Age-dependent impairment of spine morphology and synaptic plasticity in hippocampal CA1 neurons of a presenilin 1 transgenic mouse model of Alzheimer's disease.

Presenilin 1 (PS1) mutations are responsible for a majority of early onset familial Alzheimer's disease (FAD) cases, in part by increasing the production of Abeta peptides. However, emerging evidence suggests other possible effects of PS1 on synaptic dysfunction where PS1 might contribute to the pathology independent of Abeta. We chose to study the L286V mutation, an aggressive FAD mutation which has never been analyzed at the electrophysiological and morphological levels. In addition, we analyzed for the first time the long term effects of wild-type human PS1 overexpression. We investigated the consequences of the overexpression of either wild-type human PS1 (hPS1) or the L286V mutated PS1 variant (mutPS1) on synaptic functions by analyzing synaptic plasticity and associated spine density changes from 3 to 15 months of age. We found that mutPS1 induces a transient increase observed only in 4- to 5-month-old mutPS1 animals in NMDA receptor (NMDA-R)-mediated responses and LTP compared with hPS1 mice and nontransgenic littermates. The increase in synaptic functions is concomitant with an increase in spine density. With increasing age, however, we found that the overexpression of human wild-type PS1 progressively decreased NMDA-R-mediated synaptic transmission and LTP, without neurodegeneration. These results identify for the first time a transient increase in synaptic function associated with L286V mutated PS1 variant in an age-dependent manner. In addition, they support the view that the PS1 overexpression promotes synaptic dysfunction in an Abeta-independent manner and underline the crucial role of PS1 during both normal and pathological aging.

Emotional behavior in acute stroke: the Lausanne emotion in stroke study.

OBJECTIVE: To study emotional behaviors in an acute stroke population. BACKGROUND: Alterations in emotional behavior after stroke have been recently recognized, but little attention has been paid to these changes in the very acute phase of stroke. METHODS: Adult patients presenting with acute stroke were prospectively recruited and studied. We validated the Emotional Behavior Index (EBI), a 38-item scale designed to evaluate behavioral aspects of sadness, aggressiveness, disinhibition, adaptation, passivity, indifference, and denial. Clinical, historical, and imaging (computed tomography/magnetic resonance imaging) data were obtained on each subject through our Stroke Registry. Statistical analysis was performed with both univariate and multivariate tests. RESULTS: Of the 254 patients, 40% showed sadness, 49% passivity, 17% aggressiveness, 53% indifference, 76% disinhibition, 18% lack of adaptation, and 44% denial reactions. Several significant correlations were identified. Sadness was correlated with a personal history of alcohol abuse (r = P < 0.037), female gender (r = P < 0.028), and hemorrhagic nature of the stroke (r = P < 0.063). Aggressiveness was correlated with a personal history of depression (r = P < 0.046) and hemorrhage (r = P < 0.06). Denial was correlated with male gender (r = P < 0.035) and hemorrhagic lesions (r = P < 0.05). Emotional behavior did not correlate with either neurologic impairment or lesion localization, but there was an association between hemorrhage and aggressive behavior (P < 0.001), lack of adaptation (r = P < 0.015), indifference (r = P < 0.018), and denial (r = P < 0.045). CONCLUSIONS: Systematic observations of acute emotional behaviors after stroke suggest that emotional alterations are independent of mood and physical status and should be considered as a separate consequence of stroke.

Parent-child agreement and prevalence estimates of diagnoses in childhood: direct interview versus family history method.

Diagnostic information on children is typically elicited from both children and their parents. The aims of the present paper were to: (1) compare prevalence estimates according to maternal reports, paternal reports and direct interviews of children [major depressive disorder (MDD), anxiety and attention-deficit and disruptive behavioural disorders]; (2) assess mother-child, father-child and inter-parental agreement for these disorders; (3) determine the association between several child, parent and familial characteristics and the degree of diagnostic agreement or the likelihood of parental reporting; (4) determine the predictive validity of diagnostic information provided by parents and children. Analyses were based on 235 mother-offspring, 189 father-offspring and 128 mother-father pairs. Diagnostic assessment included the Kiddie-schedule for Affective Disorders and Schizophrenia (K-SADS) (offspring) and the Diagnostic Interview for Genetic Studies (DIGS) (parents and offspring at follow-up) interviews. Parental reports were collected using the Family History - Research Diagnostic Criteria (FH-RDC). Analyses revealed: (1) prevalence estimates for internalizing disorders were generally lower according to parental information than according to the K-SADS; (2) mother-child and father-child agreement was poor and within similar ranges; (3) parents with a history of MDD or attention deficit hyperactivity disorder (ADHD) reported these disorders in their children more frequently; (4) in a sub-sample followed-up into adulthood, diagnoses of MDD, separation anxiety and conduct disorder at baseline concurred with the corresponding lifetime diagnosis at age 19 according to the child rather than according to the parents. In conclusion, our findings support large discrepancies of diagnostic information provided by parents and children with generally lower reporting of internalizing disorders by parents, and differential reporting of depression and ADHD by parental disease status. Follow-up data also supports the validity of information provided by adolescent offspring.

Ascertaining late-life depressive symptoms in Europe: an evaluation of the survey version of the EURO-D scale in 10 nations. The SHARE project.

The reported prevalence of late-life depressive symptoms varies widely between studies, a finding that might be attributed to cultural as well as methodological factors. The EURO-D scale was developed to allow valid comparison of prevalence and risk associations between European countries. This study used Confirmatory Factor Analysis (CFA) and Rasch models to assess whether the goal of measurement invariance had been achieved; using EURO-D scale data collected in 10 European countries as part of the Survey of Health, Ageing and Retirement in Europe (SHARE) (n = 22,777). The results suggested a two-factor solution (Affective Suffering and Motivation) after Principal Component Analysis (PCA) in 9 of the 10 countries. With CFA, in all countries, the two-factor solution had better overall goodness-of-fit than the one-factor solution. However, only the Affective Suffering subscale was equivalent across countries, while the Motivation subscale was not. The Rasch model indicated that the EURO-D was a hierarchical scale. While the calibration pattern was similar across countries, between countries agreement in item calibrations was stronger for the items loading on the affective suffering than the motivation factor. In conclusion, there is evidence to support the EURO-D as either a uni-dimensional or bi-dimensional scale measure of depressive symptoms in late-life across European countries. The Affective Suffering sub-component had more robust cross-cultural validity than the Motivation sub-component.

Inhibition of glial cell proinflammatory activities by peroxisome proliferator-activated receptor gamma agonist confers partial protection during antimyelin oligodendrocyte glycoprotein demyelination in vitro.

Peroxisome proliferator-activated receptor gamma (PPAR-gamma) is a member of the nuclear hormone superfamily originally characterized as a regulator of adipocyte differentiation and lipid metabolism. In addition, PPAR-gamma has important immunomodulatory functions. If the effect of PPAR-gamma's activation in T-cell-mediated demyelination has been recently demonstrated, nothing is known about the role of PPAR-gamma in antibody-induced demyelination in the absence of T-cell interactions and monocyte/macrophage activation. Therefore, we investigated PPAR-gamma's involvement by using an in vitro model of inflammatory demyelination in three-dimensional aggregating rat brain cell cultures. We found that PPAR-gamma was not constitutively expressed in these cultures but was strongly up-regulated following demyelination mediated by antibodies directed against myelin oligodendrocyte glycoprotein (MOG) in the presence of complement. Pioglitazone, a selective PPAR-gamma agonist, partially protected aggregates from anti-MOG demyelination. Heat shock responses and the expression of the proinflammatory cytokine tumor necrosis factor-alpha were diminished by pioglitazone treatment. Therefore, pioglitazone protection seems to be linked to an inhibition of glial cell proinflammatory activities following anti-MOG induced demyelination. We show that PPAR-gamma agonists act not only on T cells but also on antibody-mediated demyelination. This may represent a significant benefit in treating multiple sclerosis patients.

« The Aesthetics of Song in Calvinist Piety in the Early Reformation (1536-1545) »

Contrary to common belief, aesthetics had an important function in ritual forms implemented by Reformed Calvinist Churches. The impact of aesthetics on Reformed piety rested less on images, considered to be a source of distraction, than on music. By reconsidering the evolution of Calvin's thoughts on the relationship between music and religious services between 1536 and 1543, this study reveals how Calvin came to consider that, by singing psalms, Christians in their devotion could conciliate both a cognitive process guided by the meaning of the words and an affective response triggered by the tune. For Calvin, the spiritual elevation to which religious services should lead was to emerge from the conjunction of these two impetuses.

THE HIGH DIAGNOSTIC YIELD OF A GERIATRIC OUTPATIENT CLINIC

Objectives: To determine characteristics of older patients referred to a geriatric outpatient clinic; 2) to determine the prevalence of geriatric syndromes in this population; 3) to identify main recommendations made to referring primary care physicians. Design: Cross-sectional analysis Setting: Outpatient clinic of the service of geriatric medicine at the University of Lausanne Medical Center, Lausanne, Switzerland. Participants: Community-dwelling patients aged 65 and over referred to the clinic. Measurements: Demographics, social, functional and health status data, main diagnoses identified and recommendations made for primary care physicians were collected prospectively. Results: Subjects (N=206, mean age 79.7±7.6 years, 57.3% women, 48.5% living alone, 36.9% receiving formal home care) were referred by primary care physicians (76%), hospitalists (18%), or family members (7%). Main reasons for referral were request for comprehensive assessment, cognitive evaluation, and mobility assessment (45.2%, 26.2%, and 15.5%, respectively). 21.4% of patients are independent in Lawton's Instrumental ADL and 47.1% are independent in Katz's Basic ADL, and 57.3% of patients reported having fallen once or more over the last year. Overall, 76.2% of patients had gait and balance impairment, 72.8% cognitive impairment, 57.3% polypharmacy (≥6 drugs; median 6.5±3.9, IQR 4-8), 54.4% affective disorder, 48.3% osteoporosis, 45.1% urinary incontinence and 33.8% orthostatic hypotension. Polymorbidity (≥6 geriatric syndromes) was present in 58.3% of referred patients. On average, patients received 10.6±4.0 recommendations, including fall prevention interventions (85.2 % of patients: walking aid adaptation in 48.1%, vitamin D prescription in 59.7%, home hazards assessment in 59.2%, and exercise prescription in 53.4%), referral to a memory clinic (45.6%), and treatment modifications (69.9 % of all patients and 81.6% of patients with polypharmacy, mostly psychotropic drugs discontinuation). Conclusions: Polymorbidity was frequent in these older outpatients, with polypharmacy, mobility and cognitive impairments being most prevalent. Outpatient geriatric consultation is a good opportunity to identify geriatric syndromes and propose interventions to prevent or delay functional decline.

Off-label utilization of antipsychotics

Résumé Ce travail s'inscrit dans un programme de recherche centré sur la pharmacovigilance en psychiatrie. Buts de l'étude Les nouveaux antipsychotiques atypiques sont prescrits avec beaucoup de succès, parce qu'ils présentent une sécurité dans leur emploi bien supérieure à celle des antipsychotiques classiques. Cette situation a conduit à une large prescription «off-label» (hors indication admise). Le but de ce travail a été d'étudier la pratique en matière de prescription des psychiatres hospitaliers en ce qui concerne les antipsychotiques en comparant des patients traités pour des psychoses ou d'autres indications officielles aux patients recevant un traitement antipsychotique «off-label». Méthode Dans le cadre d'un programme de pharmacovigilance - pharmacoépidemiologie, tous les médicaments prescrits à 5 jours de référence (entre 1999 et 2001) à l'hôpital psychiatrique universitaire de Lausanne (98 lits) ont été enregistrés, avec des données sur l'âge, le sexe et le diagnostic des patients. Les prescriptions de 202 patients ont été évaluées. Les patients ont été classés dans 3 groupes diagnostiques : (1) patient présentant des troubles psychotiques, (2) patient présentant des épisodes maniaques et des épisodes dépressifs avec des symptômes psychotiques, et (3) patient présentant d'autres troubles. Les groupes (1) et (2) forment une classe de patients recevant un antipsychotique pour une indication officielle, et les prescriptions dans le groupe (3) ont été considérées comme «off-label». Résultats principaux Moins de patients psychotiques ont reçu un antidépresseur (p<0.05) ou des hypnotiques non-benzodiazepine (p<0.001) comparés aux patients des deux autres groupes. Les patients présentant des troubles affectifs recevaient seulement exceptionnellement une combinaison d'un antipsychotique atypique et conventionnel, tandis qu'un nombre inférieur de patients avec des indications « off-label » ont reçu moins .souvent des antipsychotiques atypiques que ceux des deux groupes de comparaison (p<0.05). L'analyse statistique (stepwise logistic regression) a révélé que les patients présentant des troubles psychotiques avaient un risque plus élevé de recevoir un médicament antipsychotique d'une dose moyenne ou élevée, (p<0.001) en comparaison aux deux autres groupes. Conclusion Les nouveaux médicaments antipsychotiques semblent être prescrits avec moins d'hésitation principalement pour des indications admises. Les médecins prescrivent de nouveaux médicaments « off-label » seulement après avoir acquis une certaine expérience dans le domaine des indications approuvées, et ils étaient plus prudents en ce qui concerne la dose en traitant sur la base «off-label». Abstract Objective The new brands of atypical antipsychotics are very successfully prescribed because of their enhanced safety profiles and their larger pharmacological profile in comparison to the conventional antipsychotic. This has led to broad off-label utilisation. The aim of the present survey was to study the prescription practice of hospital psychiatrists with regard to antipsychotic drugs, comparing patients treated for psychoses or other registered indications to patients receiving an off-label antipsychotic treatment. Method As part of a pharmacovigilance/pharmacoepidemiology program, all drugs given on 5 reference days (1999 - 2001) in the 98-bed psychiatric hospital of the University of Lausanne, Switzerland, were recorded along with age, sex and diagnosis. The prescriptions of 202 patients were assessed. Patients were classified in 3 diagnostic groups: (1) patient with psychotic disorders, (2) patients with manic episodes and depressive episodes with psychotic symptoms, and (3) patients with other disorders. Group (1) and (2) formed the class of patients receiving an antipsychotic for a registered indication, and the prescriptions in group (3) were considered as off-label. Main results A lesser number of psychotic patients received antidepressant (p<0.05) and nonbenzodiazepine hypnotics (p<0.001) compared to the patients of the other two groups. The patients with affective disorders received only exceptionally a combination of an atypical and a conventional antipsychotic, whereas a lesser number of patients with off-label indications received less often atypical antipsychotics than those of the two comparison groups (p<0.05). Stepwise logistic regression revealed that patients with psychotic disorder were at higher risk of receiving an antipsychotic medication in medium or high dose (p<0.001), in comparison to the two other groups. Conclusions The new antipsychotic drugs seem to be prescribed with less hesitation mainly for approved indications. Physicians prescribe new drugs on off-label application only after having gained some experience in the field of the approved indications, and were more cautious with regard to dose when treating on an off-label basis.

Glutamate Transport Decreases Mitochondrial pH and Modulates Oxidative Metabolism in Astrocytes.

During synaptic activity, the clearance of neuronally released glutamate leads to an intracellular sodium concentration increase in astrocytes that is associated with significant metabolic cost. The proximity of mitochondria at glutamate uptake sites in astrocytes raises the question of the ability of mitochondria to respond to these energy demands. We used dynamic fluorescence imaging to investigate the impact of glutamatergic transmission on mitochondria in intact astrocytes. Neuronal release of glutamate induced an intracellular acidification in astrocytes, via glutamate transporters, that spread over the mitochondrial matrix. The glutamate-induced mitochondrial matrix acidification exceeded cytosolic acidification and abrogated cytosol-to-mitochondrial matrix pH gradient. By decoupling glutamate uptake from cellular acidification, we found that glutamate induced a pH-mediated decrease in mitochondrial metabolism that surpasses the Ca(2+)-mediated stimulatory effects. These findings suggest a model in which excitatory neurotransmission dynamically regulates astrocyte energy metabolism by limiting the contribution of mitochondria to the metabolic response, thereby increasing the local oxygen availability and preventing excessive mitochondrial reactive oxygen species production.

Oncology clinicians' defenses and adherence to communication skills training with simulated patients: an exploratory study.

The aim of this exploratory study was to assess the impact of clinicians' defense mechanisms-defined as self-protective psychological mechanisms triggered by the affective load of the encounter with the patient-on adherence to a communication skills training (CST). The population consisted of oncology clinicians (N = 31) who participated in a CST. An interview with simulated cancer patients was recorded prior and 6 months after CST. Defenses were measured before and after CST and correlated with a prototype of an ideally conducted interview based on the criteria of CST-teachers. Clinicians who used more adaptive defense mechanisms showed better adherence to communication skills after CST than clinicians with less adaptive defenses (F(1, 29) = 5.26, p = 0.03, d = 0.42). Improvement in communication skills after CST seems to depend on the initial levels of defenses of the clinician prior to CST. Implications for practice and training are discussed. Communication has been recognized as a central element of cancer care [1]. Ineffective communication may contribute to patients' confusion, uncertainty, and increased difficulty in asking questions, expressing feelings, and understanding information [2, 3], and may also contribute to clinicians' lack of job satisfaction and emotional burnout [4]. Therefore, communication skills trainings (CST) for oncology clinicians have been widely developed over the last decade. These trainings should increase the skills of clinicians to respond to the patient's needs, and enhance an adequate encounter with the patient with efficient exchange of information [5]. While CSTs show a great diversity with regard to their pedagogic approaches [6, 7], the main elements of CST consist of (1) role play between participants, (2) analysis of videotaped interviews with simulated patients, and (3) interactive case discussion provided by participants. As recently stated in a consensus paper [8], CSTs need to be taught in small groups (up to 10-12 participants) and have a minimal duration of at least 3 days in order to be effective. Several systematic reviews evaluated the impact of CST on clinicians' communication skills [9-11]. Effectiveness of CST can be assessed by two main approaches: participant-based and patient-based outcomes. Measures can be self-reported, but, according to Gysels et al. [10], behavioral assessment of patient-physician interviews [12] is the most objective and reliable method for measuring change after training. Based on 22 studies on participants' outcomes, Merckaert et al. [9] reported an increase of communication skills and participants' satisfaction with training and changes in attitudes and beliefs. The evaluation of CST remains a challenging task and variables mediating skills improvement remain unidentified. We recently thus conducted a study evaluating the impact of CST on clinicians' defenses by comparing the evolution of defenses of clinicians participating in CST with defenses of a control group without training [13]. Defenses are unconscious psychological processes which protect from anxiety or distress. Therefore, they contribute to the individual's adaptation to stress [14]. Perry refers to the term "defensive functioning" to indicate the degree of adaptation linked to the use of a range of specific defenses by an individual, ranging from low defensive functioning when he or she tends to use generally less adaptive defenses (such as projection, denial, or acting out) to high defensive functioning when he or she tends to use generally more adaptive defenses (such as altruism, intellectualization, or introspection) [15, 16]. Although several authors have addressed the emotional difficulties of oncology clinicians when facing patients and their need to preserve themselves [7, 17, 18], no research has yet been conducted on the defenses of clinicians. For example, repeated use of less adaptive defenses, such as denial, may allow the clinician to avoid or reduce distress, but it also diminishes his ability to respond to the patient's emotions, to identify and to respond adequately to his needs, and to foster the therapeutic alliance. Results of the above-mentioned study [13] showed two groups of clinicians: one with a higher defensive functioning and one with a lower defensive functioning prior to CST. After the training, a difference in defensive functioning between clinicians who participated in CST and clinicians of the control group was only showed for clinicians with a higher defensive functioning. Some clinicians may therefore be more responsive to CST than others. To further address this issue, the present study aimed to evaluate the relationship between the level of adherence to an "ideally conducted interview", as defined by the teachers of the CST, and the level of the clinician' defensive functioning. We hypothesized that, after CST, clinicians with a higher defensive functioning show a greater adherence to the "ideally conducted interview" than clinicians with a lower defensive functioning.

Synergistic effect of GDNF and NGF on axonal branching and elongation in vitro.

There is a clinical need to enhance functional recovery of injured peripheral nerves. Local administration of neurotrophic factors (NTFs) after surgical repair has been proposed for this purpose. Little is known, however, on the optimal local dose and dosing frequency of NTFs in a peripheral nerve defect. For increasing our knowledge on biologically relevant local NTFs concentrations and for making available an in vitro assay for assessing the bioactivity of NTFs in connection with implantable localized delivery systems, we developed in this study a bioassay for NTFs, which is based on dorsal root ganglion (DRG) explants from E9 (9 days old) chicken embryos. Axonal elongation and extent of axonal branching was analyzed microscopically after addition of glial cell line-derived neurotrophic factor (GDNF) and nerve growth factor (NGF), each alone and in combination. GDNF significantly promoted axonal elongation, but only little axonal branching, whereas NGF induced extensive axonal branching with modest axonal elongation. The combination of GDNF and NGF exerted a synergistic effect on the axonal elongation, axonal branching and growth kinetics. GDNF and NGF also enhanced the expression of their respective functional receptors Ret and TrkA on the DRG neurons. This information should be relevant for the development of implants containing NTFs and on drug therapy of damaged peripheral nerves.

5-HT2A and alpha1b-adrenergic receptors entirely mediate dopamine release, locomotor response and behavioural sensitization to opiates and psychostimulants.

Addictive properties of drugs of misuse are generally considered to be mediated by an increased release of dopamine (DA) in the ventral striatum. However, recent experiments indicated an implication of alpha1b-adrenergic receptors in behavioural responses to psychostimulants and opiates. We show now that DA release induced in the ventral striatum by morphine (20 mg/kg) is completely blocked by prazosin (1 mg/kg), an alpha1-adrenergic antagonist. However, morphine-induced increases in DA release in the ventral striatum were found to be similar in mice deleted for the alpha1b-adrenergic receptor (alpha1b-AR KO) and in wild-type (WT) mice, suggesting the presence of a compensatory mechanism. This acute morphine-evoked DA release was completely blocked in alpha1b-AR KO mice by SR46349B (1 mg/kg), a 5-HT2A antagonist. SR46349B also completely blocked, in alpha1b-AR KO mice, the locomotor response and the development of behavioural sensitization to morphine (20 mg/kg) and D-amphetamine (2 mg/kg). Accordingly, the concomitant blockade of 5-HT2A and alpha1b-adrenergic receptors in WT mice entirely blocked acute locomotor responses but also the development of behavioural sensitization to morphine, D-amphetamine or cocaine (10 mg/kg). We observed, nevertheless, that inhibitory effects of each antagonist on locomotor responses to morphine or D-amphetamine were more than additive (160%) in naïve WT mice but not in those sensitized to either drug. Because of these latter data and the possible compensation by 5-HT2A receptors for the genetic deletion of alpha1b-adrenergic receptors, we postulate the existence of a functional link between these receptors, which vanishes during the development of behavioural sensitization.

Posterior cortical atrophy: review of the recent literature.

Posterior cortical atrophy (PCA) is a group of neurodegenerative dementing disorders characterized by initial predominant visual complaints followed by progressive decline in cognitive functions. The visuospatial and visuoperceptual defects arise from the dysfunction of, respectively, the dorsal (occipito-parietal) and the ventral (occipito-temporal) streams. Clinical symptoms, results of neuropsychological examination, and findings of posterior cerebral atrophy and/or posterior hypoperfusion/hypometabolism contribute to the diagnosis. However, owing to the insidious onset of PCA and the non-specificity of initial symptoms, the diagnosis is often delayed. Specific etiologies include Alzheimer's disease, dementia with Lewy bodies, subcortical gliosis, corticobasal degeneration, and prion-associated diseases. Alzheimer's disease accounts for at least 80 % of PCA cases. Recent research has concentrated on better defining the clinical presentation of PCA, improving neuroimaging analysis, testing new neuroimaging techniques, and developing biological measurements. Selected recent papers on PCA are reviewed in this article.