A global perspective on bacterial diversity in the terrestrial deep subsurface.

While recent efforts to catalogue Earth's microbial diversity have focused upon surface and marine habitats, 12-20 % of Earth's biomass is suggested to exist in the terrestrial deep subsurface, compared to ~1.8 % in the deep subseafloor. Metagenomic studies of the terrestrial deep subsurface have yielded a trove of divergent and functionally important microbiomes from a range of localities. However, a wider perspective of microbial diversity and its relationship to environmental conditions within the terrestrial deep subsurface is still required. Our meta-analysis reveals that terrestrial deep subsurface microbiota are dominated by Betaproteobacteria, Gammaproteobacteria and Firmicutes, probably as a function of the diverse metabolic strategies of these taxa. Evidence was also found for a common small consortium of prevalent Betaproteobacteria and Gammaproteobacteria operational taxonomic units across the localities. This implies a core terrestrial deep subsurface community, irrespective of aquifer lithology, depth and other variables, that may play an important role in colonizing and sustaining microbial habitats in the deep terrestrial subsurface. An in silico contamination-aware approach to analysing this dataset underscores the importance of downstream methods for assuring that robust conclusions can be reached from deep subsurface-derived sequencing data. Understanding the global panorama of microbial diversity and ecological dynamics in the deep terrestrial subsurface provides a first step towards understanding the role of microbes in global subsurface element and nutrient cycling.

Impact of the polycarbonate strippers used in assisted reproduction techniques on embryonic development.

STUDY QUESTION: Do daily manipulations of preimplantation embryos with polycarbonate (PC)-made bisphenol A (BPA)-releasing strippers influence embryo development? SUMMARY ANSWER: Compared to glass strippers, PC strippers enhance the blastocyst development rate but this does not seem to be BPA-related. WHAT IS KNOWN ALREADY: PC strippers have been shown to release tiny amounts (around 0.5 ng/ml BPA) of BPA in routine human IVF procedures. A chronic exposure to BPA either in vivo or in vitro during the preimplantation period can impact post-implantation and post-natal development. BPA can act rapidly by binding to membrane receptors and inducing rapid non-genomic effects. STUDY DESIGN, SIZE, DURATION: This experimental study using mouse embryos had a balanced design and blinded evaluations of the endpoints. PARTICIPANTS/MATERIALS, SETTING, METHODS: In vivo fertilized zygotes were obtained from outbred Swiss CD1 mice crossings after an ovarian stimulation. The zygotes were allocated to three daily handling conditions (HCs) and cultured until Day 4 in a single human commercial medium. Each day, the embryos were handled for 20 s either in a PC stripper (HC1) or in a glass stripper (HC2). In HC3, the embryos were pre-exposed to 0.5 ng/ml BPA before being handled for 20 s in a glass stripper. Handling operations were repeated on Days 1, 2 and 3. Embryo development was assessed blindly on Day 4. Expanded blastocysts were selected for a transcriptomic analysis using Agilent Sureprint G3 Mouse GE v2 microarrays and the retrotransposon LINE1-Orf2 expression was analysed using qRT-PCR, as a proxy for a global evaluation of the epigenetic status. MAIN RESULTS AND THE ROLE OF CHANCE: Compared to the embryos manipulated in HC2 (n = 243), those in HC1 (n = 228) developed significantly more often to the blastocyst stage (55 vs 46%; P < 0.05). It appears the effect of these PC strippers was not BPA-related because embryos pre-exposed to BPA (HC3, n = 230) showed no difference in the blastocyst rate when compared to HC2 (43 vs 46%). When analysing same-stage blastocysts, we noticed no difference in the embryo gene expression between the three HC groups. LARGE SCALE DATA: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE148868. LIMITATIONS, REASONS FOR CAUTION: Our results using a mouse model designed to mimic human conditions (outbred strain, human commercial IVF dishes and a unique commercial human embryonic culture media) are reassuring since no gene was found to be differentially expressed, including LINE-1 genes, as a proxy for a global evaluation of the epigenetic status. However, no global epigenetic analysis of the genome has been performed. Furthermore, we did not evaluate post-implantation events, although BPA exposure during peri-conception could affect foeto-placental and post-natal development. WIDER IMPLICATIONS OF THE FINDINGS: Based on the precautionary principle, several European countries banned the use of BPA in baby bottles and food packaging several years before European Agencies took an official position. The question of applying this principle to plastics in closed contact with human embryos is raised. Further studies are needed for a decision to be made. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by a grant from the Agence de Biomédecine (AOR 2016). The authors declare no competing interest.

Intersphincteric resection for low rectal cancer: the risk is functional rather than oncological. A 25-year experience from Bordeaux.

AIM: There are few data evaluating the long-term outcomes of intersphincteric resection (ISR), especially the impact of inclusion of more juxtapositioned and intra-anal tumours on oncological and functional outcomes. We compared the oncological and functional results of patients treated by total mesorectal excision and ISR for low rectal cancer over a 25-year period. METHOD: This is a retrospective study from a single institution evaluating results of ISR over three periods: 1990-1998, 1999-2006 and 2007-2014. Patients treated by partial or total ISR, with or without neoadjuvant chemoradiotherapy, for low rectal cancer (≤ 6 cm from the anal verge) were included. We compared postoperative morbidity, quality of surgery and oncological and functional outcomes in the time periods studied. RESULTS: Of 813 patients operated on for low rectal cancer, 303 had ISR. Tumour stage did not differ; however, the distance of the tumour from the anorectal junction decreased from 1 to 0 cm (P < 0.001) and the distal resection margin shortened from 25 to 10 mm (P < 0.001) from 1990 to 2014. The postoperative morbidity and quality of surgery did not change significantly over time. The 5-year local recurrence (4.3% vs 5.9% vs 3.5%; P = 0.741) and disease-free survival (72% vs 71% vs 75%; P = 0.918) did not differ between the three time periods. Functional results improved during the last period; however, overall 42% of patients experienced major bowel dysfunction. CONCLUSION: Pushing the envelope of sphincter-saving resection in ultra-low rectal cancer reaching or invading the anal sphincter did not compromise oncological and functional outcomes. The main limitation of the ISR procedure appears to be functional rather than oncological, suggesting that bowel rehabilitation programmes should be developed.

Delayed coloanal anastomosis: an alternative option for restorative rectal cancer surgery after high-dose pelvic radiotherapy for prostate cancer.

AIM: Restorative total mesorectal excision (TME) for rectal cancer after high-dose pelvic radiotherapy for prostate cancer has been reported to provide an unacceptable rate of pelvic sepsis. In a previous publication we proposed that delayed coloanal anastomosis (DCAA) should be performed in this situation. The present study aimed to assess the feasibility and outcomes of this strategy. METHOD: Between 2000 and 2018, 1094 men were operated on for rectal cancer in our institution. All men with T2/T3 mid and low rectal cancer with preoperative radiotherapy and restorative TME were considered for this study (n = 416). Patients with external-beam high-dose radiotherapy (EBHRT) for prostate cancer (70-78 Gy) were identified and compared with patients with conventional long-course chemoradiotherapy (CRT) followed by TME. We compared our already published historical cohort (2000-2012), including arm A (CRT + TME; n = 236) and arm B (EBHRT + TME; n = 12), with our early cohort (2013-2018), including arm C (CRT + TME; n = 158) and arm D (EBHRT + TME-DCAA; n = 10). The end-points were morbidity, pelvic sepsis, reoperation rate and quality of the specimen. RESULTS: Overall morbidity was not significantly different between groups. Pelvic sepsis decreased from 50% (arm B) to 10% (arm D) with the use of DCAA (P = 0.074), and was similar between arms A, C and D. Quality of the specimen was not significantly different between the four groups. CONCLUSION: Our results suggest that TME with DCAA in patients with previous EBHRT is feasible, with the same postoperative pelvic sepsis rate as conventional CRT.

Long-term outcome of patients with steroid-refractory acute severe UC treated with ciclosporin or infliximab.

OBJECTIVE: Ciclosporin and infliximab have demonstrated short-term similar efficacy as second-line therapies in patients with acute severe UC (ASUC) refractory to intravenous steroids. The aim of this study was to assess long-term outcome of patients included in a randomised trial comparing ciclosporin and infliximab. DESIGN: Between 2007 and 2010, 115 patients with steroid-refractory ASUC were randomised in 29 European centres to receive ciclosporin or infliximab in association with azathioprine. Patients were followed until death or last news up to January 2015. Colectomy-free survival rates at 1 and 5 years and changes in therapy were estimated through Kaplan-Meier method and compared between initial treatment groups through log-rank test. RESULTS: After a median follow-up of 5.4 years, colectomy-free survival rates (95% CI) at 1 and 5 years were, respectively, 70.9% (59.2% to 82.6%) and 61.5% (48.7% to 74.2%) in patients who received ciclosporin and 69.1% (56.9% to 81.3%) and 65.1% (52.4% to 77.8%) in those who received infliximab (p=0.97). Cumulative incidence of first infliximab use at 1 and 5 years in patients initially treated with ciclosporin was, respectively, 45.7% (32.6% to 57.9%) and 57.1% (43.0% to 69.0%). Only four patients from the infliximab group were subsequently switched to ciclosporin. Three patients died during the follow-up, none directly related to UC or its treatment. CONCLUSIONS: In this cohort of patients with steroid-refractory ASUC initially treated by ciclosporin or infliximab, long-term colectomy-free survival was independent from initial treatment. These long-term results further confirm a similar efficacy and good safety profiles of both drugs and do not favour one drug over the other. TRIAL REGISTRATION NUMBER: EudraCT: 2006-005299-42; ClinicalTrials.gouv number: NCT00542152; post-results.

RNA interference validation of detoxification genes involved in ivermectin tolerance in Drosophila melanogaster.

Previously, we observed increased transcription levels of specific cytochrome P450 monooxygenase (P450) and adenosine triphosphate binding cassette (ABC) transporter genes in human body lice, Pediculus humanus humanus, following exposure to ivermectin using the non-invasive induction assay, which resulted in tolerance. To confirm the roles of these genes in induction and tolerance, the robust genetic model insect Drosophila melanogaster was chosen. Orthologous genes corresponding to the body louse P450 (Cyp9f2, Cyp6g2 and Cyp9h1) and ABC transporter (Mrp1, GC1824 as an ABCB type and CG3327 as an ABCG type) genes were selected for in vivo bioassay. Following a brief treatment with a sublethal dose of ivermectin, the mortality response was significantly slower, indicating the presence of tolerance. Concurrently, the transcription levels of Cyp9f2 and Mrp1 at 3 h and those of Cyp6g2, Cyp9h1, Mrp1, CG1824 and CG3327 at 6 h post-treatment were upregulated, indicating gene induction. In behavioural bioassay using GAL4/UAS-RNA interference transgenic fly lines, increased susceptibility to ivermectin was observed following heat shock in the Cyp9f2 , Cyp6g2 , Cyp9h1 , Mrp1 or CG3327-knockdown flies. Considering that these five genes are orthologous to those which had the largest over-expression level following ivermectin-induced tolerance in the body louse, the current results suggest that they are also associated with ivermectin detoxification in D. melanogaster and that body lice and D. melanogaster are likely to share, in part, similar mechanisms of tolerance to ivermectin.

Notch1 endocytosis is induced by ligand and is required for signal transduction.

The Notch signalling pathway is widely utilised during embryogenesis in situations where cell-cell interactions are important for cell fate specification and differentiation. DSL ligand endocytosis into the ligand-expressing cell is an important aspect of Notch signalling because it is thought to supply the force needed to separate the Notch heterodimer to initiate signal transduction. A functional role for receptor endocytosis during Notch signal transduction is more controversial. Here we have used live-cell imaging to examine trafficking of the Notch1 receptor in response to ligand binding. Contact with cells expressing ligands induced internalisation and intracellular trafficking of Notch1. Notch1 endocytosis was accompanied by transendocytosis of ligand into the Notch1-expressing signal-receiving cell. Ligand caused Notch1 endocytosis into SARA-positive endosomes in a manner dependent on clathrin and dynamin function. Moreover, inhibition of endocytosis in the receptor-expressing cell impaired ligand-induced Notch1 signalling. Our findings resolve conflicting observations from mammalian and Drosophila studies by demonstrating that ligand-dependent activation of Notch1 signalling requires receptor endocytosis. Endocytosis of Notch1 may provide a force on the ligand:receptor complex that is important for potent signal transduction.

Lactobacillus acidophilus versus placebo in the symptomatic treatment of irritable bowel syndrome: the LAPIBSS randomized trial.

Irritable bowel syndrome is a chronic functional gastrointestinal disorder characterized by abdominal pain/discomfort and altered bowel habits. The use of Lactobacilli as probiotics during irritable bowel syndrome is based on their interesting mechanisms of action and their excellent safety profile but little is known about their clinical efficacy due to the lack of adequately designed clinical trials. The current clinical trial protocol aims to determine the effects of a mixture of Lactobacillus acidophilus NCFM and LAFTI L10 as probiotics to improve irritable bowel syndrome symptoms (LAPIBSS). Eighty patients with a positive diagnosis of irritable bowel syndrome according to Rome III criteria were recruited to a multicentre, double-blinded, in parallel groups, placebo-controlled randomized trial. Patients were provided with a daily dose of two capsules with two strains of Lactobacilli (5x109cfu/capsule) or placebo for 8 weeks on a 1:1 ratio. The primary outcome is to obtain scores of abdominal pain/discomfort assessed with a 100-mm visual analogue scale. The secondary outcome is to obtain scores of bloating, flatus and rumbling tested with a 100-mm visual analogue scale, composite score, stool frequency and stool consistency/appearance assessed with the Bristol Stool Form scale. According to the hypothesis that abdominal pain is mainly the result of a visceral hypersensitivity, the current study protocol aims to provide high quality proof of concept data to elucidate the efficacy of a consumption of a mixture of Lactobacillus acidophilus probiotic strains after 8 weeks, for decreasing abdominal pain. Ethical approval was given by ethics committee French Consultative Committee for the Protection of Individuals in Biomedical Research of the South West (Number CPP08-014a) and ANSM (French National Agency for Medicines and Health Products Safety - Number B80623-40). The findings from LAPBISS will be disseminated through peer-reviewed publications and at scientific conferences. TRIAL REGISTRATION: EudraCT N°2008-A00844-51.

[Comparative evaluation of dermoscopy and capillaroscopy in Raynaud's phenomenon]. / Évaluation comparative de la dermatoscopie et de la capillaroscopie dans le phénomène de Raynaud.

OBJECTIVE: Raynaud's phenomenon (RP) is a common cause for consultation. Capillaroscopy is a well-established technique to detect capillary abnormalities suggestive of a connective tissue disease, but it is sometimes unavailable. The aim of this study was to compare dermoscopy and capillaroscopy in the assessment of RP. METHODS: This was a prospective single-centre observational study in adult patients consulting for RP at the Hôpital Nord Franche-Comté between January 2014 and June 2015. Dermoscopy was performed at dermatological consultations and capillaroscopy was prescribed. For each capillaroscopy and dermoscopy, the following parameters were examined: normal appearance, giant capillaries, avascular areas, dystrophic capillaries or tortuosity and haemorrhages. Kappa coefficients were calculated. RESULTS: Twenty-six patients participated in this study. The kappa coefficient was 0.76 for "normal" status, 0.78 for tortuosity, 0.70 for giant capillaries, 0.48 for haemorrhage and 0.62 for avascular areas. The global kappa coefficient was 0.33. Detection of these abnormalities with capillaroscopy was significantly associated with abnormal dermoscopic status (P<0.05). The sensitivity of dermoscopy for the detection of "abnormal" capillaroscopic status was 0.87. CONCLUSION: The correlation coefficients were good. Despite poor global concordance, 80% of patients had the same status, normal or abnormal, for both capillaroscopy and dermoscopy, which resulted in the same clinical management. Dermoscopy is thus a valuable tool screening for periungual anomalies and provides support for clinical examination by the dermatologist, although the reference method continues to be capillaroscopy.

[Evaluation of the French practices in brachytherapy using surveys]. / Évaluation par questionnaire des pratiques de la curiethérapie de prostate en France.

INTRODUCTION: Prostate cancer brachytherapy can be used as an alternative to the radical prostatectomy and radiotherapy. In the low-risk group, specific survivals are up to 95% after 10years. The aim of the study is to describe the practices in brachytherapy in France. MATERIALS AND METHODS: A survey made by AFU (French Urologic Association) and SFRO (French Society Of Oncological Radiotherapy) assessing the practices in brachytherapy in France was sent to all the urologists and radiotherapists even if they did not practice it. RESULTS: In total, 1417 surveys were sent, 285 were received coming from 211 urologists (74%) and 74 radiotherapists (26%). Sixty (21%) practiced brachytherapy (31 urologists, 29 radiotherapists). Low dose rate with permanent implants was used in 83,3%. Brachytherapy was advised for low-risk group by 90% who responded the survey, 73% used it in intermediate risk and only 13% in high risk. CONCLUSION: Brachytherapy is hardly used in low risk prostate cancer. It probably needs a reconsideration of recommendations due to the good results in association with a good picking. The urologist-radiotherapist couple is essential in the overall care of the patient. LEVEL OF EVIDENCE: 4.

Easier Control of Late-Onset Cytomegalovirus Disease Following Universal Prophylaxis Through an Early Antiviral Immune Response in Donor-Positive, Recipient-Negative Kidney Transplants.

Universal prophylaxis for cytomegalovirus (CMV) prevention is viable but, compared with a preemptive strategy, leads to higher incidence of late-onset disease (LOD) associated with poor patient and graft survival. The purpose of this study was to compare LOD with early onset disease (EOD), with a focus on the highest risk kidney transplant recipients (KTRs): CMV seronegative recipients transplanted from seropositive donors (D+R-). Since CMV control depends on both antiviral treatment and specific immune response, we also compared Vδ2-negative (Vδ2(neg) ) γδ T cell expansion involved in CMV infection resolution. EOD was defined as occurring <3 mo and LOD as occurring >3 mo after transplantation. Depending on the period, universal prophylaxis or preemptive treatment was used. Overall, 168 D+R- KTRs were included between 2003 and 2011. LOD was associated with a lower peak DNAemia (p = 0.04), fewer recurrences (odds ratio 0.16; 95% confidence interval 0.05-0.55; p = 0.01) and shorter anti-CMV curative treatment (40 vs. 60 days, p < 0.0001). As a corollary, we found that Vδ2(neg) γδ T cell expansion was faster in LOD than in EOD (31 vs. 168 days after the beginning of CMV disease, p < 0.0001). In D+R- KTRs, universal prophylaxis is associated with more LOD, which had better infection management and a faster immune response. These results support the use of universal prophylaxis over a preemptive strategy and reappraise outcomes of LOD.

Pathological brain plasticity and cognition in the offspring of males subjected to postnatal traumatic stress.

Traumatic stress in early-life increases the risk for cognitive and neuropsychiatric disorders later in life. Such early stress can also impact the progeny even if not directly exposed, likely through epigenetic mechanisms. Here, we report in mice that the offspring of males subjected to postnatal traumatic stress have decreased gene expression in molecular pathways necessary for neuronal signaling, and altered synaptic plasticity when adult. Long-term potentiation is abolished and long-term depression is enhanced in the hippocampus, and these defects are associated with impaired long-term memory in both the exposed fathers and their offspring. The brain-specific gamma isoform of protein kinase C (Prkcc) is one of the affected signaling components in the hippocampus. Its expression is reduced in the offspring, and DNA methylation at its promoter is altered both in the hippocampus of the offspring and the sperm of fathers. These results suggest that postnatal traumatic stress in males can affect brain plasticity and cognitive functions in the adult progeny, possibly through epigenetic alterations in the male germline.

Influence of organic matters on AsIII oxidation by the microflora of polluted soils.

The global AsIII-oxidizing activity of microorganisms in eight surface soils from polluted sites was quantified with and without addition of organic substrates. The organic substances provided differed by their nature: either yeast extract, commonly used in microbiological culture media, or a synthetic mixture of defined organic matters (SMOM) presenting some common features with natural soil organic matter. Correlations were sought between soil characteristics and both the AsIII-oxidizing rate constants and their evolution in accordance with inputs of organic substrates. In the absence of added substrate, the global AsIII oxidation rate constant correlated positively with the concentration of intrinsic organic matter in the soil, suggesting that AsIII-oxidizing activity was limited by organic substrate availability in nutrient-poor soils. This limitation was, however, removed by 0.08 g/L of added organic carbon. In most conditions, the AsIII oxidation rate constant decreased as organic carbon input increased from 0.08 to 0.4 g/L. Incubations of polluted soils in aerobic conditions, amended or not with SMOM, resulted in short-term As mobilization in the presence of SMOM and active microorganisms. In contrast, microbial AsIII oxidation seemed to stabilize As when no organic substrate was added. Results suggest that microbial speciation of arsenic driven by nature and concentration of organic matter exerts a major influence on the fate of this toxic element in surface soils.

Fast identification and quantification of BTEX coupling by Raman spectrometry and chemometrics.

Monoaromatic hydrocarbons (MAHs) monitoring is of environmental interest since these chemical pollutants are omnipresent. While waiting for robust sensors able to detect hydrocarbons at very low levels, the present study shows how each compound from pure BTEX mixtures can be identified fast and quantified thanks to Raman spectrometry and data processing based on the SIMPLISMA algorithm. A preprocessing module has been created to remove background contributions and a postprocessing program has been added to achieve matching and calibration. A wide range of BTEX concentrations and relative proportions has been investigated in order to determine the limitations of the processing. Output results achieved an accuracy of up to 95%. This method could be extended to other important pollutants such as polyaromatic hydrocarbons (PAHs) and chlorinated hydrocarbon derivatives.

Two-year post-transplantation cytomegalovirus DNAemia in asymptomatic kidney transplant recipients: incidence, risk factors, and outcome.

BACKGROUND: The incidence and the impact of asymptomatic cytomegalovirus (CMV) DNAemia occurring after the first year post transplantation is unknown. METHODS: In this retrospective cross-sectional study, we analyzed the incidence, risk factors, and impact of 2-year post-transplantation asymptomatic CMV DNAemia (2YCD) on graft function. We included 892 consecutive asymptomatic kidney transplant recipients transplanted for at least 2 years and all were monitored using whole blood CMV quantitative nucleic acid amplification testing (CMV-QNAT). RESULTS: Twenty-eight patients displayed 2YCD (3.1%). Using multivariate analysis in 578 patients, we found that female gender (odds ratio [OR] = 2.57, P = 0.02), a past history of CMV drug-resistance mutation (OR = 8.73, P = 0.005), and corticosteroid use (OR = 2.37, P = 0.03) were independently associated with an increased risk of 2YCD. 2YCD was associated with an increased incidence of subsequent CMV disease over the year following its diagnosis (7% vs. 0.6%, P = 0.02). Patients with 2YCD also exhibited a declining estimated glomerular filtration rate more frequently (77%) than patients with a negative CMV-QNAT (56%, P = 0.02). CONCLUSION: 2YCD appears to be a rare entity, which appears to be associated with chronic graft dysfunction.

The results of seton drainage combined with anti-TNFα therapy for anal fistula in Crohn's disease.

AIM: Combined infliximab and sphincter-sparing surgery can be effective in perianal fistula associated with Crohn's disease (CD). This study aimed to assess the efficacy of local surgery combined with infliximab on sustained fistula closure and to identify predictive factors for response after this combined treatment. METHOD: Between 2000 and 2010, 81 patients with fistulising perianal CD were included in this observational study. Drainage with a loose seton was followed by infliximab therapy. The primary end-points were the rate of complete fistula closure and time required for this to occur. RESULTS: The fistula was complex in 71 (88%) of the 81 patients. Local proctological surgery was carried out in 77 (95%), including seton drainage in 62 (80.5%) of these. This was continued for a median duration of 3.8 months and the patient then received infliximab therapy. The median follow-up after treatment was 64 months (2-263). Initial complete closure of the fistula occurred in 71 (88%) cases at a median interval of 12.4 months (1-147) from the start of treatment. Recurrence was observed in 29 (41%) patients at a median interval of 38.5 months (2-48) from the start of treatment. They were treated again with combined treatment with successful closure in 19 (65.5%) patients. The total rate of closure of the fistula was 75.3%. Female gender, anal stenosis, rectovaginal and complex fistula formation were factors independently associated with failure of combined treatment. CONCLUSION: Seton drainage for several months combined with infliximab therapy is effective in closing the fistula in 75% of patients with complex perianal fistula formation associated with CD.

Schmallenberg virus: experimental infection in goats and bucks.

BACKGROUND: Schmallenberg virus (SBV) is an emerging Orthobunyavirus of ruminant livestock species currently circulating in Europe. SBV causes a subclinical or mild disease in adult animals but vertical transmission to pregnant dams may lead to severe malformations in the offspring. Data on the onset of clinical signs, viremia and seroconversion in experimentally infected adult animals are available for cattle and sheep but are still lacking for goats. For a better understanding of the pathogenesis of SBV infection in adult ruminants, we carried out experimental infections in adult goats. Our specific objectives were: (i) to record clinical signs, viremia and seroconversion; (ii) to monitor viral excretion in the semen of infected bucks; (iii) to determine in which tissues SBV replication took place and virus-induced lesions developed. RESULTS: Four goats and two bucks were inoculated with SBV. Virus inoculation was followed by a short viremic phase lasting 3 to 4 days and a seroconversion occurring between days 7 and 14 pi in all animals. The inoculated goats did not display any clinical signs, gross lesions or histological lesions. Viral genomic RNA was found in one ovary but could not be detected in other organs. SBV RNA was not found in the semen samples collected from two inoculated bucks. CONCLUSIONS: In the four goats and two bucks, the kinetics of viremia and seroconversion appeared similar to those previously described for sheep and cattle. Our limited set of data provides no evidence of viral excretion in buck semen.

Rangeland Rummy - a board game to support adaptive management of rangeland-based livestock systems.

Rangeland-based livestock systems have to deal with the significant instability and uncertainty of the agricultural context (policy changes, volatility of input prices, etc.), and especially of the climatic context. Thus, they are particularly concerned by adaptive management strategies. To support the development of such strategies, we developed a board game including a computer model called "Rangeland Rummy". It is to be used by groups of farmers and agricultural consultants in the context of short workshops (about 3 h). Rangeland Rummy builds upon five types of material object: (i) a game board; (ii) a calendar stick indicating the starting date of the game board; (iii) sticks marked with the feed resources available for combinations of vegetation types and their management practices; (iv) cards to define animal groups and their feeding requirements throughout the year; (v) cards related to types of feed that can be attributed to animal groups throughout the year. Using these material objects, farmers collectively design a rangeland-based livestock system. This system is immediately evaluated using a computer model, i.e. a spreadsheet providing graphs and indicators providing information on, among other things, the extent to which quantitative and qualitative animal feeding requirements are covered across the year. Playing the game thus consists in collectively and iteratively designing and evaluating rangeland-based livestock systems, while confronting the players with new contextual challenges (e.g. interannual variability of weather, volatility of input prices) or new farmers' objectives (e.g. being self-sufficient for animal feeding). An example of application of Rangeland Rummy with 3 farmers in southern France is reported. Applications show that it tends to develop farmers' adaptive capacity by stimulating their discussions and the exchange of locally-relevant knowledge on management strategies and practices in rangeland-based livestock systems.

A new perspective for schizophrenia: TAAR1 agonists reveal antipsychotic- and antidepressant-like activity, improve cognition and control body weight.

Schizophrenia is a chronic, severe and highly complex mental illness. Current treatments manage the positive symptoms, yet have minimal effects on the negative and cognitive symptoms, two prominent features of the disease with critical impact on the long-term morbidity. In addition, antipsychotic treatments trigger serious side effects that precipitate treatment discontinuation. Here, we show that activation of the trace amine-associated receptor 1 (TAAR1), a modulator of monoaminergic neurotransmission, represents a novel therapeutic option. In rodents, activation of TAAR1 by two novel and pharmacologically distinct compounds, the full agonist RO5256390 and the partial agonist RO5263397, blocks psychostimulant-induced hyperactivity and produces a brain activation pattern reminiscent of the antipsychotic drug olanzapine, suggesting antipsychotic-like properties. TAAR1 agonists do not induce catalepsy or weight gain; RO5263397 even reduced haloperidol-induced catalepsy and prevented olanzapine from increasing body weight and fat accumulation. Finally, TAAR1 activation promotes vigilance in rats and shows pro-cognitive and antidepressant-like properties in rodent and primate models. These data suggest that TAAR1 agonists may provide a novel and differentiated treatment of schizophrenia as compared with current medication standards: TAAR1 agonists may improve not only the positive symptoms but also the negative symptoms and cognitive deficits, without causing adverse effects such as motor impairments or weight gain.

Gestational trophoblastic neoplasia after achieving a nondetectable serum human chorionic gonadotrophin level.

OBJECTIVE: To determine the risk of recurrent trophoblastic disease after normalisation of human chorionic gonadotrophin (hCG) levels in women with hydatidiform mole. DESIGN: A retrospective review of data from a national gestational trophoblastic disease centre. SETTING: The Trophoblastic Disease Unit, Dakar, Senegal. SAMPLE: Women with pregnancies affected by hydatidiform mole registered between 2006 and 2012. METHODS: The women were followed up in accordance with the hospital protocol 'Score de Dakar'. For women who progressed to gestational trophoblastic neoplasia (GTN) the time to onset of GTN, treatment and evolution were evaluated. The rate of evolution to GTN after normalisation of hCG was determined. MAIN OUTCOME MEASURES: Rate of occurrence of GTN after chemotherapy for hydatidiform mole. RESULTS: Five hundred and thirty-one women were diagnosed to have molar pregnancies. According to the hospital's protocol, 107 (20.2%) of these had chemotherapy and 224 (42.2%) had prophylactic chemotherapy. Five hundred and thirteen women (96.4%; 95% confidence interval [95% CI] 95.05-98.14%) achieved remission. Eighteen women (3.4%; 95% CI 1.86-4.94%) developed GTN (11 before remission and seven after remission). Seven women out of the 18 developed GTN after hCG normalisation (1.3%). Five of these seven were diagnosed beyond the recommended period of follow up. The mean interval to diagnosis of GTN was 18.7 months. These seven women underwent combination chemotherapy: five achieved complete remission whereas two died from GTN. CONCLUSIONS: Cytotoxic therapy for hydatidiform mole does not prevent GTN, it delays its diagnosis and promotes GTN after normalisation of hCG.