Discovery of novel Cyclophilin D inhibitors starting from three dimensional fragments with millimolar potencies.

Fragment-based screening by SPR enabled the discovery of chemical diverse fragment hits with millimolar binding affinities to the peptidyl-prolyl isomerase Cyclophilin D (CypD). The CypD protein crystal structures of 6 fragment hits provided the basis for subsequent medicinal chemistry optimization by fragment merging and linking yielding three different chemical series with either urea, oxalyl or amide linkers connecting millimolar fragments in the S1' and S2 pockets. We successfully improved the in vitro CypD potencies in the biochemical FP and PPIase assays and in the biophysical SPR binding assay from millimolar towards the low micromolar and submicromolar range by >1000-fold for some fragment derivatives. The initial SAR together with the protein crystal structures of our novel CypD inhibitors provide a suitable basis for further hit-to-lead optimization.

Dissecting the mechanisms of Notch induced hyperplasia.

The outcome of the Notch pathway on proliferation depends on cellular context, being growth promotion in some, including several cancers, and growth inhibition in others. Such disparate outcomes are evident in Drosophila wing discs, where Notch overactivation causes hyperplasia despite having localized inhibitory effects on proliferation. To understand the underlying mechanisms, we have used genomic strategies to identify the Notch-CSL target genes directly activated during wing disc hyperplasia. Among them were genes involved in both autonomous and non-autonomous regulation of proliferation, growth and cell death, providing molecular explanations for many characteristics of Notch induced wing disc hyperplasia previously reported. The Notch targets exhibit different response patterns, which are shaped by both positive and negative feed-forward regulation between the Notch targets themselves. We propose, therefore, that both the characteristics of the direct Notch targets and their cross-regulatory relationships are important in coordinating the pattern of hyperplasia.

Cladribine and cytarabine in refractory multisystem Langerhans cell histiocytosis: results of an international phase 2 study.

An international phase 2 study combining cladribine and cytarabine (Ara-C) was initiated for patients with refractory, risk-organ-positive Langerhans cell histiocytosis (LCH) in 2005. The protocol, comprising at least two 5-day courses of Ara-C (1 g/m(2) per day) plus cladribine (9 mg/m(2) per day) followed by maintenance therapy, was administered to 27 patients (median age at diagnosis, 0.7 years; median follow-up, 5.3 years). At inclusion, all patients were refractory after at least 1 course of vinblastine (VBL) plus corticosteroid, all had liver and spleen involvement, and 25 patients had hematologic cytopenia. After 2 courses, disease status was nonactive (n = 2), better (n = 23), or stable (n = 2), with an overall response rate of 92%. Median disease activity scores decreased from 12 at the start of therapy to 3 after 2 courses (P < .0001). During maintenance therapy, 4 patients experienced reactivation in risk organs. There were 4 deaths; 2 were related to therapy toxicity and 2 were related to reactivation. All patients experienced severe toxicity, with World Health Organization grade 4 hematologic toxicity and 6 documented severe infections. The overall 5-year survival rate was 85% (95% confidence interval, 65.2%-94.2%). Thus, the combination of cladribine/Ara-C is effective therapy for refractory multisystem LCH but is associated with high toxicity.

Image analysis and polyphenol profiling unveil red-flesh apple phenotype complexity.

BACKGROUND: The genetic basis of colour development in red-flesh apples (Malus domestica Borkh) has been widely characterised; however, current models do not explain the observed variations in red pigmentation intensity and distribution. Available methods to evaluate the red-flesh trait rely on the estimation of an average overall colour using a discrete class notation index. However, colour variations among red-flesh cultivars are continuous while development of red colour is non-homogeneous and genotype-dependent. A robust estimation of red-flesh colour intensity and distribution is essential to fully capture the diversity among genotypes and provide a basis to enable identification of loci influencing the red-flesh trait. RESULTS: In this study, we developed a multivariable approach to evaluate the red-flesh trait in apple. This method was implemented to study the phenotypic diversity in a segregating hybrid F1 family (91 genotypes). We developed a Python pipeline based on image and colour analysis to quantitatively dissect the red-flesh pigmentation from RGB (Red Green Blue) images and compared the efficiency of RGB and CIEL*a*b* colour spaces in discriminating genotypes previously classified with a visual notation. Chemical destructive methods, including targeted-metabolite analysis using ultra-high performance liquid chromatography with ultraviolet detection (UPLC-UV), were performed to quantify major phenolic compounds in fruits' flesh, as well as pH and water contents. Multivariate analyses were performed to study covariations of biochemical factors in relation to colour expression in CIEL*a*b* colour space. Our results indicate that anthocyanin, flavonol and flavanol concentrations, as well as pH, are closely related to flesh pigmentation in apple. CONCLUSTION: Extraction of colour descriptors combined to chemical analyses helped in discriminating genotypes in relation to their flesh colour. These results suggest that the red-flesh trait in apple is a complex trait associated with several biochemical factors.

Functional parcellation of the lateral mesencephalus.

The mesencephalic locomotor region (MLR), which includes the pedunculopontine nucleus (PPN) and the cuneiform nucleus (CN), has been recently identified as a key structure for locomotion and gait control in mammals. However, the function and the precise anatomy of the MLR remain unclear in humans. To study the lateral mesencephalus, we used fMRI in 15 right-handed healthy volunteers performing two tasks: imagine walking in a hallway and imagine an object moving along the same hallway. Both tasks were performed at two different speeds: normal and 30% faster. We identified two distinct networks of cortical activation: one involving motor/premotor cortices and the cerebellum for the walking task and the other involving posterior parietal and dorsolateral prefrontal cortices for the object moving task. In the lateral mesencephalus, we found that two different but anatomically connected parts of the MLR were activated during the fast condition of each task. The CN and the dorsal part of the PPN were activated during the fast imaginary walking task, whereas the ventral part of the PPN and the ventral part of the reticular formation were activated while subjects were imagining the object moving fast. Our data suggest that the lateral mesencephalus participates in different aspects of gait in humans, with the CN and dorsal PPN controlling motor aspects of locomotion and the ventral PPN being involved in integrating sensory information.

The development of a foliar fungal pathogen does react to leaf temperature!

The thermal performance curve is an ecological concept relating the phenotype of organisms and temperature. It requires characterization of the leaf temperature for foliar fungal pathogens. Epidemiologists, however, use air temperature to assess the impacts of temperature on such pathogens. Leaf temperature can differ greatly from air temperature, either in controlled or field conditions. This leads to a misunderstanding of such impacts. Experiments were carried out in controlled conditions on adult wheat plants to characterize the response of Mycosphaerella graminicola to a wide range of leaf temperatures. Three fungal isolates were used. Lesion development was assessed twice a week, whereas the temperature of each leaf was monitored continuously. Leaf temperature had an impact on disease dynamics. The latent period of M. graminicola was related to leaf temperature by a quadratic relationship. The establishment of thermal performance curves demonstrated differences among isolates as well as among leaf layers. For the first time, the thermal performance curve of a foliar fungal pathogen has been established using leaf temperature. The experimental setup we propose is applicable, and efficient, for other foliar fungal pathogens. Results have shown the necessity of such an approach, when studying the acclimatization of foliar fungal pathogens.

Study of Structural, Compression, and Soft Magnetic Properties of Fe65Ni28Mn7 Alloy Prepared by Arc Melting, Mechanical Alloying, and Spark Plasma Sintering.

Soft magnetic Fe65Ni28Mn7 (at. %) alloy was successfully synthesized by mechanical alloying and spark plasma sintering (SPS) and, in parallel, the same composition was prepared by arc melting (AM) for comparison. Several SPS conditions were tested. X-ray diffraction and scanning electron microscopy were used to investigate the structure, phase composition, and morphology of the samples. It was found that mechanical alloying produced BCC and FCC supersaturated solid solution after 130 h of milling, with a fine microstructure (i.e., crystallite size of 10 nm). Spark plasma sintering performed at 750 °C and 1000 °C under two pressures of 50 MPa and 75 MPa revealed stable FCC phases. A single FCC phase was observed after the arc melting synthesis. The magnetic properties of milled powders and solids obtained by AM and SPS were investigated. The specimen consolidated by SPS at 1000 °C under the pressure of 50 MPa exhibits soft magnetic behavior (coercivity 0.07 Oe), whereas the mechanically alloyed sample revealed hard magnetic behavior. The specimen consolidated at 750 °C under a pressure of 75 MPa showed a higher compressive strength of 1700 MPa and a Vickers hardness of 425 ± 18 HV. As a result, sintering at 750 °C/75 MPa can be utilized to enhance the mechanical properties, while those sintered at 1000 °C/50 MPa increase magnetic softness.

24-hydroxycholesterol replacement rate measured in blood is a non-invasive biomarker of brain demyelination and remyelination in cuprizone-treated mice.

In mice, dietary cuprizone causes brain demyelination with subsequent spontaneous remyelination upon return to normal chow. Heavy water (2H2O) labeling with mass spectrometric analysis can be used to measure brain de novo synthesis of several myelin components including cholesterol, phospholipids, galactocereboside (GalC) and myelin-associated proteins. 24-hydroxycholesterol (24-OHC), the major metabolite of brain cholesterol, is detected in blood and is believed to be specifically derived from CNS cholesterol metabolism. We assessed changes in syntheses of myelin components in brain and of blood sterols during cuprizone-induced experimental demyelination and remyelination, with and without thyroid hormone (T3) treatment. Mice were fed cuprizone for 4 weeks, then returned to control diet and treated with either placebo or T3 (0.005 mg/day). 2H2O was administered for the last 14 days of cuprizone diet, and for either 6, 12 or 19 days of treatment during recovery from cuprizone, after which blood and corpus callosum (CC) samples were collected (n = 5/time point/treatment). 2H incorporation into cholesterol and 24-OHC in blood and CC, and incorporation into phospholipid (PL)-palmitate, GalC, myelin basic protein (MBP) and 2',3'-cyclic-nucleotide 3'-phosphodiesterase (CNPase) in CC were measured. Cuprizone significantly (p < 0.05) decreased syntheses of cholesterol, 24-OHC, GalC, MBP, CNPase and PL-palmitate in the CC and these effects were all reversed during recovery. T3 treatment significantly (p < 0.05) increased syntheses of cholesterol, 24-OHC and palmitate compared to placebo. 24-OHC and cholesterol turnover rates in brain and blood were nearly identical and 24-OHC rates in blood paralleled rates in CC, indicating that blood 24-OHC derives primarily from the brain and reflects oligodendrocyte function. In summary, changes in synthesis of several lipid and protein components in brain during cuprizone-induced demyelination and remyelination are measurable through stable isotope labeling. Blood 24-OHC turnover rates closely reflect flux rates of brain cholesterol in response to cuprizone and T3, which alter oligodendrocyte function. Labeling of blood 24-OHC has potential as a non-invasive marker of brain de novo cholesterol synthesis and breakdown rates in demyelinating conditions.

Role of transmembrane semaphorin Sema6A in oligodendrocyte differentiation and myelination.

Myelination is regulated by extracellular proteins, which control interactions between oligodendrocytes and axons. Semaphorins are repulsive axon guidance molecules, which control the migration of oligodendrocyte precursors during normal development and possibly in demyelinating diseases. We show here that the transmembrane semaphorin 6A (Sema6A) is highly expressed by myelinating oligodendrocytes in the postnatal mouse brain. In adult mice, Sema6A expression is upregulated in demyelinating lesions in cuprizone-treated mice. The analysis of the optic nerve and anterior commissure of Sema6A-deficient mice revealed a marked delay of oligodendrocyte differentiation. Accordingly, the development of the nodes of Ranvier is also transiently delayed. We also observed an arrest in the in vitro differentiation of purified oligodendrocytes lacking Sema6A, with a reduction of the expression level of Myelin Basic Protein. Their morphology is also abnormal, with less complex and ramified processes than wild-type oligodendrocytes. In myelinating co-cultures of dorsal root ganglion neurons and purified oligodendrocytes we found that myelination is perturbed in absence of Sema6A. These results suggest that Sema6A might have a role in myelination by controlling oligodendrocyte differentiation.

How cognitive performance-induced stress can influence right VLPFC activation: an fMRI study in healthy subjects and in patients with social phobia.

The neural bases of interactions between anxiety and cognitive control are not fully understood. We conducted an fMRI study in healthy participants and in patients with an anxiety disorder (social phobia) to determine the impact of stress on the brain network involved in cognitive control. Participants performed two working memory tasks that differed in their level of performance-induced stress. In both groups, the cognitive tasks activated a frontoparietal network, involved in working memory tasks. A supplementary activation was observed in the right ventrolateral prefrontal cortex (VLPFC) in patients during the more stressful cognitive task. Region of interest analyses showed that activation in the right VLPFC decreased in the more stressful condition as compared to the less stressful one in healthy subjects and remain at a similar level in the two cognitive tasks in patients. This pattern was specific to the right when compared to the left VLPFC activation. Anxiety was positively correlated with right VLPFC activation across groups. Finally, left dorsolateral prefrontal cortex (DLPFC) activation was higher in healthy subjects than in patients in the more stressful task. These findings demonstrate that in healthy subjects, stress induces an increased activation in left DLPFC, a critical region for cognitive control, and a decreased activation in the right VLPFC, an area associated with anxiety. In patients, the differential modulation between these dorsal and ventral PFC regions disappears. This absence of modulation may limit anxious patients' ability to adapt to demanding cognitive control tasks.

Validation of a commercial version of a competitive enzyme linked immunosorbent assay for the detection of antibodies to Besnoitia besnoiti.

BACKGROUND: Several reports suggest a further spread of besnoitiosis to countries in which Besnoitia besnoiti-infected bovine herds have not been noticed yet. Cattle infected without clinical signs may represent reservoirs. Serological analyses in affected herds or animals from endemic regions are necessary to identify subclinical or inapparent infections and stop transmission to naïve animals or herds. The Monoscreen AbELISA Besnoitia besnoiti (BIO K 466) is based on a previously published in-house competitive ELISA, the Bb-cELISA1, but has a different test architecture. The present study aimed to use sera from a previous evaluation of Bb-cELISA1 to assess whether BIO K466 shows identical results. In addition, further well-characterized positive and negative samples were analysed to estimate diagnostic sensitivity and specificity. METHODS: A first set of sera consisted of a total of 305 bovine sera, collected from German herds infected by B. besnoiti, Neospora caninum or Sarcocystis spp. Sera had been characterized by reference serological tests (i.e. immunoblot, immunofluorescence antibody test and an in-house indirect ELISA). A second set consisted of 200 confirmed B. besnoiti-positive sera from French herds. Negative cattle sera (n = 624) originated from Norway and The Netherlands, countries in which bovine besnoitiosis has not been reported yet. RESULTS: Using the first set of sera, the BIO K466 showed an estimated diagnostic sensitivity of 97.9% (95% CI: 91.9%-99.6) and a diagnostic specificity of 99.5% (95% CI: 96.9%-100%) relative to reference serological tests. A direct comparison of the results revealed an almost perfect agreement between the results of the in-house Bb-cELISA1 and the commercialized version (kappa 0.98; 95% CI: 0.95-1). The validation using positive bovine sera from France and negative sera from other European countries revealed a diagnostic sensitivity of 97.5% (95% CI: 93.9%-99.1%) and specificity of 99.5% (95% CI: 98.5%-99.9%). CONCLUSION: In conclusion, BIO K 466 appears to be a suitable tool to diagnose bovine besnoitiosis, but needs further validation especially in cases of inconclusive, suspected false-positive or -negative results in other serological tests.

Elaboration and Characterization of WMoTaNb High Entropy Alloy Prepared by Powder Metallurgy Processes.

This work concerns the sintering of tungsten-based (i.e WMoTaNb) high entropy alloy (HEA) powders using the spark plasma sintering (SPS) technique and their mechanical properties. The synthesis was performed by a self-propagating high-temperature synthesis (SHS) type reaction in which the mixture of metallic oxides (WO3, MoO3 …) is reduced by magnesium. For this, a specific reactor has been developed. Different conditions including the addition of a moderator were tested. These powders are then densified by SPS technology which allows for keeping the initial microstructure of the powder. The optimization of sintering conditions was performed with the objective to control simultaneously the chemical composition, the grain growth and the densification stages.

The hippocampal region is necessary for text comprehension and memorization: a combined VBM/DTI study in neuropsychological patients.

According to the Construction-Integration model (Kintsch 1988; Kintsch 1998), two forms of representation are activated during the reading and the comprehension of a text: 1) the text base, which includes semantic propositions and 2) the situation model, corresponding to the integration of the information contained in the text to the memories and knowledge of the reader. Functional neuroimaging studies in healthy subjects have shown that the text base is underpinned by frontal regions and lateral temporal regions whereas the situation model would rather depend on the posterior cingulate cortex, the precuneus and other regions depending on the dimension studied. However, the brain regions highlighted so far were only involved in comprehension and not necessary for this cognitive ability. For the first time, we explored the brain structures necessary to understand texts using a combined VBM/DTI approach in neuropsychological patients with whom we obtained comprehension scores (text base and situation model) after the reading of narrative texts. To our great surprise and contrary to our hypotheses, which were based on the results of functional neuroimaging studies, our own results show that it is the hippocampal region that is necessary to activate and memorize/remember the text base and the situation model. The highlighting of a link between the integrity of a portion of the uncinate fasciculus which is well known to play a role in semantic processing and the performance scores of the text base suggests that the hippocampal region is necessary not only for the retrieval of the text base and of the situation model thanks to episodic memory, but also for the activation of the text base during the reading and the comprehension of a text.

Integration of differentiation signals during indirect flight muscle formation by a novel enhancer of Drosophila vestigial gene.

The gene vestigial (vg) plays a key role in indirect flight muscle (IFM) development. We show here that vg is controlled by the Notch anti-myogenic signaling pathway in myoblasts and is regulated by a novel 822 bp enhancer during IFM differentiation. Interestingly, this muscle enhancer is activated in developing fibers and in a small number of myoblasts before the fusion of myoblasts with the developing muscle fibers. Moreover, we show that this enhancer is activated by Drosophila Myocyte enhancing factor 2 (MEF2), Scalloped (SD) and VG but repressed by Twist, demonstrating a sensitivity to differentiation in vivo. In vitro experiments reveal that SD can directly bind this enhancer and MEF2 can physically interact with both SD and TWI. Cumulatively, our data reveal the interplay between different myogenic factors responsible for the expression of an enhancer activated during muscle differentiation.

Promotion of central nervous system remyelination by induced differentiation of oligodendrocyte precursor cells.

OBJECTIVE: Repair of demyelinated axons in diseases such as multiple sclerosis requires activation of the myelination program in existing or newly recruited oligodendrocyte precursor cells (OPCs). The control of OPC differentiation and initiation of myelination during repair is poorly understood. In this study, we test the ability of anti-LINGO-1 reagents to promote myelination in vitro and remyelination in the rodent adult central nervous system in vivo. METHODS: The effects of LINGO-1 antagonists on the differentiation of OPCs and the promotion of myelination has been assayed using a combination of coculture and slice culture preparations. Using three different animal models of demyelination and remyelination, we morphologically and functionally assessed the effects of LINGO-1 antagonists on OPC differentiation and myelin repair. RESULTS: The data indicate that in vitro treatment with antagonists of LINGO-1 promote OPC differentiation and myelination, whereas in vivo remyelination is accelerated in lysophosphatidylcholine- or cuprizone-induced demyelination. This remyelination is associated with enhanced OPC differentiation and functional recovery of conduction velocities in demyelinated axons. INTERPRETATION: Our studies demonstrate that LINGO-1 antagonism promotes OPC differentiation and remyelination, and suggest LINGO-1 functions as an inhibitor of OPC differentiation to retard central nervous system remyelination.

Brain hyper-reactivity to auditory novel targets in children with high-functioning autism.

Although communication and social difficulties in autism have received a great deal of research attention, the other key diagnostic feature, extreme repetitive behaviour and unusual narrow interests, has been addressed less often. Also known as 'resistance to change' this may be related to atypical processing of infrequent, novel stimuli. This can be tested at sensory and neural levels. Our aims were to (i) examine auditory novelty detection and its neural basis in children with autism spectrum conditions (ASC) and (ii) test for brain activation patterns that correlate quantitatively with number of autistic traits as a test of the dimensional nature of ASC. The present study employed event-related fMRI during a novel auditory detection paradigm. Participants were twelve 10- to 15-year-old children with ASC and a group of 12 age-, IQ- and sex-matched typical controls. The ASC group responded faster to novel target stimuli. Group differences in brain activity mainly involved the right prefrontal-premotor and the left inferior parietal regions, which were more activated in the ASC group than in controls. In both groups, activation of prefrontal regions during target detection was positively correlated with Autism Spectrum Quotient scores measuring the number of autistic traits. These findings suggest that target detection in autism is associated not only with superior behavioural performance (shorter reaction time) but also with activation of a more widespread network of brain regions. This pattern also shows quantitative variation with number of autistic traits, in a continuum that extends to the normal population. This finding may shed light on the neurophysiological process underlying narrow interests and what clinically is called 'need for sameness'.

Serologic response and safety to vaccination against avian influenza using inactivated H5N2 vaccine in zoo birds.

Due to the spread of the H5N1 highly pathogenic strain of avian influenza virus across Europe, a preventive vaccination occurred in early 2006 among 135 French zoologic institutions. Approximately 25,000 birds were vaccinated with a H5N2 inactivated vaccine. Among them, 4,369 birds were monitored by members of Association Francophone des Vétérinaires de Parc Zoologique regarding safety issues of the vaccination protocol. A total of 1,686 blood samples were collected before the first injection (n = 255), at the time of booster (n = 463), 60 day after the booster (n = 514), and 180 day (n = 229) and 330 day (n = 217) after the initial injection. Thus, sera of 126 species representing 15 different avian orders were tested using the hemagglutinin inhibition assay to evaluate seroconversion and the long-term serologic profile of selected anti-H5 antibody. Safety was considered satisfactory in all orders, and there were no deleterious effects on large-volume injection/body weight ratio. After the second injection, 71% of the birds developed a titer > or =32, with a mean titer of 558. Titers then decreased in all birds, with 42% of the remaining birds having a titer > or =32 at day 180 and only 26% at day 330. Results demonstrated that a booster 42 days after initial vaccination was mandatory to raise the titer above 32, considered to be the protective level in poultry, and to increase the number of seroconverted birds. Differences in the serologic responses among the orders and species of birds were detected and could be linked with the variation of vaccine dose injected per body weight or with species-specific immune response. The protocol for additional campaigns will be adjusted for some bird orders through the increase of injected dose or a half yearly booster to sustain better titers over the year. Vaccination is a useful tool, together with biosecurity, that should always be used as a primary method of preventing and controlling avian influenza outbreaks.

A TAT-DEF-Elk-1 peptide regulates the cytonuclear trafficking of Elk-1 and controls cytoskeleton dynamics.

The transcription factor Elk-1 plays a key role in cell differentiation, proliferation and apoptosis. This role is thought to arise from its phosphorylation by activated extracellular signal-regulated kinases (ERKs), a critical posttranslational event for the transcriptional activity of the ternary complex composed of Elk-1 and a dimer of serum response factor (SRF) at the serum response element (SRE) regulatory site of transcription. In addition to its nuclear localization, Elk-1 is found in the dendrites and soma of neuronal cells and recent evidence implicate a cytoplasmic proapoptotic function of Elk-1, via its association with the mitochondrial permeability transition pore complex. Thus, the nuclear versus cytoplasmic localization of Elk-1 seems to be crucial for its biological function. In this study we show that the excitatory neurotransmitter, glutamate, induces an ERK-dependent Elk-1 activation and nuclear relocalization. We demonstrate that Elk-1 phosphorylation on Ser383/389 has a dual function and triggers both Elk-1 nuclear translocation and SRE-dependent gene expression. Mutating these sites into inactive residues or using a synthetic penetrating peptide (TAT-DEF-Elk-1), which specifically interferes with the DEF docking domain of Elk-1, prevents Elk-1 nuclear translocation without interfering with ERK nor MSK1 (mitogen- and stress-activated protein kinase 1), a CREB kinase downstream from ERK- activation. This results in a differential regulation of glutamate-induced IEG regulation when compared with classical inhibitors of the ERK pathway. Using the TAT-DEF-Elk-1 peptide or the dominant-negative version of Elk-1, we show that Elk-1 phosphorylation controls dendritic elongation, SRF and Actin expression levels as well as cytoskeleton dynamics.

Reliving lifelong episodic autobiographical memories via the hippocampus: a correlative resting PET study in healthy middle-aged subjects.

We aimed at identifying the cerebral structures whose synaptic function subserves the recollection of lifetime's episodic autobiographical memory (AM) via autonoetic consciousness. Twelve healthy middle-aged subjects (mean age: 59 years +/- 2.5) underwent a specially designed cognitive test to assess the ability to relive richly detailed episodic autobiographical memories from five time periods using the Remember/Know procedure. We computed an index of episodicity (number of Remember responses justified by the recall of specific events and details) and an index of retrieval spontaneity, and additionally an index of semanticized memories (number of Know responses). The regional cerebral blood flow (rCBF) was measured in the resting state, with H(2)O(15) as part of an activation PET study. The indexes were correlated with blood flow using volumes of interest in frontotemporal regions, including hippocampus and voxel-wise analyses in SPM. With both analyses, significant correlations were mainly found between the index of episodicity and rCBF in the medial temporal lobe, including hippocampus, across the five time periods (unlike the index of semanticized memories) and between the spontaneity index and rCBF in the prefrontal areas. These results highlight, in healthy subjects, the distinct role of these two structures in AM retrieval and support the view that the hippocampus is needed for reexperiencing detailed episodic memories no matter how old they are.

Birth-related characteristics, congenital malformation, maternal reproductive history and neuroblastoma: the ESCALE study (SFCE).

Since neuroblastoma occurs very early in children's lives, it has been hypothesized that pre- and perinatal factors may play a role in its etiology. This study investigated the role of birth characteristics, congenital malformation and maternal reproductive history in neuroblastoma. The data used were generated by the national population-based case-control study, ESCALE, conducted in France in 2003-2004. The mothers of 191 neuroblastoma cases and 1,681 controls, frequency-matched by age and gender, were interviewed by telephone, using a standardized questionnaire, on several factors including pregnancy, medical history, lifestyle, childhood medical conditions and exposures. A positive association between congenital malformation and all neuroblastoma cases was observed [Odds ratio (OR) = 2.2, 95% confidence interval (95% CI): 1.1-4.5]. Congenital malformations were highly associated to neuroblastoma in children aged less than 1 year (OR = 16.8, 95% CI: 3.1-90), while no association was observed in children aged 1 year or more (OR = 1.0, 95% CI: 0.3-2.9). A negative association with a maternal history of spontaneous abortions was also found (OR = 0.6, 95% CI: 0.4-0.9). The results strongly support the hypothesis that congenital anomalies may be associated with neuroblastoma, particularly in infant (less than 1 year of age).