[What can we expect from clinical trials in psychiatry?] / Que peut-on attendre des essais cliniques en psychiatrie ?

Clinical trials in psychiatry allow to build the regulatory dossiers for market authorization but also to document the mechanism of action of new drugs, to build pharmacodynamics models, evaluate the treatment effects, propose prognosis, efficacy or tolerability biomarkers and altogether to assess the impact of drugs for patient, caregiver and society. However, clinical trials have shown some limitations. Number of recent dossiers failed to convince the regulators. The clinical and biological heterogeneity of psychiatric disorders, the pharmacokinetic and pharmacodynamics properties of the compounds, the lack of translatable biomarkers possibly explain these difficulties. Several breakthrough options are now available: quantitative system pharmacology analysis of drug effects variability, pharmacometry and pharmacoepidemiology, Big Data analysis, brain modelling. In addition to more classical approaches, these opportunities lead to a paradigm change for clinical trials in psychiatry.

Epidemiological investigation of a human leptospirosis case reported in a suburban area near Marseille.

Leptospirosis has been re-emerging in both developed and developing countries, including in Europe, where the phenomenon has notably been associated with urban transmission. In this work, we describe an epidemiological investigation that demonstrated a case of human infection due to peri-urban transmission of Leptospira interrogans serovar icterohaemorrhagiae in southeastern France.

Toscana virus infections: a case series from France.

Toscana virus (TOSV) is a neglected sandfly-borne pathogen in Mediterranean countries. Although discovered four decades ago, articles that describe the clinical aspects are scarce and consist mostly of case reports, with few series of cases. We studied retrospectively symptomatic TOSV infections in patients hospitalized in Marseille (France) from 2004 to 2011. Seventeen patients were classified as probable or confirmed cases. Fourteen cases (82%) occurred between June and September, and 3 cases in March, April and November. Two cases were potentially imported from Croatia and Tuscany. All patients presented with fever and neurological signs were observed such as aseptic meningitis (n = 6), muscular symptoms (n = 3), or encephalitis (n = 4). The outcome was always favorable. At the acute stage, anti TOSV IgM were observed in 14/17 patients, neutralization tests were positive for 3/8 patients, and RT-PCR confirmed TOSV infections in 5/8 CSF specimens.

Present forest biodiversity patterns in france related to former Roman agriculture.

Combined archaeological and ecological investigations in a large ancient oak forest in Central France have revealed a dense network of ancient human settlements dating from the Roman period. We demonstrate a strong correlation between present-day forest plant diversity patterns and the location of Roman farm buildings. Plant species richness strongly increases toward the center of the settlements, and the frequency of neutrophilous and nitrogen-demanding species is higher. This pattern is paralleled by an increase in soil pH, available P, and delta(15)N, indicating the long-term impact of former agricultural practices on forest biogeochemical cycles. These extensive observations in a forested region on acid soils complement and confirm previous results from a single Roman settlement on limestone. Ancient Roman agricultural systems are increasingly being identified in contemporary French forests; the broad extent and long-lasting effects of previous cultivation shown in this study require that land-use history be considered as a primary control over biodiversity variations in many forest landscapes, even after millennia of abandonment.

Roles of soil chemistry and water availability in site-related delta(13)C variations in French beech forests.

The carbon isotopic composition (delta(13)C) of wood and leaf cellulose of beech trees (Fagus sylvatica L.) was studied at 80 sites in northeastern France. We sampled sites with contrasting water balance, depending on soil type and precipitation. We tested the hypothesis that inter-site variations in plant delta(13)C reflect the spatial distribution of soil water availability, and we assessed whether delta(13)C could be used as a bioindicator of soil water availability. Patterns of variation in delta(13)C were compared with estimates of monthly water balance and with other soil characteristics. Between-site variability in delta(13)C was high (2.9 per thousand range in wood cellulose, 2.1 per thousand in leaf cellulose), but variation in water availability appeared to be only a minor factor contributing to this variation in delta(13)C. Unexpectedly, spatial variations in wood and leaf cellulose delta(13)C were significantly and positively related to soil fertility expressed by soil pH (r = 0.42 and 0.43, respectively) and cation content. On average, trees growing on acidic soils displayed 0.5 per thousand lower delta(13)C in both wood and leaf material than trees growing on neutral or calcareous soils. Our initial hypothesis of a strong negative relationship between delta(13)C and site water availability was not confirmed. In the study zone, neither wood nor leaf delta(13)C appeared to be a reliable bioindicator of spatial variations in water availability. Possible causes for the lack of a relationship are discussed. Our findings confirm, under natural conditions, the strong effect of soil fertility on water-use efficiency previously observed in experiments. This effect needs to be considered in isotopic studies involving different sites.

Spatial and temporal variability of foliar mineral concentration in beech (Fagus sylvatica) stands in northeastern France.

Foliar mineral concentration may provide a basis for monitoring the consequences of long-term environmental changes, such as eutrophication and acidification of soils, or increase in atmospheric CO(2) concentration. However, analytical drifts and inter-tree and year-to-year variations may confound environmental effects on long-term changes in foliar mineral concentration. We have characterized the relative effects of these potentially confounding factors on foliar carbon, nitrogen, phosphorus, calcium, potassium, magnesium and manganese concentrations in 118 pure beech (Fagus sylvatica L.) stands, sampled in 1969-71 and 1996-97. Interannual fluctuations of these elements were quantified in a subset of six beech stands monitored for 5 years. Intercalibration between the methods used at each sampling period for nitrogen and phosphorus analyses showed significant, but low, relative differences (0.8 and 3.3% for N and P, respectively). Based on inter-tree variability, elements could be arranged in four groups: C (constant), N and P (low variability), K and Ca (medium variability), Mn and Mg (high variability). Inter-tree coefficients of variation were 2, 6, 8, 15, 18, 22 and 27%, respectively. Year-to-year fluctuations increased in the order N, P, Mg, K, Ca, and Mn coefficients of variation of 4, 4, 7, 9, 11, 15 and 29%, respectively). Between the two sampling periods, foliar N concentration increased 12%, whereas decreases were observed for P (-23%), Mg (-38%) and Ca (-16%). Ratios of N/P, N/K and N/Mg increased by 42, 19 and 77%, respectively. These changes were larger than the interannual variations for P, Mg, N/P, N/Mg and Mg/Ca. Decreasing concentrations of P and cations were particularly marked for trees growing on acidic soils, whereas the positive N trend did not depend on soil type. Both increasing atmospheric CO(2) concentrations and acidification of forest soils could contribute to decreasing P and cation concentrations in foliage. The increase in foliar N concentration with time suggests a nitrogen deposition effect. Whatever the causes of these changes, the large shift in element ratios indicates an accelerating imbalance between nitrogen and cation status.

δ15N of forest soil and understorey vegetation reflect the former agricultural land use.

Since the middle of the 19th century, the area covered by forests in France has doubled. These new forests grow on previous agricultural lands. We have studied the influence of this agricultural history on the 15N abundance of present-day forests planted on farmlands in the Vosges mountains (north-eastern France) between 1898 and 1930. Different types of land use were identified from old cadastres (1814-1836) of 16 farms. Ancient forests adjacent to farmlands were used as controls. Former pastures, meadows, croplands, gardens and ancient forests were compared for soil δ15N (fraction <50 µm and total soil), C/N, P and N content and fern (Dryopteris carthusiana) δ15N. The mean δ15N of soil increased in the order ancient forests (+0.0‰)

Simultaneous eutrophication and acidification of a forest ecosystem in North-East France.

Surveys of ground layer vegetation are a reliable tool for monitoring spatial and temporal variations of the forest environment. In 1991, 47 vegetation plots first sampled in 1972 in a forest of the Lorraine Plain, North-East France, were resampled. This beech-oak forest had both acidic and calcareous soils depending on the thickness of alluvial deposits above the calcareous bedrock. The mean number of species per sample increased from 32 to 39 during this period and the frequency of nitrophilic species increased throughout the forest. On acidic soils, acidophilic species increased in frequency, while on calcareous soils there were no systematic changes. Multivariate statistical analysis clearly distinguished two gradients in this set of vegetation samples: acidity and nitrogen availability of soils. Along the first gradient, a shift of the plots towards a more acidic state occurred during the past 19 years on acidic soils only. Along the second one. a strong eutrophication happened on both acidic and calcareous soils, indicating an enrichment in nitrogen of forest ecosystems. Possible causes of these changes are discussed, namely sylviculture changes, aging of the stands and pollution. Atmospheric nitrogen inputs seem to be the most probable cause of eutrophication.

Using artificial intelligence languages for the calculation of inbreeding coefficients--new tools for an old problem.

A computer program was written for the calculation of inbreeding coefficients in pedigrees. Trees and recursivity allow a very efficient codification into LISP or PROLOG.