Expressive writing intervention for mothers following the birth of their premature baby.

The birth of a preterm infant is in most cases unexpected and can be a distressing experience for parents. Parents of premature babies report more stress, experience more adjustment difficulties and need for support during the first year after delivery compared to parents of infants born at term. It has been documented that parents may experience posttraumatic stress reactions, anxiety and depression following the premature birth of their baby, which subsequently may impact on the mother-baby-interactions, their attachment relationship and the cognitive, social and behavioural development of the baby. In this pilot study, we offered an expressive writing intervention to women who recently had a premature baby to alleviate their psychological distress and to improve their physical health. During the expressive writing intervention, women were asked to write down their deepest thoughts and feelings about the most traumatic aspect of their experience of having a premature baby for 15 min over three consecutive days. The aims of the study were as follows: (1) To evaluate the effect of expressive writing on psychological and physical health in women who recently had a premature baby. (2) To evaluate the effect of expressive writing on the use of healthcare services and medication in this population. (3) To evaluate the acceptability and feasibility of this intervention for this population. Forty participants were randomly allocated to either the expressive writing intervention group or a wait list control group. Pre- and post questionnaires to evaluate the effectiveness of the expressive writing intervention, as well as their acceptability and feasibility were completed. The intervention took place when the baby was 3 months of corrected age. Post-measures were completed at 1 and 3 months following the intervention. Results and their clinical implications will be discussed with regards to the implementation of this safe and cost-effective method as a preventative measure in the routine care of women who recently gave birth to a premature baby

Binge eating in binge eating disorder: a break-down of emotion regulatory process?

Current explanatory models for binge eating in binge eating disorder (BED) mostly rely onmodels for bulimianervosa (BN), although research indicates different antecedents for binge eating in BED. This studyinvestigates antecedents and maintaining factors in terms of positive mood, negative mood and tension in asample of 22 women with BED using ecological momentary assessment over a 1-week. Values for negativemood were higher and those for positive mood lower during binge days compared with non-binge days.During binge days, negative mood and tension both strongly and significantly increased and positive moodstrongly and significantly decreased at the first binge episode, followed by a slight though significant, andlonger lasting decrease (negative mood, tension) or increase (positive mood) during a 4-h observation periodfollowing binge eating. Binge eating in BED seems to be triggered by an immediate breakdown of emotionregulation. There are no indications of an accumulation of negative mood triggering binge eating followed byimmediate reinforcing mechanisms in terms of substantial and stable improvement of mood as observed inBN. These differences implicate a further specification of etiological models and could serve as a basis fordeveloping new treatment approaches for BED.

Automatic top-down processing explains common left occipito-temporal responses to visual words and objects.

Previous studies have demonstrated that a region in the left ventral occipito-temporal (LvOT) cortex is highly selective to the visual forms of written words and objects relative to closely matched visual stimuli. Here, we investigated why LvOT activation is not higher for reading than picture naming even though written words and pictures of objects have grossly different visual forms. To compare neuronal responses for words and pictures within the same LvOT area, we used functional magnetic resonance imaging adaptation and instructed participants to name target stimuli that followed briefly presented masked primes that were either presented in the same stimulus type as the target (word-word, picture-picture) or a different stimulus type (picture-word, word-picture). We found that activation throughout posterior and anterior parts of LvOT was reduced when the prime had the same name/response as the target irrespective of whether the prime-target relationship was within or between stimulus type. As posterior LvOT is a visual form processing area, and there was no visual form similarity between different stimulus types, we suggest that our results indicate automatic top-down influences from pictures to words and words to pictures. This novel perspective motivates further investigation of the functional properties of this intriguing region.

Does Semantic Context Benefit Speech Understanding through "Top-Down" Processes? Evidence from Time-resolved Sparse fMRI.

When speech is degraded, word report is higher for semantically coherent sentences (e.g., her new skirt was made of denim) than for anomalous sentences (e.g., her good slope was done in carrot). Such increased intelligibility is often described as resulting from "top-down" processes, reflecting an assumption that higher-level (semantic) neural processes support lower-level (perceptual) mechanisms. We used time-resolved sparse fMRI to test for top-down neural mechanisms, measuring activity while participants heard coherent and anomalous sentences presented in speech envelope/spectrum noise at varying signal-to-noise ratios (SNR). The timing of BOLD responses to more intelligible speech provides evidence of hierarchical organization, with earlier responses in peri-auditory regions of the posterior superior temporal gyrus than in more distant temporal and frontal regions. Despite Sentence content × SNR interactions in the superior temporal gyrus, prefrontal regions respond after auditory/perceptual regions. Although we cannot rule out top-down effects, this pattern is more compatible with a purely feedforward or bottom-up account, in which the results of lower-level perceptual processing are passed to inferior frontal regions. Behavioral and neural evidence that sentence content influences perception of degraded speech does not necessarily imply "top-down" neural processes.

VEGF and TNF up-regulate, NSAID down-regulate SOX18 protein level in HUVEC

Angiogenesis, the process of generating new blood vessels, is essential to embryonic development, organ formation, tissue regeneration and remodeling, reproduction and wound healing. Also, it plays an important role in many pathological conditions, including chronic inflammation and cancer. Angiogenesis is regulated by a complex interplay of growth factors, inflammatory mediators, adhesion molecules, morphogens and guidance molecules. Transcription factor SOX18 is transiently expressed in nascent endothelial cells during embryonic development and postnatal angiogenesis, but little is known about signaling pathways controlling its expression. The aim of this study was to investigate whether pro-angiogenic molecules and pharmacological inhibitors of angiogenesis modulate SOX18 expression in endothelial cells. Therefore, we treated human umbilical vein endothelial cells (HUVEC) with angiogenic factors, extracellular matrix proteins, inflammatory cytokines and nonsteroidal anti-inflammatory drugs (NSAID) and monitored SOX18 expression. We have observed that the angiogenic factor VEGF and the inflammatory cytokine TNF increase, while the NSAID ibuprofen and NS398 decrease the SOX18 protein level. These results for the first time demonstrate that SOX18 expression is modulated by factors and drugs known to positively or negatively regulate angiogenesis. This opens the possibility of pharmacological manipulation of SOX18 gene expression in endothelial cells to stimulate or inhibit angiogenesis.

The behavioral relevance and top-down susceptibility of early, low level multisensory interactions in humans

Abstract (English)General backgroundMultisensory stimuli are easier to recognize, can improve learning and a processed faster compared to unisensory ones. As such, the ability an organism has to extract and synthesize relevant sensory inputs across multiple sensory modalities shapes his perception of and interaction with the environment. A major question in the scientific field is how the brain extracts and fuses relevant information to create a unified perceptual representation (but also how it segregates unrelated information). This fusion between the senses has been termed "multisensory integration", a notion that derives from seminal animal single-cell studies performed in the superior colliculus, a subcortical structure shown to create a multisensory output differing from the sum of its unisensory inputs. At the cortical level, integration of multisensory information is traditionally deferred to higher classical associative cortical regions within the frontal, temporal and parietal lobes, after extensive processing within the sensory-specific and segregated pathways. However, many anatomical, electrophysiological and neuroimaging findings now speak for multisensory convergence and interactions as a distributed process beginning much earlier than previously appreciated and within the initial stages of sensory processing.The work presented in this thesis is aimed at studying the neural basis and mechanisms of how the human brain combines sensory information between the senses of hearing and touch. Early latency non-linear auditory-somatosensory neural response interactions have been repeatedly observed in humans and non-human primates. Whether these early, low-level interactions are directly influencing behavioral outcomes remains an open question as they have been observed under diverse experimental circumstances such as anesthesia, passive stimulation, as well as speeded reaction time tasks. Under laboratory settings, it has been demonstrated that simple reaction times to auditory-somatosensory stimuli are facilitated over their unisensory counterparts both when delivered to the same spatial location or not, suggesting that audi- tory-somatosensory integration must occur in cerebral regions with large-scale spatial representations. However experiments that required the spatial processing of the stimuli have observed effects limited to spatially aligned conditions or varying depending on which body part was stimulated. Whether those divergences stem from task requirements and/or the need for spatial processing has not been firmly established.Hypotheses and experimental resultsIn a first study, we hypothesized that auditory-somatosensory early non-linear multisensory neural response interactions are relevant to behavior. Performing a median split according to reaction time of a subset of behavioral and electroencephalographic data, we found that the earliest non-linear multisensory interactions measured within the EEG signal (i.e. between 40-83ms post-stimulus onset) were specific to fast reaction times indicating a direct correlation of early neural response interactions and behavior.In a second study, we hypothesized that the relevance of spatial information for task performance has an impact on behavioral measures of auditory-somatosensory integration. Across two psychophysical experiments we show that facilitated detection occurs even when attending to spatial information, with no modulation according to spatial alignment of the stimuli. On the other hand, discrimination performance with probes, quantified using sensitivity (d'), is impaired following multisensory trials in general and significantly more so following misaligned multisensory trials.In a third study, we hypothesized that behavioral improvements might vary depending which body part is stimulated. Preliminary results suggest a possible dissociation between behavioral improvements andERPs. RTs to multisensory stimuli were modulated by space only in the case when somatosensory stimuli were delivered to the neck whereas multisensory ERPs were modulated by spatial alignment for both types of somatosensory stimuli.ConclusionThis thesis provides insight into the functional role played by early, low-level multisensory interac-tions. Combining psychophysics and electrical neuroimaging techniques we demonstrate the behavioral re-levance of early and low-level interactions in the normal human system. Moreover, we show that these early interactions are hermetic to top-down influences on spatial processing suggesting their occurrence within cerebral regions having access to large-scale spatial representations. We finally highlight specific interactions between auditory space and somatosensory stimulation on different body parts. Gaining an in-depth understanding of how multisensory integration normally operates is of central importance as it will ultimately permit us to consider how the impaired brain could benefit from rehabilitation with multisensory stimula-Abstract (French)Background théoriqueDes stimuli multisensoriels sont plus faciles à reconnaître, peuvent améliorer l'apprentissage et sont traités plus rapidement comparé à des stimuli unisensoriels. Ainsi, la capacité qu'un organisme possède à extraire et à synthétiser avec ses différentes modalités sensorielles des inputs sensoriels pertinents, façonne sa perception et son interaction avec l'environnement. Une question majeure dans le domaine scientifique est comment le cerveau parvient à extraire et à fusionner des stimuli pour créer une représentation percep- tuelle cohérente (mais aussi comment il isole les stimuli sans rapport). Cette fusion entre les sens est appelée "intégration multisensorielle", une notion qui provient de travaux effectués dans le colliculus supérieur chez l'animal, une structure sous-corticale possédant des neurones produisant une sortie multisensorielle différant de la somme des entrées unisensorielles. Traditionnellement, l'intégration d'informations multisen- sorielles au niveau cortical est considérée comme se produisant tardivement dans les aires associatives supérieures dans les lobes frontaux, temporaux et pariétaux, suite à un traitement extensif au sein de régions unisensorielles primaires. Cependant, plusieurs découvertes anatomiques, électrophysiologiques et de neuroimageries remettent en question ce postulat, suggérant l'existence d'une convergence et d'interactions multisensorielles précoces.Les travaux présentés dans cette thèse sont destinés à mieux comprendre les bases neuronales et les mécanismes impliqués dans la combinaison d'informations sensorielles entre les sens de l'audition et du toucher chez l'homme. Des interactions neuronales non-linéaires précoces audio-somatosensorielles ont été observées à maintes reprises chez l'homme et le singe dans des circonstances aussi variées que sous anes- thésie, avec stimulation passive, et lors de tâches nécessitant un comportement (une détection simple de stimuli, par exemple). Ainsi, le rôle fonctionnel joué par ces interactions à une étape du traitement de l'information si précoce demeure une question ouverte. Il a également été démontré que les temps de réaction en réponse à des stimuli audio-somatosensoriels sont facilités par rapport à leurs homologues unisensoriels indépendamment de leur position spatiale. Ce résultat suggère que l'intégration audio- somatosensorielle se produit dans des régions cérébrales possédant des représentations spatiales à large échelle. Cependant, des expériences qui ont exigé un traitement spatial des stimuli ont produits des effets limités à des conditions où les stimuli multisensoriels étaient, alignés dans l'espace ou encore comme pouvant varier selon la partie de corps stimulée. Il n'a pas été établi à ce jour si ces divergences pourraient être dues aux contraintes liées à la tâche et/ou à la nécessité d'un traitement de l'information spatiale.Hypothèse et résultats expérimentauxDans une première étude, nous avons émis l'hypothèse que les interactions audio- somatosensorielles précoces sont pertinentes pour le comportement. En effectuant un partage des temps de réaction par rapport à la médiane d'un sous-ensemble de données comportementales et électroencépha- lographiques, nous avons constaté que les interactions multisensorielles qui se produisent à des latences précoces (entre 40-83ms) sont spécifique aux temps de réaction rapides indiquant une corrélation directe entre ces interactions neuronales précoces et le comportement.Dans une deuxième étude, nous avons émis l'hypothèse que si l'information spatiale devient perti-nente pour la tâche, elle pourrait exercer une influence sur des mesures comportementales de l'intégration audio-somatosensorielles. Dans deux expériences psychophysiques, nous montrons que même si les participants prêtent attention à l'information spatiale, une facilitation de la détection se produit et ce toujours indépendamment de la configuration spatiale des stimuli. Cependant, la performance de discrimination, quantifiée à l'aide d'un index de sensibilité (d') est altérée suite aux essais multisensoriels en général et de manière plus significative pour les essais multisensoriels non-alignés dans l'espace.Dans une troisième étude, nous avons émis l'hypothèse que des améliorations comportementales pourraient différer selon la partie du corps qui est stimulée (la main vs. la nuque). Des résultats préliminaires suggèrent une dissociation possible entre une facilitation comportementale et les potentiels évoqués. Les temps de réactions étaient influencés par la configuration spatiale uniquement dans le cas ou les stimuli somatosensoriels étaient sur la nuque alors que les potentiels évoqués étaient modulés par l'alignement spatial pour les deux types de stimuli somatosensorielles.ConclusionCette thèse apporte des éléments nouveaux concernant le rôle fonctionnel joué par les interactions multisensorielles précoces de bas niveau. En combinant la psychophysique et la neuroimagerie électrique, nous démontrons la pertinence comportementale des ces interactions dans le système humain normal. Par ailleurs, nous montrons que ces interactions précoces sont hermétiques aux influences dites «top-down» sur le traitement spatial suggérant leur occurrence dans des régions cérébrales ayant accès à des représentations spatiales de grande échelle. Nous soulignons enfin des interactions spécifiques entre l'espace auditif et la stimulation somatosensorielle sur différentes parties du corps. Approfondir la connaissance concernant les bases neuronales et les mécanismes impliqués dans l'intégration multisensorielle dans le système normale est d'une importance centrale car elle permettra d'examiner et de mieux comprendre comment le cerveau déficient pourrait bénéficier d'une réhabilitation avec la stimulation multisensorielle.

Monoamine oxidase A down-regulation contributes to high metanephrine concentration in pheochromocytoma.

CONTEXT: The high diagnostic performance of plasma-free metanephrines (metanephrine and normetanephrine) (MN) for pheochromocytoma (PHEO) results from the tumoral expression of catechol-O-methyltransferase (COMT), the enzyme involved in O-methylation of catecholamines (CAT). Intriguingly, metanephrine, in contrast to epinephrine, is not remarkably secreted during a stress in hypertensive or normotensive subjects, whereas in PHEO patients CAT and MN are both raised to high levels. Because epinephrine and metanephrine are almost exclusively produced by the adrenal medulla, this suggests distinct CAT metabolism in chromaffin cells and pheochromocytes. OBJECTIVE: The objective of the study was to compare CAT metabolism between adrenal medulla and PHEO tissue regarding related enzyme expression including monoamine oxidases (MAO) and COMT. DESIGN: A multicenter comparative study was conducted. STUDY PARTICIPANTS: The study included 21 patients with a histologically confirmed PHEO and eight adrenal glands as control. MAIN OUTCOME MEASURES: CAT, dihydroxyphenol-glycol, 3,4-dihydroxyphenylacetic acid, and MN were measured in adrenal medulla and PHEO tissue. Western blot, quantitative RT-PCR and immunofluorescence studies for MAOA, MAOB, tyrosine hydroxylase, dopamine β-hydroxylase, L-amino acid decarboxylase, and COMT were applied on tissue homogenates and cell preparations. RESULTS: At both the protein and mRNA levels, MAOA and COMT are detected less often in PHEO compared with adrenal medulla, conversely to tyrosine hydroxylase, L-amino acid decarboxylase, and dopamine β-hydroxylase, much more expressed in tumor tissue. MAOB protein is detected less often in tumor but not differently expressed at the mRNA level. Dihydroxyphenol-glycol is virtually absent from tumor, whereas MN, produced by COMT, rises to 4.6-fold compared with adrenal medulla tissue. MAOA down-regulation was observed in 100% of tumors studied, irrespectively of genetic alteration identified; on the other hand, MAOA was strongly expressed in all adrenal medulla collected independently of age, gender, or late sympathetic activation of the deceased donor. CONCLUSION: High concentrations of MN in tumor do not only arise from CAT overproduction but also from low MAOA expression, resulting in higher substrate availability for COMT.

Progesterone down-regulates the open probability of the amiloride-sensitive epithelial sodium channel via a Nedd4-2-dependent mechanism.

Activation of the mitogen-activated protein (MAP) kinase cascade by progesterone in Xenopus oocytes leads to a marked down-regulation of activity of the amiloride-sensitive epithelial sodium channel (ENaC). Here we have studied the signaling pathways involved in progesterone effect on ENaC activity. We demonstrate that: (i) the truncation of the C termini of the alphabetagammaENaC subunits results in the loss of the progesterone effect on ENaC; (ii) the effect of progesterone was also suppressed by mutating conserved tyrosine residues in the Pro-X-X-Tyr (PY) motif of the C termini of the beta and gamma ENaC subunits (beta(Y618A) and gamma(Y628A)); (iii) the down-regulation of ENaC activity by progesterone was also suppressed by co-expression ENaC subunits with a catalytically inactive mutant of Nedd4-2, a ubiquitin ligase that has been previously demonstrated to decrease ENaC cell-surface expression via a ubiquitin-dependent internalization/degradation mechanism; (iv) the effect of progesterone was significantly reduced by suppression of consensus sites (beta(T613A) and gamma(T623A)) for ENaC phosphorylation by the extracellular-regulated kinase (ERK), a MAP kinase previously shown to facilitate the binding of Nedd4 ubiquitin ligases to ENaC; (v) the quantification of cell-surface-expressed ENaC subunits revealed that progesterone decreases ENaC open probability (whole cell P(o), wcP(o)) and not its cell-surface expression. Collectively, these results demonstrate that the binding of active Nedd4-2 to ENaC is a crucial step in the mechanism of ENaC inhibition by progesterone. Upon activation of ERK, the effect of Nedd4-2 on ENaC open probability can become more important than its effect on ENaC cell-surface expression.

Down-regulation of NOSII gene expression by iontophoresis of anti-sense oligonucleotide in endotoxin-induced uveitis.

Transcorneoscleral iontophoresis was used to enhance ocular penetration of a 21-bp NH(2) protected anti-NOSII oligonucleotides (ODNs) (fluorescein or infrared-41 labeled) in Lewis rats. Both histochemical localization and acrylamide sequencing gels were used. To evaluate the potential to down-regulate NOSII expression in the rat model of endotoxin-induced uveitis (EIU), anti-sense NOSII ODN, scrambled ODN or saline were iontophorezed into these animals' eyes. Iontophoresis facilitated the penetration of intact ODNs into the intraocular tissues of the rat eye and only the eyes receiving ODNs and electrical current demonstrated intact ODNs within the ocular tissues of both segments of the eye. Iontophoresis of anti-NOSII ODN significantly down-regulated the expression of NOSII expression in iris/ciliary body compared to the saline or scrambled ODN treated eyes. Nitrite production was also significantly reduced in the anti-NOSII applied eyes compared to those treated with saline. Using this system, intraocular delivery of ODNs can be significantly enhanced increasing the potential for successful gene therapy for human eye diseases.

Development of spatial integration depends on top-down and interhemispheric connections that can be perturbed in migraine: a DCM analysis.

In humans, spatial integration develops slowly, continuing through childhood into adolescence. On the assumption that this protracted course depends on the formation of networks with slowly developing top-down connections, we compared effective connectivity in the visual cortex between 13 children (age 7-13) and 14 adults (age 21-42) using a passive perceptual task. The subjects were scanned while viewing bilateral gratings, which either obeyed Gestalt grouping rules [colinear gratings (CG)] or violated them [non-colinear gratings (NG)]. The regions of interest for dynamic causal modeling were determined from activations in functional MRI contrasts stimuli > background and CG > NG. They were symmetrically located in V1 and V3v areas of both hemispheres. We studied a common model, which contained reciprocal intrinsic and modulatory connections between these regions. An analysis of effective connectivity showed that top-down modulatory effects generated at an extrastriate level and interhemispheric modulatory effects between primary visual areas (all inhibitory) are significantly weaker in children than in adults, suggesting that the formation of feedback and interhemispheric effective connections continues into adolescence. These results are consistent with a model in which spatial integration at an extrastriate level results in top-down messages to the primary visual areas, where they are supplemented by lateral (interhemispheric) messages, making perceptual encoding more efficient and less redundant. Abnormal formation of top-down inhibitory connections can lead to the reduction of habituation observed in migraine patients.

Twenty-year trends in the prevalence of Down syndrome and other trisomies in Europe: impact of maternal age and prenatal screening.

This study examines trends and geographical differences in total and live birth prevalence of trisomies 21, 18 and 13 with regard to increasing maternal age and prenatal diagnosis in Europe. Twenty-one population-based EUROCAT registries covering 6.1 million births between 1990 and 2009 participated. Trisomy cases included live births, fetal deaths from 20 weeks gestational age and terminations of pregnancy for fetal anomaly. We present correction to 20 weeks gestational age (ie, correcting early terminations for the probability of fetal survival to 20 weeks) to allow for artefactual screening-related differences in total prevalence. Poisson regression was used. The proportion of births in the population to mothers aged 35+ years in the participating registries increased from 13% in 1990 to 19% in 2009. Total prevalence per 10 000 births was 22.0 (95% CI 21.7-22.4) for trisomy 21, 5.0 (95% CI 4.8-5.1) for trisomy 18 and 2.0 (95% CI 1.9-2.2) for trisomy 13; live birth prevalence was 11.2 (95% CI 10.9-11.5) for trisomy 21, 1.04 (95% CI 0.96-1.12) for trisomy 18 and 0.48 (95% CI 0.43-0.54) for trisomy 13. There was an increase in total and total corrected prevalence of all three trisomies over time, mainly explained by increasing maternal age. Live birth prevalence remained stable over time. For trisomy 21, there was a three-fold variation in live birth prevalence between countries. The rise in maternal age has led to an increase in the number of trisomy-affected pregnancies in Europe. Live birth prevalence has remained stable overall. Differences in prenatal screening and termination between countries lead to wide variation in live birth prevalence.