A European perspective--the European clinical research infrastructures network.

Evaluating research outcomes requires multinational cooperation in clinical research for optimization of treatment strategies and comparative effectiveness research, leading to evidence-based practice and healthcare cost containment. The European Clinical Research Infrastructures Network (ECRIN) is a distributed ESFRI (European Strategy Forum on Research Infrastructures) roadmap pan-European infrastructure designed to support multinational clinical research, making Europe a single area for clinical studies, taking advantage of its population size to access patients, and unlocking latent scientific potential. Servicing multinational trials started during its preparatory phase, and ECRIN will now apply for an ERIC (European Research Infrastructures Consortium) status by 2011. By creating a single area for clinical research in Europe, this achievement will contribute to the implementation of the Europe flagship initiative 2020 'Innovation Union', whose objectives include defragmentation of the research and education capacity, tackling the major societal challenges starting with the area of healthy ageing, and removing barriers to bring ideas to the market.

[Emotional reactivity in euthymic bipolar patients]. / Réactivité émotionnelle chez les patients bipolaires en phase de normothymie.

BACKGROUND: Euthymic states in bipolar disorders are usually considered to be lacking serious psychiatric disorders. Moreover, recent results prove the need to take an interest in a potential emotional dysregulation during these intercrisis periods. Therefore, it seems relevant not only to focus on the emotions tonality (sadness/euphoria) felt by patients, but also on the intensity of their emotional background. Several reasons argue for a disturbance of emotional reactivity in euthymic bipolar patients. First, most bipolar patients spontaneously claim they have a higher sensitivity than average, which may lead to extreme emotional reactions, even during intercrisis periods. Secondly, the emotional reactivity is a way to raise the question of the bipolar patients' vulnerability to stress in euthymic periods. Several studies have shown the impact of stressful life events on the rate of relapse into bipolar disorders. The aim of this study is to examine the emotional reactivity of euthymic bipolar patients in comparison with a control group, using a test of emotional induction. Our hypothesis is that euthymic bipolar patients have a higher emotional reactivity than controls. METHOD: One hundred and forty-five subjects were recruited: 90 controls and 55 euthymic bipolar patients. The patients were interviewed by a trained psychologist using the French version of the DIGS providing DSM-IV diagnosis. The euthymic state was confirmed with both MADRS (score<12) and Bech's Manic Scale (score<4). The subjective emotional reactivity of the subjects was assessed using a method of emotional induction, based on viewing a set of 18 (positive, negative or neutral) pictures. The subjects have to appreciate the valence (pleasant, neutral or unpleasant thoughts) and assess the arousal (degree of emotion triggered by each picture). RESULTS: On average, euthymic bipolar patients report the same valence and arousal to positive (F [1.143]=0.18, p=0.68) and negative (F [1.143]=0.52, p=0.47) pictures as control subjects. Neutral pictures, however, were considered more pleasant and moving by euthymic bipolar patients than by control subjects (F [1.143]=8.40, p=0.004). CONCLUSION: Euthymic bipolar patients seem to present an emotional hyperactivity which occurs especially in neutral situations. These results partly corroborate outcomes of other authors, while providing a new methodology through the emotional induction test. The highlight of emotional hyperreactivity during intercrisis periods allows us to understand differently the topic of specific vulnerability to stress of bipolar patients. This hypersensitivity could lead to thymic decompensations and could be linked with an emotional dysregulation, potential endophenotype of the bipolar pathology. Beyond the interest in understanding the physiopathology of the bipolar disorder, it could be associated with several clinical applications as well as in the psychoeducational field and in the screening of the individual risk within the family of bipolar subjects.

Impact on adherence and sustained virological response of psychiatric side effects during peginterferon and ribavirin therapy for chronic hepatitis C.

BACKGROUND: The psychiatric side effects of interferon, often responsible for dose reduction or treatment discontinuation, represent a major limitation in the treatment of chronic hepatitis C (CHC). AIM: To prospectively assess the impact on adherence and sustained virological response (SVR) of the occurrence of psychiatric side effects during peginterferon and ribavirin therapy for CHC. METHODS: Ninety-eight consecutive treatment-naïve CHC patients receiving a standard course of peginterferon plus ribavirin were systematically screened for psychiatric side effects, using DSM-IV, at baseline and both during and after treatment. RESULTS: Psychiatric side effects occurred in 38 patients (39%), mostly within the first 12 weeks (87%), and always consisted of mood disorders. Overall, 68% of patients achieved an SVR (71% of patients with mood disorders and 68% of those without; P = N.S.). Peginterferon and ribavirin dose reductions did not differ between patients with mood disorders and those without (46% vs. 37%, respectively; P = N.S. and 13% vs. 22%, respectively; P = N.S.). Anti-viral therapy had to be discontinued in four patients (nonresponse: two, hyperthyroidism: one, psychiatric event: one). CONCLUSION: Early detection and appropriate management of psychiatric side effects during peginterferon and ribavirin therapy for CHC allow optimizing adherence and virological efficacy.

Decreased brain tryptophan availability as a partial determinant of post-partum blues.

BACKGROUND: The post-partum blues is a transient mood alteration affecting most women a few days after delivery. Its stereotypic pattern of symptoms and time course, peaking on post-partum day 3-5, is suggestive of biological determinants superimposed on psycho-social factors. This study was designed to evaluate the possible role of the serotonin system during this period through assessment of brain tryptophan availability. METHODS: Blood samples from 50 women were collected just before (D0) and 3 days after (D3) delivery. Based on plasma concentration of tryptophan, amino acids competing with tryptophan for transport across the blood-brain barrier and on their respective affinities for this transporter, a brain tryptophan availability index (BTAI) was calculated and its variation correlated with the intensity of post-partum blues evaluated through the Kennerley and Gath score at D3. RESULTS: The BTAI showed a -15% decrease between D0 and D3 (p < 0.01, paired t-test). This decrease was not supported by a drop in plasma tryptophan since its level rather increased (+19%). There was no evidence for change in placental indoleamine-2,3-dioxygenase activity since the variation in plasma l-kynurenine (+12%) paralleled the change in tryptophan level. The decreased BTAI appeared the consequence of a dramatic increase in plasma levels of most amino acids, particularly the competitor aminoacids leucine, isoleucine, valine and tyrosine, during the early post-partum. This decrease in brain tryptophan availability was concomitant to the post-partum blues, whose intensity significantly correlated with the amplitude of BTAI variation (Pearson's coefficient -0.283, p < 0.05). CONCLUSION: This study suggests that generalized, large amplitude metabolic and/or nutritional changes occurring in the early post-partum result in a transient decrease in brain tryptophan availability, partly accounting for the mood alteration referred to as the post-partum blues, a model for the triggering of puerperal mood disorder in vulnerable women.

[Baby blues: characterization and influence of psycho-social factors]. / Le baby blues: caractérisation clinique et influence de variables psycho-sociales.

BACKGROUND: Within days following birth, most women are showing signs of mood changes, commonly named baby blues. Due to the frequency of this condition, baby blues is considered as a physiological state probably associated to biological modifications. Some studies have shown an existing link between the intensity of the baby blues and post-partum mood disorder. Therefore, it seems important to report and explore in more details the clinical background related the condition. The aim of this study was to demonstrate the possibility of a link between the intensity of the baby blues and some specific factors like maternal self-esteem, maternal childcare stress and social background, and also to define the symptoms of the baby blues from core dimensions in mood disorders. METHOD: Mothers were recruited few hours before giving birth in a teaching hospital. At the third day following birth, an appointment was made to obtain the necessary information (past medical history and social history) and history of previous mood disorders. The mood was evaluated from the scale of the intensity of baby blues from Kennerly and Gath (1989). Moreover, evaluations at day 3 and week 6 post birth of self-esteem in relation to motherhood (Maternal self-report Inventory from Shea and Tronick, 1988), stress in relation with the care of the baby (Childcare Stress Inventory from Cutrona, 1983) and the social support (Social Support scale from Bruchon-Schweitzer, 1998) were undertaken. RESULTS: 95 women were included in the final sample. The intensity of the baby blues was explained by the type of pregnancy (p=0.002), a low maternal self-esteem (p=0.025), high levels of stress in relation to the care of the baby (p=0.074). The basic clinical characteristic of the baby blues seems to be due to an increase in the emotional reaction with a sharp feelings, leading to a lability rather than an affect sad tonality. CONCLUSION: The baby blues seems to be a physiological process whereby the intensity is influenced by psychological factors. Consequently the diminution of self-esteem with motherhood and the increase of stress in relation to the care of the baby appeared to be significant factors in the intensity of the baby blues. Moreover, the clinical characteristics found in this study implies that the baby blues is more related to hypomania rather than to depression syndrome. This non-pathological state could be the first stage leading to a puerperal psychosis in predisposed women, which is mainly characterized by manic symptoms.

Characterization of genes with increased expression in human glioblastomas.

In the present study, we have used the gene expression data available in the SAGE database in an attempt to identify glioblastoma molecular markers. Of 129 genes with more than 5-fold difference found by comparison of nine glioblastoma with five normal brain SAGE libraries, 44 increased their expression in glioblastomas. Most corresponding proteins were involved in angiogenesis, host-tumor immune interplay, multidrug resistance, extracellular matrix (ECM) formation, IGF-signalling, or MAP-kinase pathway. Among them, 16 genes had a high expression both in glioblastomas and in glioblastoma cell lines suggesting their expression in transformed cells. Other 28 genes had an increased expression only in glioblastomas, not in glioblastoma cell lines suggesting an expression possibly originated from host cells. Many of these genes are among the top transcripts in activated macrophages, and involved in immune response and angiogenesis. This altered pattern of gene expression in both host and tumor cells, can be viewed as a molecular marker in the analysis of malignant progression of astrocytic tumors, and as possible clues for the mechanism of disease. Moreover, several genes overexpressed in glioblastomas produce extracellular proteins, thereby providing possible therapeutic targets. Further characterization of these genes will thus allow them to be exploited in molecular classification of glial tumors, diagnosis, prognosis, and anticancer therapy.

Patterns of expression of TSC-22 protein in astrocytic gliomas.

AIM: To evaluate expression patterns of protein product of putative tumor suppressor gene TSC-22 in human astrocytic tumors by immunohistochemical approach. METHODS: Plasmid pET-23d-TSC22 was constructed for the expression of human TSC-22 protein in bacterial system, and polyclonal rabbit antibodies against recombinant TSC-22 were produced. Immunohistochemical analysis of TSC-22 and GFAP expression with the use of anti-human-TSC-22- and anti-human-GFAP-antibodies was performed on histological slides of astrocytic tumors. RESULTS: Immunohistochemical analysis has shown that the number of cells expressing TSC-22 was significantly lower in glioblastoma tissues than that in diffuse astrocytoma. Double immunohistochemical staining of astrocytic tumors using anti-human-TSC-2- and anti-human-GFAP-antibodies showed that both TSC-22 and GFAP expression is co-localized in astrocytes. CONCLUSION: TSC-22 protein is expressed in astrocytes, but not in macrophage/microglial cells. In more aggressive forms of astrocytic tumors decreased expression of TSC-22 mRNA correlates with its lowered expression on protein level.

p73 gene transcripts in human brain tumors: overexpression and altered splicing in ependymomas.

The p73 gene encodes a protein that shares structural and functional homologies with the p53 tumor suppressor protein. The p73 gene is monoallelically expressed in normal tissue, maps to chromosome 1p36 and is deleted in human neuroblastoma cell lines. Alternative splicing of exon 13 in p73 transcripts generates two isoforms, p73alpha and p73beta, that differ in their carboxy-terminus and in their ability to form homotypic interactions. In this study, we investigated, in 129 human central nervous system tumors of various histological types, the levels of p73 transcripts and the splicing characteristics of p73 mRNA. Whereas p73 mRNA content was consistently low in most tumoral types, especially in meningiomas, some glioblastomas, medulloblastomas and metastases exhibited elevated p73 mRNA content. However, ependymomas expressed consistently high amounts of p73 mRNA, significantly different from the other tumoral types. Whereas the short (p73beta) isoform accounted for 20-25% of the total p73 mRNA in most of the tumors, these splicing characteristics were altered in ependymomas (only 9% of p73beta) and in neurinomas (up to 53% of p73beta). These observations suggest tissular or tumoral differences in the control of p73 gene transcription and alternative splicing, and raise the problem of the role of p73 isoforms in the control of tumor growth, particularly in ependymomas.

Conditional coupling of striatal dopamine D1 receptor to transcription factors: ontogenic and regional differences in CREB activation.

The coupling of striatal dopamine D1 receptors to c-fos transcription exhibit all-or-none regional and ontogenic differences: the D1 agonist SKF 38393 fails to induce c-fos expression in the striatum, except during the early postnatal period in the striosomes, or in the caudal extremity of the striatum in adult animals. In an attempt to better delineate the mechanism responsible for interrupting or enabling this conditional coupling of D1 receptors to c-fos transcription we have examined, through immunocytochemistry and gel shift assay, the activation of the cyclic AMP-response element binding protein (CREB) transcription factor in response to the D1 agonist in the murine striatum. Phosphorylated-CREB (P-CREB) immunoreactivity in response to the dopamine D1 agonist (+/-)SKF 38393 (15 mg/kg, i.p.) was prominent in the caudal extremity of the striatum in adult animals (P90). In neonatal (P5) mice, P-CREB immunoreactive neurons were observed both in the caudal and in the rostral parts of the striatum, without obvious patchy distribution. Gel shift assays performed on nuclear protein extracts from either the rostral or the caudal part of striatal tissue of neonatal (P5) or adult (P90) mice provided quantitative assessment, showing differences both in the amplitude and in the time course of the response, since P-CREB binding in adults culminated 45 min after (+/-)SKF 38393 (15 mg/kg, i.p.) injection, wheareas the peak value appeared as soon as 10 min after injection in P5 mouse pups, suggesting the involvement of partly distinct transduction pathways.

Three different anti-myelin antibodies in a case of demyelinating dysglobulinemic peripheral neuropathy.

We report the case of a patient with a severe, predominantly motor, demyelinating neuropathy associated with an IgM kappa biclonal gammopathy. Immunoblot studies showed IgM reactivity against MAG, and IgG reactivity against a peripheral nerve myelin-specific protein of approximately 35 kDa. Immunodetection by thin layer chromatography showed IgM reactivity towards GM1 and GD1b, as well as towards SGPG and SGLPG. This case illustrates the existence of overlapping syndromes among dysglobulinemic neuropathies, and points to an interaction of different autoantibodies in the pathogenesis of the nerve lesions.

Involvement of the caudal striatum in auditory processing: c-fos response to cortical application of picrotoxin and to auditory stimulation.

The topographical organization of corticostriatal connections have been postulated to follow a longitudinal pattern, each cortical area projecting on a longitudinal strip stretching along the whole rostro-caudal axis of the striatum. However, compared to the rostral striatal region, the caudal striatum exhibits distinct features in terms of connectivity and neuronal phenotype. The induction of c-fos expression in the striatum by cortical activation or sensory stimulation may throw more light on these functional corticostriatal relationships. In the present study, we examined the effects of cortical activation by local application of picrotoxin on the Fos-immunoreactivity (Fos-IR) in the striatum of the mouse, with special reference to the caudal part of the striatum. Activation of the auditory cortex induced a dense ipsilateral Fos-IR restricted to the caudal striatum i.e., in the caudo-medial striatum and in the caudal part of fundus striati, and a very sparse labelling in the medial region of the rostral striatum. Conversely, activation of both sensori-motor and visual cortices only resulted in Fos-IR in the main rostral part of the striatum, without response in the caudal extremity of the striatum. On the other hand, visual or auditory stimulation in awake animals failed to induce c-fos expression in the striatum. However, using quantitative in-situ hybridization for c-fos mRNA, we found that auditory, but not visual stimulation significantly potentiated the c-fos response to the D1 agonist SKF 38393 (2 mg/kg, i.p.) in the caudal part of the striatum. These functional observations suggest that, despite a more widespread cortico-striatal connection pattern deduced from tracing experiments, the strongest functional projections from the auditory system mainly converge onto a restricted part of the caudal striatum, according to a connection pattern that is reminiscent of the transverse segmentation proposed in early lesioning studies of corticostriatal projections.

Transient neonatal elevation in hypothalamic estrogen receptor mRNA in prenatally-stressed male rats.

Prenatal stress in rats has been found to alter the sexual dimorphism of brain structures and the sexual behavior of male offspring, pointing to an impaired masculinization of the brain during the perinatal period of brain sexual differentiation. Masculinization of the brain depends on the presence during this critical period of three main elements: adequate levels of testosterone, aromatase activity (locally converting testosterone to estradiol), and brain estrogen receptor (ER) density. In the present study, we measured by reverse transcription-polymerase chain reaction (RT-PCR) the levels of ER messenger RNA (mRNA) expression in the hypothalamus of either prenatally-stressed or control male rats at postnatal (P) days 3, 12 and 90. During the early postnatal period (P3), hypothalamic ER mRNA expression was higher in prenatally stressed male rats (6.12 +/- 0.37) than in controls (4.51 +/- 0.55) (P = 0.015). This difference was not, however, found at a later developmental stage (P12, 5.39 +/- 0.65 versus 5.39 +/- 0.47) or in adult animals (P90, 6.79 +/- 1.55 versus 7.07 +/- 1.11). This transient elevation of hypothalamic ER mRNA expression resembles the developmental profile of ER mRNA in females. These observations support the idea that androgens play a pivotal role in the demasculinization process, and suggest that testosterone production or aromatization is reduced in prenatally-stressed males during the perinatal period of sexual differentiation, leading to a transient upregulation of unstimulated estrogen receptors.

Interleukin-13 and interleukin-4 act as interleukin-6 inducers in human microglial cells.

The effect of interleukin 4 (IL-4) and IL-13 on IL-6 and IL-1 beta production by human embryonic microglial cells and human peripheral blood monocyte cells (PBMC) was compared. IL-4 or IL-13 increase intra-cellular IL-6 mRNA and IL-6 titres in supernatants of microglial cells whereas they decreased IL-6 production by PBMC tested in the same conditions. IL-4 and IL-13 increased also IL-1 beta production by human microglial cells. Stimulations associating IL-4 or IL-13 and IL-1 beta had an additive effect on IL-6 production by microglial cells, whereas, in the same conditions, an inhibitory effect was observed in PBMC. In contrast, dexamethasone downregulated IL-6 production by microglial cells and PBMC. Finally, IL-1 receptor (IL-1r) type 1 and IL-1r type 2 were detected on human microglial cells but it was demonstrated that IL-13 and IL-4 acted as IL-6 inducers in human microglial cells independently of the IL-1/IL-1r pathway.

Postnatal ontogeny of dopamine D3 receptors in the mouse brain: autoradiographic evidence for a transient cortical expression.

The expression of dopamine D3 receptors is relatively low in the adult brain and is mainly restricted to the limbic region. We studied here the postnatal development of these receptors in the mouse brain by quantitative autoradiography using [3H](+/-)-7-OH-DPAT as ligand. In all brain regions examined, there was a progressive increase in D3 receptor protein expression from birth to the weaning period, a pattern reminiscent of that of dopamine D2 rather than D1 receptors. In broad outline, the regional distribution of D3 receptors during brain ontogeny resembled that observed in adult animals, the labelling being detected earlier in the structures with the higher density in the adult. The highest and earliest expression of D3 receptors was observed in the islands of Calleja and olfactory tubercle, where [3H]7-OH-DPAT binding was already present at birth. D3 receptors appeared at postnatal day 4 in the nucleus accumbens, at postnatal day 8 in the substantia nigra, in the medial mamillary nucleus and in the anterior thalamic complex, and at postnatal day 11 in the archaeocerebellum. In contrast to other brain structures where the developmental pattern of D3 receptor expression parallelled its distribution and density in the adult brain, there was a transient cortical expression of [3H]7-OH-DPAT binding between postnatal days 6 and 15, confined to a longitudinal strip in the dorso-lateral part of the parietal cortex. This expression had disappeared by postnatal day 21 and was not detected in adult mice. These developmental findings, and particularly the transient cortical expression of functional receptors, point to the involvement of D3 receptors in ontogenic processes.

Differential expression of inducible nitric oxide synthase mRNA in human brain tumours.

Messenger RNA encoding the inducible form of human nitric oxide synthase (iNOS) was quantified by reverse transcription and polymerase chain reaction (RT-PCR) in tissue samples from glioblastomas and meningiomas. iNOS mRNA expression was considerably higher in the glioblastoma than in the meningioma specimens (mean +/- s.e.m., 41.18 +/- 11.5, n = 25, vs 5.31 +/- 0.98, n = 21; p < 0.0001). Moreover, iNOS expression appeared as a polymorphic character among glioblastomas, as individual tumours expressed either high (n = 6), intermediate (n = 10) or low (n = 9) levels of iNOS mRNA.

Prenatal stress in rats facilitates amphetamine-induced sensitization and induces long-lasting changes in dopamine receptors in the nucleus accumbens.

Exposure of rats to restraint stress during late pregnancy produces offspring with a variety of behavioral and neurobiological alterations. It has been suggested that prenatal stress leads to long-lasting changes in the hypothalamo-pituitary-adrenal axis in the offspring. One feature of prenatally-stressed rats is a susceptibility to amphetamine self-administration. Since this behavior has been related to amphetamine-induced sensitization and the activity of the mesolimbic dopamine system, we measured dopamine receptor densities and amphetamine-induced sensitization in these animals. The motor response to the first administration of amphetamine was similar in both prestressed and unstressed groups of adult animals, but after repeated drug injections, behavioral sensitization was observed sooner in the prenatally-stressed rats than in the controls. In separate groups of adult animals, densities of D1, D2 and D3 dopamine receptor subtypes in the striatum and nucleus accumbens were measured in prenatally-stressed and control rats by quantitative autoradiography using [3H]SCH23390, [3H]sulpiride and [3H]7-OH-DPAT as ligands respectively. Prenatal stress was found to produce the following alterations in the adult offspring: (i) no significant change in D1 receptor binding in either striatum or nucleus accumbens; (ii) a significant (+24%) increase in D2 receptor binding in the nucleus accumbens; (iii) a significant decrease in D3 receptor binding in both the shell (-16%) and the core (-26%) of the nucleus accumbens. These observations indicate that prenatal stress induces long-lasting changes in the dopamine sensitivity of the nucleus accumbens and in the capacity to develop amphetamine-induced sensitization in adulthood. The possible relationship between an impaired control of corticosterone secretion in prenatally-stressed animals and long-term changes in the mesolimbic dopamine system is discussed.

Dopaminergic control of gene transcription during striatal ontogeny: c-fos induction by D1 receptor activation in the developing striosomes.

During striatal development, dopamine afferents initially reach the striosomal compartment, and this early dopamine innervation is thought to influence, through the D1 receptors first expressed in the developing patches, the phenotype of target striatal cells. Dopaminergic control of gene expression during ontogeny could be mediated by transcription factors such as c-fos, whose expression is regulated by synaptic signals. However, in the striatum of intact adult animals, D1 dopamine agonists fail to induce c-fos expression. The c-fos response to D1 receptor activation in adults requires a previous sensitization of dopaminergic receptors by chronic treatment with reserpine or by lesion of the nigro-striatal pathway. In this work, we investigated through in situ hybridization the ability of striatal cells to express c-fos messenger RNA (mRNA) in response to the D1 agonist SKF 38393 (4 to 8 mg/kg) in developing mice. During a transient postnatal period, c-fos expression in a patchy distribution was induced by D1 receptor activation: only a faint response was detected on postnatal day 1, but islands of strong hybridization signals for c-fos mRNA in response to the D1 agonist were observed at postnatal day 3, with a progressive decrease in intensity from day 6 to day 15. The distribution of this transient c-fos response corresponded to the early striosomal compartment since it matched with the regions of intense mu-opioid and dopamine-D1 receptor binding, as assessed by autoradiography performed on adjacent sections. By day 21, as in adult animals, no more c-fos response to D1 agonists was observed, except in the most caudal division of the striatum. Strong expression, which persisted into adulthood, was detected in this region from the third postnatal day. This induction of striatal c-fos expression by D1 agonists during early postnatal development is indicative of an enhanced sensitivity of D1 receptors or of D1-associated transduction pathways compared to the adult pattern, and suggests a possible role for dopamine-controlled c-fos gene expression in the development of target striatal neurons during this critical period.

Hormonal control of neural function in the adult brain.

Although the mechanisms by which peripheral hormones modulate complex behaviors are far from being well understood, recent advances in deciphering the mechanisms of hormone action in the brain are promising. Current areas of interest include the molecular mechanisms of steroid receptor action, the steroid modulation of synaptic function, and the mediation of steroid-regulated neuronal and glial plasticity by growth factors or proteins associated with brain development.