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Background: Erosive degenerative disc disease, also known as Modic type 1 changes, is usually characterized by low back pain with an inflammatory pain pattern, as seen in spondyloarthropathies. Intravenous pamidronate has proven to be effective in patients with ankylosing spondylitis who are refractory to nonsteroidal antiinflammatory drugs, and in painful bone diseases in general, such as Paget's disease, fibrous dysplasia or vertebral fractures. We therefore hypothesize that pamidronate would be effective in treating low back pain associated with Modic type 1 changes., Methods/design: This study, called PEPTIDE (short for the French title "Etude Prospective sur l'Efficacité et la tolérance du PamidronaTe dans les dIscopathies Degeneratives Erosives"), will be a double-blind, randomized, placebo-controlled, parallel group, phase two clinical trial. A total of 48 patients will be recruited. These patients will be randomly assigned to one of the two groups, with 24 patients in each group: one group will be given pamidronate and the other a placebo. Pamidronate will be administered at a dose of 90 mg per day for two days consecutively, and every patient, irrespective of treatment group, will be given paracetamol to maintain blinding by preventing drug-induced fever. The primary outcome measure is a between-group difference of 30 points on a 100 mm Visual Analogue Scale (VAS) at three months. Secondary outcome measures are improvement in functional status and the drug's safety. Primary and secondary outcome measures will be assessed at each visit (inclusion, at six weeks, three months, and six months). If the primary goal is not attained, the patient will be offered a rigid or semi-rigid back brace, irrespective of the treatment group., Discussion: To date, only local treatments, for example intradiscal corticosteroid therapy, lumbar arthrodesis or back braces have been studied in randomized, controlled trials, with controversial results. This trial is currently ongoing and, if conclusive, should provide physicians with an acceptable alternative to those treatments. The results should be publicly available in spring 2015., Trial Registration: ClinicalTrials.gov number, NCT01799616.

To characterize the eel contamination by dioxin-like (dl) and non dioxin-like (ndl) polychlorinated biphenyls (PCBs) and polychlorinated dibenzo-p-dioxins and furans (PCDD/Fs), sixty-two eels from the Loire estuary (France) were analyzed. PCB contamination significantly increased from glass eel stage (3.71 ± 1.85 and 15.2 ± 4.2 ng g(-1) dw) to other life stages (for yellow eels: 62.8 ± 34.4 and 382 ± 182 ng g(-1) dw; for silver eels: 93.7 ± 56.3 and 463 ± 245 ng g(-1) dw respectively for dl and ndl-PCBs). An inter-site variability based on PCB levels and profiles was observed among the three studied sites. For glass eels, the profile was mainly characterized by less chlorinated PCBs contrary to the other eels, displaying a different bioaccumulation pathway. Overall, the contamination level in the eels from this estuary was shown to be low for PCDD/Fs and intermediate for dl and ndl-PCBs, compared to other international/national areas. However, more than 60% of the studied silver eels displayed higher values for PCDD/F and dl-PCB WHO2005 TEQ than the EU permissible level of 10 pg g(-1) ww. This statement suggests a potential exposure to PCBs through eel consumption, especially with silver eels, and also points out apparent contamination that could eventually affect the reproductive success of the species., (Copyright © 2013. Published by Elsevier B.V.)

Background: Association mapping studies offer great promise to identify polymorphisms associated with phenotypes and for understanding the genetic basis of quantitative trait variation. To date, almost all association mapping studies based on structured plant populations examined the main effects of genetic factors on the trait but did not deal with interactions between genetic factors and environment. In this paper, we propose a methodological prospect of mixed linear models to analyze genotype by environment interaction effects using association mapping designs. First, we simulated datasets to assess the power of linear mixed models to detect interaction effects. This simulation was based on two association panels composed of 90 inbreds (pearl millet) and 277 inbreds (maize)., Results: Based on the simulation approach, we reported the impact of effect size, environmental variation, allele frequency, trait heritability, and sample size on the power to detect the main effects of genetic loci and diverse effect of interactions implying these loci. Interaction effects specified in the model included SNP by environment interaction, ancestry by environment interaction, SNP by ancestry interaction and three way interactions. The method was finally used on real datasets from field experiments conducted on the two considered panels. We showed two types of interactions effects contributing to genotype by environment interactions in maize: SNP by environment interaction and ancestry by environment interaction. This last interaction suggests differential response at the population level in function of the environment., Conclusions: Our results suggested the suitability of mixed models for the detection of diverse interaction effects. The need of samples larger than that commonly used in current plant association studies is strongly emphasized to ensure rigorous model selection and powerful interaction assessment. The use of ancestry interaction component brought valuable information complementary to other available approaches.

Key Message: Linkage analysis confirmed the association in the region of PHYC in pearl millet. The comparison of genes found in this region suggests that PHYC is the best candidate. Major efforts are currently underway to dissect the phenotype-genotype relationship in plants and animals using existing populations. This method exploits historical recombinations accumulated in these populations. However, linkage disequilibrium sometimes extends over a relatively long distance, particularly in genomic regions containing polymorphisms that have been targets for selection. In this case, many genes in the region could be statistically associated with the trait shaped by the selected polymorphism. Statistical analyses could help in identifying the best candidate genes into such a region where an association is found. In a previous study, we proposed that a fragment of the PHYTOCHROME C gene (PHYC) is associated with flowering time and morphological variations in pearl millet. In the present study, we first performed linkage analyses using three pearl millet F2 families to confirm the presence of a QTL in the vicinity of PHYC. We then analyzed a wider genomic region of ~100 kb around PHYC to pinpoint the gene that best explains the association with the trait in this region. A panel of 90 pearl millet inbred lines was used to assess the association. We used a Markov chain Monte Carlo approach to compare 75 markers distributed along this 100-kb region. We found the best candidate markers on the PHYC gene. Signatures of selection in this region were assessed in an independent data set and pointed to the same gene. These results foster confidence in the likely role of PHYC in phenotypic variation and encourage the development of functional studies.

The genus Phoenix (Arecaceae) comprises 14 species distributed from Cape Verde Islands to SE Asia. It includes the economically important species Phoenix dactylifera. The paucity of differential morphological and anatomical useful characters, and interspecific hybridization, make identification of Phoenix species difficult. In this context, the development of reliable DNA markers for species and hybrid identification would be of great utility. Previous studies identified a 12 bp polymorphic chloroplast minisatellite in the trnG (GCC)-trnfM (CAU) spacer, and showed its potential for species identification in Phoenix. In this work, in order to develop an efficient DNA barcode marker for Phoenix, a longer cpDNA region (700 bp) comprising the mentioned minisatellite, and located between the psbZ and trnfM (CAU) genes, was sequenced. One hundred and thirty-six individuals, representing all Phoenix species except P. andamanensis,were analysed. The minisatellite showed 2-7 repetitions of the 12 bp motif, with 1-3 out of seven haplotypes per species. Phoenix reclinata and P. canariensis had species-specific haplotypes. Additional polymorphisms were found in the flanking regions of the minisatellite, including substitutions, indels and homopolymers. All this information allowed us to identify unambiguously eight out of the 13 species, and overall 80% of the individuals sampled. Phoenix rupicola and P. theophrasti had the same haplotype, and so had P. atlantica, P. dactylifera, and P. sylvestris (the "date palm complex" sensu Pintaud et al. 2013). For these species, additional molecular markers will be required for their unambiguous identification. The psbZ-trnfM (CAU) region therefore could be considered as a good basis for the establishment of a DNA barcoding system in Phoenix, and is potentially useful for the identification of the female parent in Phoenix hybrids.

Background: The script concordance test (SCT) is a method for assessing clinical reasoning of medical students by placing them in a context of uncertainty such as they will encounter in their future daily practice. Script concordance testing is going to be included as part of the computer-based national ranking examination (iNRE).This study was designed to create a script concordance test in rheumatology and use it for DCEM3 (fifth year) medical students administered via the online platform of the Clermont-Ferrand medical school., Methods: Our SCT for rheumatology teaching was constructed by a panel of 19 experts in rheumatology (6 hospital-based and 13 community-based). One hundred seventy-nine DCEM3 (fifth year) medical students were invited to take the test. Scores were computed using the scoring key available on the University of Montreal website. Reliability of the test was estimated by the Cronbach alpha coefficient for internal consistency., Results: The test comprised 60 questions. Among the 26 students who took the test (26/179: 14.5%), 15 completed it in its entirety. The reference panel of rheumatologists obtained a mean score of 76.6 and the 15 students had a mean score of 61.5 (p = 0.001). The Cronbach alpha value was 0.82., Conclusions: An online SCT can be used as an assessment tool for medical students in rheumatology. This study also highlights the active participation of community-based rheumatologists, who accounted for the majority of the 19 experts in the reference panel.A script concordance test in rheumatology for 5th year medical students.

Amborella trichopoda Baill. (Amborellaceae, Amborellales), the sole living member of the sister group to all other extant angiosperms, is endemic to New Caledonia. We addressed the intraspecific phylogeography of Amborella by investigating whether its present population genetic structure could be related to its current and past habitats. We found moderate range-wide genetic diversity based on nuclear microsatellite data and detected four well-differentiated, geographically distinct genetic groups using Bayesian clustering analyses. We modelled the ecological niche of Amborella based on the current climatic and environmental conditions. The predictive ability of the model was very good throughout the Central East mainland zone, but Amborella was predicted in the northern part of the island where this plant has not been reported. Furthermore, no significant barrier was detected based on habitat suitability that could explain the genetic differentiation across the area. Conversely, we found that the main genetic clusters could be related to the distribution of the suitable habitat at the last glacial maximum (LGM, c. 21,000 years BP), when Amborella experienced a dramatic 96.5% reduction in suitable area. At least two lineages survived in distinct putative refugia located in the Massif des Lèvres and in the vicinity of Mount Aoupinié. Our findings finally confirmed the importance of LGM rainforest refugia in shaping the current intra- and interspecific diversity in New Caledonian plants and revealed the possibility of an as yet unreported refugium. The combination of niche modelling and population genetics thereby offered novel insight into the biogeographical history of an emblematic taxon., (© 2013 John Wiley & Sons Ltd.)

Background: Clonal propagation is a particular reproductive system found in both the plant and animal kingdoms, from human parasites to clonally propagated crops. Clonal diversity provides information about plant and animal evolutionary history, i.e. how clones spread, or the age of a particular clone. In plants, this could provide valuable information about agrobiodiversity dynamics and more broadly about the evolutionary history of a particular crop. We studied the evolutionary history of yam, Dioscorea rotundata. In Africa, Yam is cultivated by tuber clonal propagation., Results: We used 12 microsatellite markers to identify intra-clonal diversity in yam varieties. We then used this diversity to assess the relative ages of clones. Using simulations, we assessed how Approximate Bayesian Computation could use clonal diversity to estimate the age of a clone depending on the size of the sample, the number of independent samples and the number of markers. We then applied this approach to our particular dataset and showed that the relative ages of varieties could be estimated, and that each variety could be ranked by age., Conclusions: We give a first estimation of clone age in an approximate Bayesian framework. However the precise estimation of clone age depends on the precision of the mutation rate. We provide useful information on agrobiodiversity dynamics and suggest recurrent creation of varietal diversity in a clonally propagated crop.

The principles of treating rheumatoid arthritis (RA) have changed considerably in recent years. Disease-modifying treatment (if possible, methotrexate) should be started as soon as the diagnosis of RA is made. The purpose of treatment is to achieve remission or, alternatively, low disease activity, and patients should be assessed every 1-3 months if they have early RA in order to achieve this aim. The same principles of treatment should apply in the elderly. However, it is more difficult to assess RA activity in the elderly. Overall disease activity and/or pain may be overestimated, as elderly patients may suffer from other diseases. Conversely, the number of joints with synovitis can be underestimated compared with young patients, and regular ultrasound assessment should therefore be considered. Treatment may be more difficult because of concomitant diseases and the increase in drug-related side effects. The role of corticosteroids is still controversial as their short-term symptomatic effects on clinical activity and potential medium-term effect on structural deterioration are counter-balanced by their side effects. Dosages of methotrexate need to be adjusted for creatinine clearance. The anti-tumor necrosis factors (TNFs) appear to be slightly less effective in the elderly. The frequency of adverse effects of anti-TNFs is higher in an elderly population, although the same is seen with comparator disease-modifying treatments. Limited information is available for rituximab and tocilizumab. Uncertainties remain about the management of RA in the elderly as there have been few studies in this population. The safety of the biotherapies therefore still needs to be confirmed, together with the benefit-risk balance of corticosteroid therapy compared with biological therapy.

Objective: To study the influence of several factors (rheumatoid factor [RF], anti-cyclic citrullinated peptide [anti-CCP], serum Ig level, and Epstein-Barr virus [EBV] load) on clinical response to rituximab (RTX) after 6 months in rheumatoid arthritis (RA) patients., Methods: Sixty-four patients receiving RTX (two 1-gm doses 2 weeks apart) for active RA were prospectively included. RF, anti-CCP, gamma globulin level, and EBV load were assessed prior to the first RTX cycle. Clinical responses were analyzed 6 months after RTX initiation using the European League Against Rheumatism criteria. Univariate and multivariate analyses were performed to identify factors associated with RTX response at 6 months., Results: The mean disease duration was 16.4 years and 46 patients (71.9%) had already received at least 1 anti-tumor necrosis factor agent prior to RTX. At 6 months, 46 patients (71.9%) had a good to moderate response to RTX. Anti-CCP positivity was associated with a good to moderate response (odds ratio [OR] 4, 95% confidence interval [95% CI] 1.04-15.5; P = 0.04). RF positivity (P = 0.26) and positive initial EBV load (P = 0.16) were not associated with a good to moderate response. Hyperimmunoglobulin was correlated with a poorer response to RTX than normal Ig levels (OR 0.04, 95% CI 0.005-0.28; P = 0.002)., Conclusion: Anti-CCP positivity was a predictor of good to moderate response to RTX in RA patients. On the other hand, high Ig levels were associated with a poorer outcome in contrast to previous findings. Further support from larger studies is necessary so as to optimize the management of the RA patients with high Ig levels., (Copyright © 2013 by the American College of Rheumatology.)

Objective: The increased cardiovascular risk associated with AS is attributable to multiple factors: disease activity, systemic inflammation, traditional risk factors and NSAIDs. This study aimed to investigate the effects of 24 and 52 weeks of TNF-α inhibitor treatment on arterial stiffness and cardiovascular risk factors., Methods: Arterial stiffness was measured using the augmentation index (AIx) and pulse wave velocity (PWV), while other cardiovascular risk factors [lipid profile, blood pressure (BP) and BMI] were collected for active AS patients., Results: In total, 49 patients, comprising 30 men, were included in the study, with a mean age of 46.9 (12.1) years. Of these, 20 (40.8%) patients were current smokers, while 10 were treated for hypertension. Patients had long-standing [11.9 (9.2) years] and active AS, with a high initial BASDAI [55.0 (18.2)]. Regarding treatment, 26 patients received etanercept, 17 adalimumab and 6 infliximab. No changes were observed in PWV and AIx after 6 or 12 months following TNF-α blockade [PWV 6.97 (2.03) m/s, 6.92 (1.81) m/s and 7.10 (1.95) m/s at baseline, 6 months and 1 year, respectively, P = 0.64; AIx 19.5 (13.1%), 20.2 (12.8%), 18.3 (13.5%), respectively, P = 0.87]. Lipid profiles and other cardiovascular risk factors were unchanged. However, BASDAI, BASFI and biological inflammation were significantly improved., Conclusion: Arterial stiffness was not improved after 6 and 12 months of anti-TNF-α therapy. However, treatment decreased biological inflammation and disease activity without causing any changes in lipid profiles and other traditional cardiovascular risk factors.

Background: Systemic inflammation plays an important role in the increased cardiac risk observed in rheumatoid arthritis (RA). Effective control of inflammation and disease activity may be of benefit in reducing cardiovascular risk in RA patients., Objective: Our study was conducted in patients with active RA to investigate the effects of 24-week abatacept treatment on aortic stiffness measured by pulse wave velocity (PWV)., Results: The study included 21 patients, of whom 17 were females, with a mean age of 65.2±13.7 years. Ten patients had positive rheumatoid factors, 16 positive anti-citrullinated protein antibodies, and 19 presented an erosive form of RA. Sixteen patients were nonresponders to anti-tumor necrosis factor-alpha treatments. After 6 months of abatacept treatment, there was a significant increase in PWV levels (9.8±2.9 versus 8.5±3.9 m/second; P=0.02). A nonsignificant increase in total cholesterol and low-density lipoprotein cholesterol was observed. There was also a significant increase in high-density lipoprotein cholesterol levels, which led to a nonsignificant decrease in atherogenic index. The improvement in disease activity was significant, and there was a decrease of systemic inflammatory parameters, but without reaching statistical significancy. Changes in PWV were significantly correlated with changes in Disease Activity Score on 28 joints based on erythrocyte sedimentation rate (r=0.46; P=0.035) and in high-density lipoprotein cholesterol (r=-0.38; P=0.046). No correlation was observed with changes in C-reactive protein and in other parameters of lipid profile or in steroid dose., Conclusion: The worsening of aortic stiffness found after 6 months of abatacept therapy might be due to an insufficient decrease in systemic inflammation.

Premise of the Study: Informative markers are required for assessing the diversity of Amborella trichopoda, the only species of its order, endemic to New Caledonia and considered to be the sister species to all flowering plants. Therefore, expressed sequence tag (EST)-based microsatellite markers were developed. •, Methods and Results: Fifty-five microsatellite loci were characterized in 14896 putative unigenes, which were generated by assembling A. trichopoda ESTs from the public sequence database. Seventeen markers revealed polymorphism in 80 adult shrubs from three populations. The number of alleles per locus ranged from two to 12, with a total of 132 alleles scored. The mean expected heterozygosity per population ranged from 0.336 to 0.567. •, Conclusions: These markers offer an appropriate amount of variation to investigate genetic diversity structure, gene flow, and other conservation issues.

The plant domestication process is associated with considerable modifications of plant phenotype. The identification of the genetic basis of this adaptation is of great interest for evolutionary biology. One of the methods used to identify such genes is the detection of signatures of selection. However, domestication is generally associated with major demographic effects. It is therefore crucial to disentangle the effects of demography and selection on diversity. In this study, we investigated selection in a flowering time pathway during domestication of pearl millet. We first used a random set of 20 genes to model pearl millet domestication using approximate Bayesian computation. This analysis showed that a model with exponential growth and wild-cultivated gene flow was well supported by our data set. Under this model, the domestication date of pearl millet is estimated at around 4,800 years ago. We assessed selection in 15 pearl millet DNA sequences homologous to flowering time genes and showed that these genes underwent selection more frequently than expected. We highlighted significant signatures of selection in six pearl millet flowering time genes associated with domestication or improvement of pearl millet. Moreover, higher deviations from neutrality were found for circadian clock-associated genes. Our study provides new insights into the domestication process of pearl millet and shows that a category of genes of the flowering pathway were preferentially selected during pearl millet domestication.

Objectives: To assess the efficacy and safety of rituximab (RTX) in patients with refractory idiopathic inflammatory myopathies (IIMs)., Methods: RTX efficacy was based on improvement in three criteria: creatine phosphokinase (CPK) level, daily CS dose and physicians' opinion. A decrease in CPK level or CS dose was significant if it was >25%., Results: Thirty patients were studied (21 women; age 52.5 years, disease duration 6.1 years). All had previously received immunosuppressors (ISs). Twenty-five patients received 1 g of RTX twice 2 weeks apart and five received 4 weekly RTX infusions (375 mg/m(2)). RTX was given in association with IS in 21 patients. Twenty-eight patients received CS (mean dose 21.2 mg/day). Mean follow-up was 17.2 months. Thirteen adverse events were reported, including seven infections and one serious infection (pyelonephritis). RTX was effective in 16 patients. Duration of efficacy was 15.5 months. Of the 20 patients with baseline CPK level ≥2 × upper limit of normal (ULN), 11 (55%) improved. The main level fell from 20.7 to 11 × ULN. CS decreased in 15 patients, stopped in 4, remained stable in 8 and increased in the remaining 3. The CS dose decreased from 21.2 to 9.9 mg/day. The physicians' opinion was favourable in 21 patients. Manual muscle testing was performed in only five patients: it increased from 87 to 91/100 at 6 months., Conclusions: RTX was well tolerated and had some beneficial effects on patients with IIM, the main limitation of this study resulted in a lack of manual muscle testing.

Identifying the molecular bases of adaptation is a key issue in evolutionary biology. Genome scan is an efficient approach for identifying important molecular variation involved in adaptation. Association mapping also offers an opportunity to gain insight into genotype-phenotype relationships. Using these two approaches coupled with environmental data should help to come up with a refined picture of the evolutionary process underlying adaptation. In this study, we first conducted a selection scan analysis on a transcription factor gene family. We focused on the MADS-box gene family, a gene family which plays a crucial role in vegetative and flower development. Twenty-one pearl millet populations were sampled along an environmental gradient in West Africa. We identified one gene, i.e. PgMADS11, using Bayesian analysis to detect selection signatures. Polymorphism at this gene was also associated with flowering time variation in an association mapping framework. Finally, we found that PgMADS11 allele frequencies were closely associated with annual rainfall. Overall, we determined an efficient way to detect functional polymorphisms associated with climate variation in non-model plants by combining genome scan and association mapping. These results should help monitor the impact of recent climatic changes on plant adaptation., (© 2010 Blackwell Publishing Ltd.)

Background: In the past few years, functional genomics information has been rapidly accumulating on Rubiaceae species and especially on those belonging to the Coffea genus (coffee trees). An increasing number of expressed sequence tag (EST) data and EST- or genomic-derived microsatellite markers have been generated, together with Conserved Ortholog Set (COS) markers. This considerably facilitates comparative genomics or map-based genetic studies through the common use of orthologous loci across different species. Similar genomic information is available for e.g. tomato or potato, members of the Solanaceae family. Since both Rubiaceae and Solanaceae belong to the Euasterids I (lamiids) integration of information on genetic markers would be possible and lead to more efficient analyses and discovery of key loci involved in important traits such as fruit development, quality, and maturation, or adaptation. Our goal was to develop a comprehensive web data source for integrated information on validated orthologous markers in Rubiaceae., Description: MoccaDB is an online MySQL-PHP driven relational database that houses annotated and/or mapped microsatellite markers in Rubiaceae. In its current release, the database stores 638 markers that have been defined on 259 ESTs and 379 genomic sequences. Marker information was retrieved from 11 published works, and completed with original data on 132 microsatellite markers validated in our laboratory. DNA sequences were derived from three Coffea species/hybrids. Microsatellite markers were checked for similarity, in vitro tested for cross-amplification and diversity/polymorphism status in up to 38 Rubiaceae species belonging to the Cinchonoideae and Rubioideae subfamilies. Functional annotation was provided and some markers associated with described metabolic pathways were also integrated. Users can search the database for marker, sequence, map or diversity information through multi-option query forms. The retrieved data can be browsed and downloaded, along with protocols used, using a standard web browser. MoccaDB also integrates bioinformatics tools (CMap viewer and local BLAST) and hyperlinks to related external data sources (NCBI GenBank and PubMed, SOL Genomic Network database)., Conclusion: We believe that MoccaDB will be extremely useful for all researchers working in the areas of comparative and functional genomics and molecular evolution, in general, and population analysis and association mapping of Rubiaceae and Solanaceae species, in particular.

The effect of the addition of nitrate to winery wastewaters to control the formation of VFA in order to prevent odours during storage and treatment was studied in batch bioreactors at different NO(3)/chemical oxygen demand (COD) ratios and at full scale in natural evaporation ponds (2 x 7000 m(2)) by measuring olfactory intensity. In the absence of nitrate, butyric acid (2304 mgL(-1)), acetic acid (1633 mgL(-1)), propionic acid (1558 mgL(-1)), caproic acid (499 mgL(-1)) and valeric acid (298 mgL(-1)) were produced from reconstituted winery wastewater. For a ratio of NO(3)/COD=0.4 gg(-1), caproic and valeric acids were not formed. The production of butyric and propionic acids was reduced by 93.3% and 72.5%, respectively, at a ratio of NO(3)/COD=0.8, and by 97.4% and 100% at a ratio of NO(3)/COD=1.2 gg(-1). Nitrate delayed and decreased butyric acid formation in relation to the oxidoreduction potential. Studies in ponds showed that the addition of concentrated calcium nitrate (NITCAL) to winery wastewaters (3526 m(3)) in a ratio of NO(3)/COD=0.8 inhibited VFA production, with COD elimination (94%) and total nitrate degradation, and no final nitrite accumulation. On the contrary, in ponds not treated with nitrate, malodorous VFA (from propionic to heptanoïc acids) represented up to 60% of the COD. Olfactory intensity measurements in relation to the butanol scale of VFA solutions and the ponds revealed the pervasive role of VFA in the odour of the untreated pond as well as the clear decrease in the intensity and not unpleasant odour of the winery wastewater pond enriched in nitrates. The results obtained at full scale underscored the feasibility and safety of the calcium nitrate treatment as opposed to concentrated nitric acid.

In order to evaluate the attractiveness of France for conducting international clinical trials, a survey is performed every two years among pharmaceutical companies that are based in France or have affiliates in France. Initiated in 2006, the current survey was much more representative than the previous ones with 20 companies accounting for 61% of the French market. This survey included 352 international phase II and III clinical studies carried out in 2004 and 2005, 74 countries, 17 345 centres and 137 989 patients. France has participated to half of the overall number of international clinical trials. France ranked among the best European recruiters (0,19 patient/1000 inhabitants) at the second position behind Scandinavian countries, taking in account numbers of inhabitants. Protocols are now to be given the go-ahead by Ethics Committee (CCPPRB) within 60 days. With a high productivity in phase IIb and in oncology, France is still an attractive place to locate clinical research.

In order to evaluate the attractiveness of France for conducting international clinical trials, a survey is performed every two years among pharmaceutical companies that are based in France or have affiliates in France. Initiated in 2006, the current survey was much more representative than the previous ones with 20 companies accounting for 61% of the French market. This survey included 352 international phase II and III clinical studies carried out in 2004 and 2005, 74 countries, 17 345 centres and 137 989 patients. France has participated to half of the overall number of international clinical trials. France ranked among the best European recruiters (0,19 patient/1000 inhabitants) at the second position behind Scandinavian countries, taking in account numbers of inhabitants. Protocols are now to be given the go-ahead by Ethics Committee (CCPPRB) within 60 days. With a high productivity in phase IIb and in oncology, France is still an attractive place to locate clinical research., (Copyright © 2006 Société Française de Pharmacologie et de Thérapeutique. Publié par Elsevier Masson SAS.)

Biopsies of normal human cerebral cortex were fixed by aldehydes and their ultrastructure was studied. Two main types of vessels are observed, capillaries and metarterioles, and around them two types of pericytes are described: a microgliocyte-like pericyte which is either surrounded by a nervous basal membrane, or laying outside this membrane; endothelial-like pericytes which are frequently observed inside the metarterioles perivascular space and contain many lysosomes. Endothelial-like pericytes have probably a metabolic function and microgliocyte-like pericytes are more involved in a role of mechanic regulation of the microcirculation. This hypothesis is supported by the observation of a microgliocyte interposed between two endothelial processes and protuding into the vascular lumen.

Microglia-like cells and endothelial cells may influence capillary blood output. 1) Microglia-like cells are sometimes interposed between two endothelial processes with which they are nexus-linked. In this position, they protude in vascular lumen which is considerably reduced. 2) Endothelial cells present no contractile filaments but their nucleus and surrounding cytoplasm may protude in vascular lumen, constituting a "coussinet-like" structure. Thus, regulation by specialized structures observed by Legait in brain arteries seems to occur even in the smallest ramifications of brain cortical vessels.