SwissParam: a fast force field generation tool for small organic molecules.

The drug discovery process has been deeply transformed recently by the use of computational ligand-based or structure-based methods, helping the lead compounds identification and optimization, and finally the delivery of new drug candidates more quickly and at lower cost. Structure-based computational methods for drug discovery mainly involve ligand-protein docking and rapid binding free energy estimation, both of which require force field parameterization for many drug candidates. Here, we present a fast force field generation tool, called SwissParam, able to generate, for arbitrary small organic molecule, topologies, and parameters based on the Merck molecular force field, but in a functional form that is compatible with the CHARMM force field. Output files can be used with CHARMM or GROMACS. The topologies and parameters generated by SwissParam are used by the docking software EADock2 and EADock DSS to describe the small molecules to be docked, whereas the protein is described by the CHARMM force field, and allow them to reach success rates ranging from 56 to 78%. We have also developed a rapid binding free energy estimation approach, using SwissParam for ligands and CHARMM22/27 for proteins, which requires only a short minimization to reproduce the experimental binding free energy of 214 ligand-protein complexes involving 62 different proteins, with a standard error of 2.0 kcal mol(-1), and a correlation coefficient of 0.74. Together, these results demonstrate the relevance of using SwissParam topologies and parameters to describe small organic molecules in computer-aided drug design applications, together with a CHARMM22/27 description of the target protein. SwissParam is available free of charge for academic users at www.swissparam.ch.

Dispersion of natural arsenic in the Malcantone watershed, Southern Switzerland: field evidence for repeated sorption-desorption and oxidation-reduction processes

In recent years, elevated arsenic concentrations have been found in waters and soils of many, countries, often resulting in a health threat for the local population. Switzerland is not an exception and this paper deals with the release and subsequent fate of arsenic in a 200-km(2) mountainous watershed, characterized by crystalline silicate rocks (gneisses, schists, amphibolites) that contain abundant As-bearing sulfide ore deposits, some of which have been mined for iron and gold in the past. Using analytical methods common for mineralogical, ground water and soil studies (XRD, XRF, XAS-XANES and -EXAFS, electron microprobe, extraction, ICP, AAS with hydride generator, ion chromatography), seven different field situations and related dispersion processes of natural arsenic have been studied: (1) release by rock weathering, (2) transport and deposition by water and ice; (3) release of As to the ground and surface water due to increasing pH; (4) accumulation in humic soil horizons; (5) remobilization by reduction in water-saturated soils and stagnant ground waters; (6) remobilization by using P-rich fertilizers or dung and (7) oxidation, precipitation and dilution in surface waters. Comparison of the results with experimental adsorption studies and speciation diagrams from the literature allows us to reconstruct and identify the typical behavior of arsenic in a natural environment under temperate climatic conditions. The main parameters identified are: (a) once liberated from the primary minerals, sorption processes on Fe-oxy-hydroxides dominate over Al-phases, such as Al-hydroxides or clay minerals and limit the As concentrations in the spring and well waters between 20 and 300 mug/l. (b) Precipitation as secondary minerals is limited to the weathering domain, where the As concentrations are still high and not yet too diluted by rain and soils waters. (c) Although neutral and alkaline pH conditions clearly increase the mobility of As, the main factor to mobilize As is a low redox potential (Eh close or below 0 mV), which favors the dissolution of the Fe-oxy-hydroxides on which the As is sorbed. (d) X-ray absorption spectroscopy (XAS) of As in water-logged humic forest soils indicates that the reduction to As III only occurs at the solid-water interface and that the solid contains As as As V (e) A and Bh horizons of humic cambisols can effectively capture As when As-rich waters flow through them. Complex spatial and temporal variation of the various parameters in a watershed results in repeated mobilization and immobilization of As, which continuously transports As from the upper to the lower part of a watershed and ultimately to the ocean. (C) 2004 Elsevier B.V. All rights reserved.

Cyclododecane exposure in the field of conservation and restoration of art objects

PURPOSE: Recent work practices in the conservation and restoration involve the use of cyclododecane (CDD, CAS 294-62-2) to protect fragile artifacts during their handling or transportation. Little is known about its toxicity, and no previous exposure has been reported. A short field investigation was conducted to characterize the exposure conditions to both CDD vapors and aerosols.METHODS: Measurements were conducted in the laboratory of conservation and restoration of the archeological service in Bern (Switzerland). Three indoor and four outdoor typical work situations, either during brush or spray gun applications, were investigated. Measurements were performed on charcoal adsorbent tube and analyzed by a gas chromatograph equipped with a flame ionization detector.RESULTS: Measurements have been conducted during both brush and spray gun applications. Indoor exposures were of 0.75-15.5 mg/m(3), while outdoors exposures were 19.5-53.9 mg/m(3). Exposures appear to be extremely localized due to both physicochemical properties and application methods of the CDD. Vapor exposure increases dramatically with the confinement of the workplace.CONCLUSION: Preventive measures should be undertaken to limit as much as possible these exposures. Field work in confined areas (ditches, underground) is of particular concern. CDD-coated artifacts or materials should be stored in ventilated areas to avoid delayed exposures. [Authors]

B1-insensitive T2 preparation for improved coronary magnetic resonance angiography at 3 T.

At 3 T, the effective wavelength of the RF field is comparable to the dimension of the human body, resulting in B1 standing wave effects and extra variations in phase. This effect is accompanied by an increase in B0 field inhomogeneity compared to 1.5 T. This combination results in nonuniform magnetization preparation by the composite MLEV weighted T2 preparation (T2 Prep) sequence used for coronary magnetic resonance angiography (MRA). A new adiabatic refocusing T2 Prep sequence is presented in which the magnetization is tipped into the transverse plane with a hard RF pulse and refocused using a pair of adiabatic fast-passage RF pulses. The isochromats are subsequently returned to the longitudinal axis using a hard RF pulse. Numerical simulations predict an excellent suppression of artifacts originating from B1 inhomogeneity while achieving good contrast enhancement between coronary arteries and surrounding tissue. This was confirmed by an in vivo study, in which coronary MR angiograms were obtained without a T2 Prep, with an MLEV weighted T2 Prep and the proposed adiabatic T2 Prep. Improved quantitative and qualitative coronary MRA image measurement was achieved using the adiabatic T2 Prep at 3 T.

The discriminatory power of MALDI-TOF mass spectrometry to differentiate between isogenic teicoplanin-susceptible and teicoplanin-resistant strains of methicillin-resistant Staphylococcus aureus.

To explore the discriminatory power of matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) for detecting subtle differences in isogenic isolates, we tested isogenic strains of Staphylococcus aureus differing in their expression of resistance to methicillin or teicoplanin. More important changes in MALDI-TOF MS spectra were found with strains differing in methicillin than in teicoplanin resistance. In comparison, very minor or no changes were recorded in pulsed-field gel electrophoresis profiles or peptidoglycan muropeptide digest patterns of these strains, respectively. MALDI-TOF MS might be useful to detect subtle strain-specific differences in ionizable components released from bacterial surfaces and not from their peptidoglycan network.

Poly-N-acetyl glucosamine fibers are synergistic with vacuum-assisted closure in augmenting the healing response of diabetic mice.

BACKGROUND: Vacuum-assisted closure (VAC) has become the preferred modality to treat many complex wounds but could be further improved by methods that minimize bleeding and facilitate wound epithelialization. Short fiber poly-N-acetyl glucosamine nanofibers (sNAG) are effective hemostatic agents that activate platelets and facilitate wound epithelialization. We hypothesized that sNAG used in combination with the VAC device could be synergistic in promoting wound healing while minimizing the risk of bleeding. METHODS: Membranes consisting entirely of sNAG nanofibers were applied immediately to dorsal excisional wounds of db/db mice followed by application of the VAC device. Wound healing kinetics, angiogenesis, and wound-related growth factor expression were measured. RESULTS: The application of sNAG membranes to wounds 24 hours before application of the VAC device was associated with a significant activation of wounds (expression of PDGF, TGFβ, EGF), superior granulation tissue formation rich in Collagen I as well as superior wound epithelialization (8.6% ± 0.3% vs. 1.8% ± 1.1% of initial wound size) and wound contraction. CONCLUSIONS: The application of sNAG fiber-containing membranes before the application of the polyurethane foam interface of VAC devices leads to superior healing in db/db mice and represents a promising wound healing adjunct that can also reduce the risk of bleeding complications.

Comparative testing of a miniature diffusion size classifier to assess airborne ultrafine particles under field conditions

Miniature diffusion size classifiers (miniDiSC) are novel handheld devices to measure ultrafine particles (UFP). UFP have been linked to the development of cardiovascular and pulmonary diseases; thus, detection and quantification of these particles are important for evaluating their potential health hazards. As part of the UFP exposure assessments of highwaymaintenance workers in western Switzerland, we compared a miniDiSC with a portable condensation particle counter (P-TRAK). In addition, we performed stationary measurements with a miniDiSC and a scanning mobility particle sizer (SMPS) at a site immediately adjacent to a highway. Measurements with miniDiSC and P-TRAK correlated well (correlation of r = 0.84) but average particle numbers of the miniDiSC were 30%âeuro"60% higher. This difference was significantly increased for mean particle diameters below 40 nm. The correlation between theminiDiSC and the SMPSduring stationary measurements was very high (r = 0.98) although particle numbers from the miniDiSC were 30% lower. Differences between the three devices were attributed to the different cutoff diameters for detection. Correction for this size dependent effect led to very similar results across all counters.We did not observe any significant influence of other particle characteristics. Our results suggest that the miniDiSC provides accurate particle number concentrations and geometric mean diameters at traffic-influenced sites, making it a useful tool for personal exposure assessment in such settings.

Cosmopolitan Capital and the Internationalization of the Field of Business Elites: Evidence from the Swiss Case

The aim of this contribution is to explore how the recent internationalization and the increasing importance of 'cosmopolitan capital' has impacted on the structure and character of the field of the Swiss business elite. For this purpose we will develop the notion of cosmopolitan capital and comparatively investigate the field of the Swiss business elite in 1980, 2000 and 2010 with multiple correspondence analysis. We can show that in this period international managers with transnational careers and networks not only grow in number, but come to conquer the apex of the biggest and highest capitalized Swiss firms. At the same time, national forms of capital decline in importance and Swiss managers themselves are differentiated increasingly into national and international fractions.

Female-biased dispersal in the monogamous mammal Crocidura russula: evidence from field data and microsatellite patterns.

We investigated dispersal patterns in the monogamous Crocidura russula, based both on direct field observations (mark-recapture data) and on genetic analyses (microsatellite loci). Natal dispersal was found to be low. Most juveniles settled within their natal territory or one immediately adjacent. Migration rate was estimated to two individuals per year and per population. The correlation between genetic and geographical distances over a 16 km transect implies that migration occurs over short ranges. Natal dispersal was restricted to first-litter juveniles weaned in early May; this result suggests a direct dependence of dispersal on reproductive opportunities. Natal dispersal was highly female biased, a pattern unusual among mammals. Its association with monogamy provides support for the resource-competition model of dispersal. Our results demonstrate that a state-biased dispersal can be directly inferred from microsatellite genotype distributions, which opens new perspectives for empirical studies in this area.

Video-assisted right supradiaphragmatic thoracic duct ligation for non traumatic recurrent chylothorax

Introduction : Un chylothorax est une pathologie comprenant des manifestations respiratoires, nutritionnelles et immunologiques. La récidive du chylothorax ou l'échec du traitement conservateur imposent un traitement chirurgical. Ce travail rapporte notre expérience de ligature supra-diaphragmatique, vidéo-assistée du canal thoracique, pour chylothorax récurrent non traumatique. Patients et méthodes : Entre 1999 et 2004, nous avons recensé six observations (quatre du côté droit, un du côté gauche et un bilateral) Le chylothorax s'est développé chez trois patients traités par radio et chimiothérapie pour tumeur (deux lymphomes et une tumeur du sein) un dans le contexte d'une lymphangioléiomatose et un après greffe cardiaque. Résultats : Les patients ont bénéficié sous anesthésie générale, d'une ligature du canal thoracique supra-diaphragmatique, vidéo-assistée. Le temps opératoire moyen a été de 102 minutes. Le chylothorax a régressé chez cinq des six patients en sept jours. Un patient a été repris par thoracotomie droite au huitième jour pour chylothorax persistant. Dans la phase post-opératoire, un patient a développé une détresse respiratoire nécessitant une ventilation mécanique. Un autre patient a présenté un chylopéritoine important traité par un stent de Le Veen®. Le séjour moyen a été de quatorze jours sans mortalité péri-opératoire. Conclusion : Le traitement du chylothorax non traumatique récurrent est, en première intention, un traitement médical. En cas de récidive ou d'échec du traitement conservateur, le traitement chirurgical par ligature du canal thoracique supra- diaphragmatique, vidéo-assistée, permet de traiter avec succès le chylothorax récurrent non traumatique. -- Background: Chylothorax is an uncommon disorder with respiratory, nutritional and immunological manifestations. Surgical management is indicated in case of recurrence or failure after conservative treatment. We report our experience with video-assisted right-sided supradiaphrag¬matic thoracic duct ligation for non-traumatic, non-postoperative persistent or recurrent chylothorax. Patients and methods: The medical records of six patients operated at our institution between 1999 and 2004 were retrospectively reviewed. A right-sided chylothorax was found in four patients, a left-sided in one, and a bilateral in one. Three patients developed chylothorax after chemotherapy and chest irradiation for malignant diseases (lymphoma in two patients and breast cancer in one), one in the context of lymphangioleiomyomatosis, one due to a non-diagnosed lymphoma, and one after heart transplantation. Results: The mean operative time was 102 min, with an average length of hospital stay of 14 days. Persistent cessation of chylous effusion within 7 days after surgery was observed in 5/6 patients without recurrence during a mean follow-up time of 41 months. One patient with undiagnosed mediastinal lymphoma required re-operation and thoracic duct ligation on day 8 by right-sided thoracotomy due to persistent chylothorax. No 30-day mortality was recorded. Two patients presented postoperative complications including respiratory insufficiency requiring mechanical ventilation in one, and chylous ascites development requiring peritoneo-venous LeVeen shunting in one patient. Conclusions: Recurrent or persistent non-traumatic chylothorax may be successfully treated by video-assisted right supradiaphragmatic thoracic duct ligation.

Electrically assisted ocular gene therapy.

Electrotransfer and iontophoresis are being developed as innovative non-viral gene delivery systems for the treatment of eye diseases. These two techniques rely on the use of electric current to allow for higher transfection yield of various ocular cell types in vivo. Short pulses of relatively high-intensity electric fields are used for electrotransfer delivery, whereas the iontophoresis technique is based on the application of low voltage electric current. The basic principles of these techniques and their potential therapeutic application for diseases of the anterior and posterior segments of the eye are reviewed. Iontophoresis has been found most efficient for the delivery of small nucleic acid fragments such as antisense oligonucleotides, siRNA, or ribozymes. Electrotransfer, on the other hand, is being developed for the delivery of oligonucleotides or custom designed plasmids. The wide range of strategies already validated and the potential for targeting specific types of cells confirm the promising early observations made using electrotransfer and iontophoresis. These two nonviral delivery systems are safe and can be used efficiently for targeted gene delivery to ocular tissues in vivo. At the present, their application for the treatment of ocular human diseases is nearing its final stages of adaptation and practical implementation at the bedside.

Dissociation of thymic positive and negative selection in transgenic mice expressing major histocompatibility complex class I molecules exclusively on thymic cortical epithelial cells.

Thymic positive and negative selection of developing T lymphocytes confronts us with a paradox: How can a T-cell antigen receptor (TCR)-major histocompatibility complex (MHC)/peptide interaction in the former process lead to transduction of signals allowing for cell survival and in the latter induce programmed cell death or a hyporesponsive state known as anergy? One of the hypotheses put forward states that the outcome of a TCR-MHC/peptide interaction depends on the cell type presenting the selecting ligand to the developing thymocyte. Here we describe the development and lack of self-tolerance of CD8(+) T lymphocytes in transgenic mice expressing MHC class I molecules in the thymus exclusively on cortical epithelial cells. Despite the absence of MHC class I expression on professional antigen-presenting cells, normal numbers of CD8(+) cells were observed in the periphery. Upon specific activation, transgenic CD8(+) T cells efficiently lysed syngeneic MHC class I(+) targets in vitro and in vivo, indicating that thymic cortical epithelium (in contrast to medullary epithelium and antigen-presenting cells of hematopoietic origin) is incapable of tolerance induction. Thus, compartmentalization of the antigen-presenting cells involved in thymic positive selection and tolerance induction can (at least in part) explain the positive/negative selection paradox.

The activity of Crocidura russula (Insectivora, Soricidae) in the field and in captivity

Studied was the activity of the shrew Crocidura russula in the field (by radioactive tracking) and in laboratory (by continuous recording of nest temperature and by video). Under natural conditions, the total daily activity remained nearly constant throughout the year accounting for about 33 % of the total time. Activity was polyphasic and showed a daily rhythm; on an average, one activity phases occured every two hours and lasted 36 min. The activity periods of captive shrews were generally shorter, but always more frequent, and the total daily activity of captive shrews was much lower in winter. Two experiments carried out in the filed on shrews artificially fed, demonstrated that under natural conditions, foraging takes a major part of the winter activity. The activity patterns of Crocidura russula are compared with those of another European shrew, Sorex araneus.

The response of a Swiss university hospital's palliative care consult team to assisted suicide within the institution.

In January 2006 the Centre Hospitalier Universitaire Vaudois (CHUV), a large university hospital in Lausanne, Switzerland, became the first hospital in Switzerland to allow assisted suicide (AS) in exceptional cases within its walls. However, euthanasia is illegal. This decision has posed several ethical and practical dilemmas for the hospital's palliative care consult service. To address these, the team embarked on a formal process of open dialogue amongst its members with the goal of identifying a collective response and position. This process involved meetings every 4 to 6 weeks over the course of 10 months. An iterative process unfolded. One of the principal dilemmas relates to finding a balance between the team's position against AS and the patient's autonomy and the institution's directive. Although all team members expressed opposition to AS, there were mixed opinions as to whether or not the team members should be present during the act if requested so by patients. Some thought this could be misinterpreted as complicity in the act and could send out mixed messages to the public and other health professionals about palliative care. Others felt that the team's commitment to nonabandonment obliged them to be present even if they did not provide the drug or give any advice or assistance. The implications of nonabandonment are explored, as are several other questions such as whether or not the teams are obliged to provide detailed information on AS when requested by patients.