A compact-rigid multi-analyser for energy and angle filtering of high-resolution X-ray experiments. Part 2. Efficiency of a single-crystal-comb.

Diffraction instruments using filtering by one or several analyser crystals exist since the 1980s and 1990s at synchrotron radiation sources, but, due to its low efficiency, this filtering is little used on laboratory sources. In order to overcome this limitation, the efficiency of a small diffraction filtering multi-analyzer block (MAD block) realized with a `single-crystal-comb' curved on a rigid support is demonstrated here. The geometry of this curved surface is logarithmic spiral and is optimized to allow multi-filtering over a relatively important diffraction angular range and to be also applicable over an X-ray spectral range. The efficiency of such a small rigid-compact MAD block consisting of this single-crystal-comb generating 20-50 Si(111) single-crystal blades, associated with a block of Soller collimators, is demonstrated. The angle between each crystal is 0.1°, so the measurement range of the comb is 2-5°. The geometry of this system has been optimized for operation with a synchrotron X-ray source over an energy range of 22 keV to 46 keV and could be used with laboratory X-ray sources (Ag Kα1, 22.1 keV). This MAD block complements and exploits the qualities of the `photon-counting' detectors which have very low intrinsic noise. Their joint efficacy is supported by powder pattern measurements of a LaB6 reference sample and of several heterogeneous samples of cultural heritage materials, carried out at 22 keV on the D2AM beamline at the ESRF. Their signal-to-noise ratio is excellent (1000/1) and allows the detection thresholds of the measurements (from 3-1% to 0.1%) to detect minor phases in the studies of `real' heterogeneous materials to be drastically improved.

Brucellosis in dairy herds: Farm characteristics and practices in relation to likely adoption of three potential private-public partnership (PPP) vaccination control strategies in West and Central Africa.

Brucellosis is regarded as one of the highest burden zoonotic diseases to persist in many regions globally. While sustained vaccination against B. abortus in an endemic setting can markedly reduce the prevalence of large ruminant and human brucellosis and benefit local livelihoods, the implementation of effective and sustainable control programmes has often failed in the worst affected areas. In a cross-sectional study of 728 peri-urban dairy farmers in nine areas of six West and Central African countries, levels of commercialization and farm characteristics were examined alongside B. abortus seroprevalence estimates to hypothesize the most appropriate model for brucellosis vaccination delivery in each country. Demographic and economic data were collated and used to describe the farming systems currently in place. Furthermore, these data were utilized in a likelihood assessment to generate a quantitative score to hypothesize which of three private-public partnership (PPP) vaccine delivery models, that is 1) transformative, 2) transactional or 3) collaborative, would be most appropriate in each setting. The study sites had substantial differences in their levels of dairy commercialization and the farming practices employed; the heterogeneity across the study sites was evident in the conclusions of which models would be appropriate for vaccination delivery. While Lomé (Togo) had a strong indication for a transformative PPP model, Burkina Faso had strong indication for the collaborative PPP model. Of the remaining study sites, the scores were less dominant for any one model with Cameroon and Ivory Coast sites only just scoring highest on the transformative model and Senegal and Mali sites only just scoring highest on the collaborative model. Interestingly, none of the countries included in the study scored highest on the transactional model which currently is the most commonplace delivery model in the majority of sub-Saharan African countries.

Effect of 6-month high-impact step aerobics and resistance training on BMD and tibial bending strength in sedentary premenopausal women.

The rationale of this study was to examine the effectiveness of 6-month high-impact step aerobics (SA) or moderate-intensity resistance training exercise (RT) on bone mineral density (BMD) and bone bending strength in sedentary women. Results show that SA enhanced BMD in the heel, lower leg, and lumbar spine 2. INTRODUCTION: To determine the effectiveness of 6 months of high-impact step aerobics (SA) or moderate-intensity resistance training (RT) on areal bone mineral density (aBMD) and tibial bending strength in sedentary premenopausal women. METHODS: Sixty-nine women (20-35 years old) who were randomly assigned to RT (n = 22), SA (n = 26), or non-treatment control (CON, n = 21) groups completed the study. SA had a minimum of 50 high-impact landings each training session. RT had a periodized lower body resistance training program incorporating eight exercises (65-85% of 1 repetition maximum: 1-RM). Both RT and SA met 3 times weekly. aBMD was assessed using dual X-ray absorptiometry (DXA). Tibial bending strength was assessed using mechanical response tissue analysis (MRTA). Measurements at 6 months were compared to baseline using ANCOVA, adjusted for baseline measures and covariates with α = 0.05. RESULTS: Calcaneus aBMD (0.0176 vs -0.0019 or -0.0009 g/cm2 relative to RT, p < 0.004, and CON, p < 0.006, respectively), lower leg aBMD (0.0105 vs -0.0036 g/cm2, relative to RT, p = 0.02), and lumbar spine 2 (L2) aBMD (0.0082 vs -0.0157 g/cm2 relative to CON, p < 0.02) were significantly greater in the SA group after 6 months. Tibial bending strength and bone resorption biomarkers were unchanged in all three groups after 6 months. CONCLUSION: Sedentary premenopausal women engaging in 6 months of high-impact aerobic exercise improved aBMD in the calcaneus, lower leg, and L2.

Association between body mass index, bone bending strength, and BMD in young sedentary women.

The rationale was to determine whether body mass index (BMI) is a predictor of bone bending strength and bone mineral density (BMD) in young sedentary women. Results show that BMI is not a predictor of bone bending strength and that young women with low BMI also have low BMD. INTRODUCTION: The purpose of this study was to determine whether body mass index (BMI) is a predictor of tibial or ulnar bending strength and bone mineral density (BMD) in sedentary women. METHODS: Sedentary women (n = 34), age 19-27 years, with low BMI (LBMI < 18.5 kg/m2, n = 16), and normal or high BMI (NHBMI between 18.5 and 29.9 kg/m2, n = 18) participated as study subjects. Study outcomes included tibial and ulnar bending strength (EI in Nm2) using a non-invasive mechanical response tissue analyzer (MRTA); BMD and bone mineral content (BMC) of the whole body (WB), femoral neck (FN), total hip (TH), lumbar spine 1-4 (LS1-4), and ulna; and bone turnover biomarkers. RESULTS: The LBMI group have lower (p < 0.01) body weight [group difference (Δ) = 32.0%], lean mass (LM) (Δ = 23.1%), fat mass (FM) (Δ = 77.2%), and tibial bending strength (Δ = 22.0%), compared to the NHBMI. The LBMI group also have lower (all p < 0.025) BMC in WB (Δ = 19.9%), FN (Δ = 20.1%) and TH (Δ = 19.0%), compared to the NHMBI, not in BMD results. Multivariate regression analysis shows that significant predictors of tibial bending strength are tibia length (adjusted R2 = .341), age (adjusted R2 = .489), ulna BMD (adjusted R2 = .536), and LM (adjusted R2 = .580). BMI was positively correlated with tibial EI (p < 0.05), height, weight, FM, LM, body fat% (all p < 0.01), and BMD of WB, FN, TH, and LS 1-4 (p < 0.05 or < 0.01). CONCLUSIONS: Our results show that BMI is not a significant predictor of tibial or ulnar bending strength in young sedentary women.

Local Ancestry to Identify Selection in Response to Trypanosome Infection in Baoulé x Zebu Crossbred Cattle in Burkina Faso.

The genomes of crossbred (admixed) individuals are a mosaic of ancestral haplotypes formed by recombination in each generation. The proportion of these ancestral haplotypes in certain genomic regions can be responsible for either susceptibility or tolerance against pathogens, and for performances in production traits. Using a medium-density genomic marker panel from the Illumina Bovine SNP50 BeadChip, we estimated individual admixture proportions for Baoulé x Zebu crossbred cattle in Burkina Faso, which were tested for trypanosome infection by direct ELISA from blood samples. Furthermore, we calculated local ancestry deviation from average for each SNP across 29 autosomes to identify potential regions under selection in the trypanotolerant Baoulé cattle and their crossbreds. We identified significant deviation from the local average ancestry (above 5 and 10% genome-wide thresholds) on chromosomes 8 and 19 in the positive animals, while the negative ones showed higher deviation on chromosomes 6, 19, 21, and 22. Some candidate genes on chromosome 6 (PDGFRA) and chromosome 19 (CDC6) have been found associated to trypanotolerance in West African taurines. Screening for F ST outliers in trypanosome positive/negative animals we detected seven variants putatively under selection. Finally, we identified a minimum set of highly ancestry informative markers for routine admixture testing. The results of this study contribute to a better understanding of the genetic basis of trypanotolerance in Baoulé cattle and their crossbreeds. Furthermore, we provide a small informative marker set to monitor admixture in this valuable indigenous breed. As such, our results are important for conserving the genetic uniqueness and trypanotolerance of Baoulé cattle, as well as for the improvement of Baoulé and Zebu crossbreds in specific community-based breeding programs.

Genome-wide association study of trypanosome prevalence and morphometric traits in purebred and crossbred Baoulé cattle of Burkina Faso.

In this study, single-SNP GWAS analyses were conducted to find regions affecting tolerance against trypanosomosis and morphometrics traits in purebred and crossbred Baoulé cattle of Burkina Faso. The trypanosomosis status (positive and negative) and a wide set of morphological traits were recorded for purebred Baoulé and crossbred Zebu x Baoulé cattle, and genotyped with the Illumina Bovine SNP50 BeadChip. After quality control, 36,203 SNPs and 619 animals including 343 purebred Baoulé and 279 crossbreds were used for the GWAS analyses. Several important genes were found that can influence morphological parameters. Although there were no genes identified with a reported strong connection to size traits, many of them were previously identified in various growth-related studies. A re-occurring theme for the genes residing in the regions identified by the most significant SNPs was pleiotropic effect on growth of the body and the cardiovascular system. Regarding trypanosomosis tolerance, two potentially important regions were identified in purebred Baoulé on chromosomes 16 and 24, containing the CFH, CRBN, TRNT1 and, IL5RA genes, and one additional genomic region in Baoulé, x Zebu crossbreds on chromosome 5, containing MGAT4C and NTS. Almost all of these regions and genes were previously related to the trait of interest, while the CRBN gene was to our knowledge presented in the context of trypanosomiasis tolerance for the first time.

Brucellosis in dairy herds: A public health concern in the milk supply chains of West and Central Africa.

Ten herd-level cross-sectional studies were conducted in peri-urban dairy production areas of seven West and Central African countries (Burkina Faso, Burundi, Cameroon, Mali, Niger, Senegal and Togo). The objectives were to estimate herd level Brucella spp. seroprevalence and identify risk factors for seropositivity. In each of the ten study areas, herds (between 52 and 142 per area, total = 965) were selected probabilistically and a structured questionnaire was administered to gather information on their structure and management. A bulk milk sample from each herd was tested by indirect ELISA for Brucella spp. For each area, herd seroprevalence estimates were obtained after adjusting for the assumed performance of the diagnostic test. Herd level risk factors for Brucella spp. seropositivity were identified by means of stratified logistic regression, with each peri-urban zone as a stratum. Area-specific models were also explored. Estimated herd seroprevalences were: Lomé (Togo) 62.0% (95% CI:55.0-69.0), Bamako (Mali) 32.5% (95% CI:28.0-37.0), Bujumbura (Burundi) 14.7% (95%CI:9.4-20.8), Bamenda (Cameroon) 12.6% (95% CI:7.6-21.9), Ouagadougou (Burkina Faso) 3.0% (95% CI:1.0-9.1), Ngaoundere (Cameroon) 2.3% (95% CI:1.0-7.0), Thies (Senegal) 1.3% (95% CI:0.1, 5.3), Niamey (Niger) 1.2% (95% CI:0.08-5.3), Dakar (Senegal) 0.2% (95% CI:0.01-1.7) and Niakhar (Senegal) <0.04%. Logistic regression modelling revealed transhumant herds to be at lower risk of infection (adjusted OR: 0.25, 95% CI: 0.13 - 0.5) and in one of the areas (Bamenda), regular purchase of new animals was found to be strongly associated with Brucella spp. seropositivity (adjusted OR = 5.3, 95% CI: 1.4-25.9). Our findings confirm that Brucella spp. circulates among dairy cattle supplying milk to urban consumers in West and Central Africa, posing a serious public health concern. Control programs are urgently needed in areas such as Lomé or Bamako, where more than 30% of the herds show evidence of infection.

GESSE: Predicting Drug Side Effects from Drug-Target Relationships.

The in silico prediction of unwanted side effects (SEs) caused by the promiscuous behavior of drugs and their targets is highly relevant to the pharmaceutical industry. Considerable effort is now being put into computational and experimental screening of several suspected off-target proteins in the hope that SEs might be identified early, before the cost associated with developing a drug candidate rises steeply. Following this need, we present a new method called GESSE to predict potential SEs of drugs from their physicochemical properties (three-dimensional shape plus chemistry) and to target protein data extracted from predicted drug-target relationships. The GESSE approach uses a canonical correlation analysis of the full drug-target and drug-SE matrices, and it then calculates a probability that each drug in the resulting drug-target matrix will have a given SE using a Bayesian discriminant analysis (DA) technique. The performance of GESSE is quantified using retrospective (external database) analysis and literature examples by means of area under the ROC curve analysis, "top hit rates", misclassification rates, and a χ(2) independence test. Overall, the robust and very promising retrospective statistics obtained and the many SE predictions that have experimental corroboration demonstrate that GESSE can successfully predict potential drug-SE profiles of candidate drug compounds from their predicted drug-target relationships.

GES polypharmacology fingerprints: a novel approach for drug repositioning.

Polypharmacology is now recognized as an increasingly important aspect of drug design. We previously introduced the Gaussian ensemble screening (GES) approach to predict relationships between drug classes rapidly without requiring thousands of bootstrap comparisons as in current promiscuity prediction approaches. Here we present the GES "computational polypharmacology fingerprint" (CPF), the first target fingerprint to encode drug promiscuity information. The similarity between the 3D shapes and chemical properties of ligands is calculated using PARAFIT and our HPCC programs to give a consensus shape-plus-chemistry ligand similarity score, and ligand promiscuity for a given set of targets is quantified using the GES fingerprints. To demonstrate our approach, we calculated the CPFs for a set of ligands from DrugBank that are related to some 800 targets. The performance of the approach was measured by comparing our CPF with an in-house "experimental polypharmacology fingerprint" (EPF) built using publicly available experimental data for the targets that comprise the fingerprint. Overall, the GES CPF gives very low fall-out while still giving high precision. We present examples of polypharmacology relationships predicted by our approach that have been experimentally validated. This demonstrates that our CPF approach can successfully describe drug-target relationships and can serve as a novel drug repurposing method for proposing new targets for preclinical compounds and clinical drug candidates.

Contribution of molecular diagnosis to the management of cutaneous leishmaniasis in travellers.

Cutaneous leishmaniasis is one of the most frequent skin diseases occurring after travelling in endemic areas. Optimal management requires identification of the species of Leishmania involved. In this study we aimed to evaluate the use of molecular diagnosis as routine, in comparison with direct examination and culture. Thirty positive diagnoses were carried out between 2007 and 2013. Classical PCR enabled 11 positive cases to be identified that were found to be negative by conventional methods. Sequencing led to the identification of eight different species. Routine use of PCR and sequencing appears very efficient in the management of cutaneous leishmaniasis.

Highly specific and sensitive pharmacophore model for identifying CXCR4 antagonists. Comparison with docking and shape-matching virtual screening performance.

HIV infection is initiated by fusion of the virus with the target cell through binding of the viral gp120 protein with the CD4 cell surface receptor protein and the CXCR4 or CCR5 coreceptors. There is currently considerable interest in developing novel ligands that can modulate the conformations of these coreceptors and, hence, ultimately block virus-cell fusion. Herein, we present a highly specific and sensitive pharmacophore model for identifying CXCR4 antagonists that could potentially serve as HIV entry inhibitors. Its performance was compared with docking and shape-matching virtual screening approaches using 3OE6 CXCR4 crystal structure and high-affinity ligands as query molecules, respectively. The performance of these methods was compared by virtually screening a library assembled by us, consisting of 228 high affinity known CXCR4 inhibitors from 20 different chemotype families and 4696 similar presumed inactive molecules. The area under the ROC plot (AUC), enrichment factors, and diversity of the resulting virtual hit lists was analyzed. Results show that our pharmacophore model achieves the highest VS performance among all the docking and shape-based scoring functions used. Its high selectivity and sensitivity makes our pharmacophore a very good filter for identifying CXCR4 antagonists.

Benchmarking of HPCC: A novel 3D molecular representation combining shape and pharmacophoric descriptors for efficient molecular similarity assessments.

Since 3D molecular shape is an important determinant of biological activity, designing accurate 3D molecular representations is still of high interest. Several chemoinformatic approaches have been developed to try to describe accurate molecular shapes. Here, we present a novel 3D molecular description, namely harmonic pharma chemistry coefficient (HPCC), combining a ligand-centric pharmacophoric description projected onto a spherical harmonic based shape of a ligand. The performance of HPCC was evaluated by comparison to the standard ROCS software in a ligand-based virtual screening (VS) approach using the publicly available directory of useful decoys (DUD) data set comprising over 100,000 compounds distributed across 40 protein targets. Our results were analyzed using commonly reported statistics such as the area under the curve (AUC) and normalized sum of logarithms of ranks (NSLR) metrics. Overall, our HPCC 3D method is globally as efficient as the state-of-the-art ROCS software in terms of enrichment and slightly better for more than half of the DUD targets. Since it is largely admitted that VS results depend strongly on the nature of the protein families, we believe that the present HPCC solution is of interest over the current ligand-based VS methods.

[Professional practices and perceptions about job retention systems for the chronically ill: a qualitative study in south-eastern France]. / Pratiques et perceptions des professionnels vis-à-vis du dispositif de maintien dans l'emploi: étude qualitative en région Provence-Alpes-Côte d'Azur.

BACKGROUND: Continued employment of people with health problems that reduce their ability to work is a major social issue. The French measures to optimize job retention are characterized by a multiplicity of participants, and their efficacy depends largely on the capacity of these different participants to work together. The objective of this study was to document the perceived role, attitudes and practices of participants involved in these job retention measures and of general practitioners, as well as their difficulties in this domain. METHODS: In 2009, 15 semi-directive interviews were conducted in the region of Provence-Alpes-Côte d'Azur (PACA) of occupational physicians, general practitioners, and other participants involved in the occupational reclassification of workers no longer completely fit for their job. The data collected were analyzed from a thematic perspective. RESULTS: The different groups of professionals questioned agreed on the primacy of the role of the occupational physician, on the importance of early consideration of each worker's case, and on the need to work together as partners to optimize the prospects of job retention. This study nonetheless showed numerous communication difficulties between the various professionals: although informal exchanges have developed over time, the efficacy of the system seems to be limited by a lack of clarity about the role of each institution, divergences of opinions on some key points including the role of the physicians caring for the patient, and, more largely, lack of information about the tools for job retention. CONCLUSION: The distribution of homogeneous knowledge, the development of multidisciplinary collaborative practices and the pooling of the lessons of experience between the different groups of participants are essential for the success of job retention procedures.

Effect of high-impact aerobics and strength training on BMD in young women aged 20-35 years.

To evaluate the effects of a 12-month exercise intervention using either high-impact step aerobic exercise or moderate-intensity strength training on areal bone mineral density (aBMD) we studied 51 untrained women, aged 20-35 years, for this study. Whole body and heel and wrist aBMD were measured by dual-energy X-ray absorptiometry (DXA, Hologic or PIXI Lunar). Subjects were randomly assigned to: impact-loaded step aerobic exercise (SA, n=15), moderate-intensity lower body strength training (ST, n=16) or non-exercise control (CON, n=20). Data analysis only included those who completed 95% of each training routine and attended at least 80% of all sessions. Group differences in aBMD, leg press strength and urinary cross-link deoxypridinoline (µDPD) were analysed using analysis of variance. After a 12-month intervention, the SA elicited an increase in aBMD of the heel (4.4%, p<0.05) and leg press strength (15%, p<0.05), relative to baseline. Meanwhile, the ST showed an increase in leg press strength (48%, p<0.05) with no significant increase in aBMD at any measured site. Similar and unchanged µDPD was observed in all 3 groups at baseline, 6 and 12 months. In conclusion, a 12-month high-impact step aerobic exercise resulted in a significant increase in the heel aBMD in untrained young women, who complied with the exercise regimen. A moderate intensity strength training intervention of similar duration had no effect on aBMD although leg strength increased significantly.

Double-barrel fibular graft for metaphyseal areas reconstruction around the knee.

UNLABELLED: The metaphyses around the knee (distal femoral and proximal tibial) are junction areas subject to considerable stress. Double-barrel free vascular fibular graft (D-FVFG) provides good bone augmentation and restores the metaphyseal cone; the present study assessed its capacity to restore metaphyseal anatomy and axis and investigated its impact on the neighboring knee joint. MATERIAL AND METHODS: Eight D-FVFGs performed for metaphyseal segmental bone defect were followed up for a mean 6.5 years (range, 3-14 years). There were seven femoral nonunions, five of which were septic, and one chondrosarcoma of the tibia. Osteosynthesis used an external fixator (EF) in six cases (four of which bridged the knee), a double plate on the tibia in one case, and intramedullary nailing of the femur in two cases, including one to replace an EF. Adjuvant bone graft was associated in six cases. A protective leg brace was maintained for a mean 16.0±4.0 months. Three arthrolyses were required after final union. RESULTS: Union was achieved in all cases, after a mean 6.4±2.1 months. Sixty-four percent of defect volume was reconstructed. The immediate postoperative mechanical femorotibial angle was 180.3±6.0° and 174.5±5.7° at FU. Mean knee flexion was 96.9±36.0° and extension -5.0±10.0°. Three patients showed symptomatic arthritis at follow-up. DISCUSSION: D-FVFG satisfactorily restored the anatomy of the metaphyseal area. EF knee bridging seemed to impair varus correction, on top of the systematic problem of stiffness. When possible, internal fixation in first intention or as EF replacement appears to be preferable. Arthritic deterioration of the knee is worsened by initial joint lesions and femorotibial varus. LEVEL OF EVIDENCE: Level IV. TYPE OF STUDY: retrospective.

[Occupational physicians and occupational cancers: attitudes, opinions, practices. A qualitative study in South Eastern France]. / Médecins du travail et cancers professionnels : attitudes, opinions et pratiques. Une recherche qualitative dans le Sud-Est de la France.

BACKGROUND: A qualitative study was conducted in 2008 of occupational physicians (OPs) in south-eastern France to document their attitudes, opinions and practices on prevention and screening of occupational cancers. This was done to provide elements to prepare the questionnaire of a quantitative study in 2009. METHODS: Semi-structured interviews were conducted using a structured interview guide with 20 OPs. The data collected were subjected to an analysis of thematic content type. RESULTS: The analysis revealed that OPs face many difficulties when preventing occupational cancers. For most of OPs, these difficulties appeared related to "external factors": lack of involvement of employers and minimization of risks by employers and employees. Lack of time, overload and, for some OPs, perceived lack of independence towards employers, were also mentioned as barriers to cancer prevention. This study also suggested hypotheses related to OPs themselves (internal factors): perceived lack of effectiveness and, trend to minimize the risks of occupational cancer in their geographical area. Finally, the results suggest a significant heterogeneity of OPs' practices regarding occupational cancer screening. CONCLUSION: These results raise several hypotheses that will be addressed further in the quantitative survey. They warn about the difficulties of a profession that seems to encounter a demographic and identity crisis.

General practitioners and patients with psychological stress at work.

INTRODUCTION: Identifying patients with psychological stress at work (PSW) and managing them are complex tasks. We studied the frequency of PSW as perceived by general practitioners (GPs), their practices in such situations, and the factors associated with these perceptions and practices, especially drug prescription. METHODS: Cross-sectional telephone study of GPs in southeastern France with a questionnaire about knowledge, attitudes, behavior, and practices in occupational health. We explored the management of PSW with a case-vignette of a 45-year-old supermarket cashier consulting for psychological stress that he or she attributes to the job. RESULTS: In all, 391 GPs participated; 87.2% reported that they encountered PSW often in their practice. GPs reported that they would treat the case-vignette patient by prescribing anxiolytics (66.5%) or sick leaves (65.7%) or referral to an occupational physician (80.3%) or a mental health specialist (44.8%). A multiple logistic regression showed that GPs reported prescribing an anxiolytic most frequently for the vignette-patient when they saw a high number of patients daily, asked patients about working conditions, suggested a sick leave or a referral to a specialist to the case-vignette patient and perceived more obstacles to reporting an occupational disease. CONCLUSION: Our study suggests that PSW is perceived by GPs as one of the principal work-related health problems and that in such situations, most GPs say they would prescribe drugs and sick leave and refer the patient to an occupational physician. Initial and continuing education programs and good practice guidelines would be useful to help them deal with these problems.

Trends in drug consumption and risk of transmission of HIV and hepatitis C virus among injecting drug users in Switzerland, 1993-2006.

As a part of the HIV behavioural surveillance system in Switzerland, repeated cross-sectional surveys were conducted in 1993, 1994, 1996, 2000 and 2006 among attenders of all low threshold facilities (LTFs) with needle exchange programmes and/or supervised drug consumption rooms for injection or inhalation in Switzerland. Data were collected in each LTF over five consecutive days, using a questionnaire that was partly completed by an interviewer and partly self administered. The questionnaire was structured around three topics: socio-demographic characteristics, drug consumption, health and risk/preventive behaviour. Analysis was restricted to attenders who had injected drugs during their lifetime (IDUs). Between 1993 and 2006, the median age of IDUs rose by 10 years. IDUs are severely marginalised and their social situation has improved little. The borrowing of used injection equipment (syringe or needle already used by other person) in the last six months decreased (16.5% in 1993, 8.9% in 2006) but stayed stable at around 10% over the past three surveys. Other risk behaviour, such as sharing spoons, cotton or water, was reported more frequently, although also showed a decreasing trend. The reported prevalence of HIV remained fairly stable at around 10% between 1993 and 2006; reported levels of hepatitis C virus (HCV) prevalence were high (56.4% in 2006). In conclusion, the overall decrease in the practice of injection has reduced the potential for transmission of infections. However as HCV prevalence is high this is of particular concern, as the current behaviour of IDUs indicates a potential for further spreading of the infection. Another noteworthy trend is the significant decrease in condom use in the case of paid sex.

Induced fit in liver X receptor beta: a molecular dynamics-based investigation.

Ligand induced fit phenomenon occurring at the ligand binding domain of the liver X receptor beta (LXRbeta) was investigated by means of molecular dynamics. Reliability of a 4-ns trajectory was tested from two distinct LXRbeta crystal complexes 1PQ6B/GW and 1PQ9B/T09 characterized by an open and a closed state of the pocket, respectively. Crossed complexes 1PQ6B/T09 and 1PQ9B/GW were then submitted to the same molecular dynamic conditions, which were able to recover LXRbeta conformations similar to the original crystallography data. Analysis of "open to closed" and "closed to open" conformational transitions pointed out the dynamic role of critical residues lining the ligand binding pocket involved in the local remodeling upon ligand binding (e.g., Phe271, Phe329, Phe340, Arg319, Glu281). Altogether, the present study indicates that the molecular dynamic protocol is a consistent approach for managing LXRbeta-related induced fit process. This protocol could therefore be used for refining ligand docking solutions of a structure-based design strategy.