor in a multidimensional setting. We found spatial information like geology, altitude and coordinates to have stronger influences on IRC than building related variables like foundation type, building type and year of construction. Based on kernel estimation we developed an approach to determine the local probability of IRC to exceed 300 Bq/m3. In addition to that we developed a confidence index in order to provide an estimate of uncertainty of the map. All methods allow an easy creation of tailor-made maps for different building characteristics. Our work is an essential step towards a 222Rn risk assessment which accounts at the same time for different architectural situations as well as geological and geographical conditions. For the communication of 222Rn hazard to the population we recommend to make use of the probability map based on kernel estimation. The communication of 222Rn hazard could for example be implemented via a web interface where the users specify the characteristics and coordinates of their home in order to obtain the probability to be above a given IRC with a corresponding index of confidence. Taking into account the health effects of 222Rn, our results have the potential to substantially improve the estimation of the effective dose from 222Rn delivered to the Swiss population.

Precession electron diffraction in the transmission electron Microscope: electron crystallography and orientational mapping

Precession electron diffraction (PED) is a hollow cone non-stationary illumination technique for electron diffraction pattern collection under quasikinematicalconditions (as in X-ray Diffraction), which enables “ab-initio” solving of crystalline structures of nanocrystals. The PED technique is recently used in TEMinstruments of voltages 100 to 300 kV to turn them into true electron iffractometers, thus enabling electron crystallography. The PED technique, when combined with fast electron diffraction acquisition and pattern matching software techniques, may also be used for the high magnification ultra-fast mapping of variable crystal orientations and phases, similarly to what is achieved with the Electron Backscatter Diffraction (EBSD) technique in Scanning ElectronMicroscopes (SEM) at lower magnifications and longer acquisition times.

Mapping the Membrane Topology of Hepatitis C Virus Nonstructural Protein 4B

BACKGROUND: Nonstructural protein 4B (NS4B) plays an essential role in the formation of the hepatitis C virus (HCV) replication complex. It is an integral membrane protein that has only poorly been characterized to date. In particular, a precise membrane topology is thus far elusive. Here, we explored a novel strategy to map the membrane topology of HCV NS4B. METHODS: Selective permeabilization of the plasma membrane, maleimide-polyethyleneglycol (mPEG) labeling of natural or engineered cysteine residues and immunoblot analyses were combined to map the membrane topology of NS4B. Cysteine substitutions were introduced at carefully selected positions within NS4B and their impact on HCV RNA replication and infectious virus production analyzed in cell culture. RESULTS: We established a panel of viable HCV mutants with cysteine substitutions at strategic positions within NS4B. These mutants are infectious and replicate to high levels in cell culture. In parallel, we adapted and optimized the selective permeabilization and mPEG labeling techniques to Huh-7 human hepatocellular carcinoma cells which can support HCV infection and replication. CONCLUSIONS: The newly established experimental tools and techniques should allow us to refine the membrane topology of HCV NS4B in a physiological context. The expected results should enhance our understanding of the functional architecture of the HCV replication complex and may provide new opportunities for antiviral intervention in the future.

The Brief Psychiatric Rating Scale (version 4.0) factorial structure and its sensitivity in the treatment of outpatients with unipolar depression.

The 24-item Brief Psychiatric Rating Scale (BPRS, version 4.0) enables the rater to measure psychopathology severity. Still, little is known about the BPRS's reliability and validity outside of the psychosis spectrum. The aim of this study was to examine the factorial structure and sensitivity to change of the BPRS in patients with unipolar depression. Two hundred and forty outpatients with unipolar depression were administered the 24-item BPRS. Assessments were conducted at intake and at post-treatment in a Crisis Intervention Centre. An exploratory factor analysis of the 24-item BPRS produced a six-factor solution labelled "Mood disturbance", "Reality distortion", "Activation", "Apathy", "Disorganization", and "Somatization". The reduction of the total BPRS score and dimensional scores, except for "Activation", indicates that the 24-item BPRS is sensitive to change as shown in patients that appeared to have benefited from crisis treatment. The findings suggest that the 24-item BPRS could be a useful instrument to measure symptom severity and change in symptom status in outpatients presenting with unipolar depression.

Colorectal cancer metastasis: the DNA repair inhibitor Dbait increases sensitivity to hyperthermia and improves efficacy of radiofrequency ablation.

PURPOSE: To assess the usefulness of combining hyperthermia with a DNA repair inhibitor (double-strand break bait [Dbait]) and its potential application to radiofrequency ablation (RFA) in a preclinical model of human colorectal cancer. MATERIALS AND METHODS: The local ethics committee of animal experimentation approved all investigations. First, the relevance was assessed by studying the survival of four human colorectal adenocarcinoma cell cultures after 1 hour of hyperthermia at 41°C or 43°C with or without Dbait. Human colon adenocarcinoma cells (HT-29) were grafted subcutaneously into nude mice (n = 111). When tumors reached approximately 500 mm(3), mice were treated with Dbait alone (n = 20), sublethal RFA (n = 21), three different Dbait schemes and sublethal RFA (n = 52), or a sham treatment (n = 18). RFA was performed to ablate the tumor center alone. To elucidate antitumor mechanisms, 39 mice were sacrificed for blinded pathologic analysis, including assessment of DNA damage, cell proliferation, and tumor necrosis. Others were monitored for tumor growth and survival. Analyses of variance and log-rank tests were used to evaluate differences. RESULTS: When associated with mild hyperthermia, Dbait induced cytotoxicity in all tested colon cancer cell lines. Sublethal RFA or Dbait treatment alone moderately improved survival (median, 40 days vs 28 days for control; P = .0005) but combination treatment significantly improved survival (median, 84 days vs 40 days for RFA alone, P = .0004), with approximately half of the animals showing complete tumor responses. Pathologic studies showed that the Dbait and RFA combination strongly enhances DNA damage and coagulation areas in tumors. CONCLUSION: Combining Dbait with RFA sensitizes the tumor periphery to mild hyperthermia and increases RFA antitumor efficacy.