PACAP promotes neural stem cell proliferation in adult mouse brain

In recent years, it has become evident that neural stem cells in the adult mammalian brain continuously generate new neurons, mainly in the hippocampus and olfactory bulb. Although different growth factors have been shown to stimulate neurogenesis in the adult brain, very little is known about the role of neuropeptides in this process. Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide with pleiotropic effects acting through three receptors to which it has high affinity, namely, PACAP receptor 1 (PAC1), vasoactive intestinal peptide (VIP) receptor 1, and VIP receptor 2. We show that PAC1 is expressed in the neurogenic regions of the adult mouse brain, namely the ventricular zone of the lateral ventricle and the hippocampal dentate gyrus. Cultured neural stem cells isolated from the lateral ventricle wall of adult mice express PAC1 and proliferate in vitro in response to two PAC1 agonists, PACAP and Maxadilan, but not VIP at physiologic concentrations, indicating PAC1 as a mediator of neural stem cell proliferation. Pharmacologic and biochemical characterization of PACAP-induced neural stem cell proliferation revealed the protein kinase C pathway as the principal signaling pathway, whereas addition of epidermal growth factor synergistically enhanced the proliferating effect of PACAP. Further in vitro characterization of the effect of PACAP on neural stem cells showed PACAP capable of stimulating ex novo in vitro formation of multipotent neurospheres with the capacity to generate both neuronal and glial cells. Finally, intracerebroventricular infusion of PACAP increases cell proliferation in the ventricular zone of the lateral ventricle and the dentate gyrus of the hippocampus. We conclude that PACAP, through PAC1, is a potent mediator of adult neural stem cell proliferation.     

Rapid eye movement sleep behavior disorder in parkinsonism with parkin mutations

Rapid eye movement sleep behavior disorder (RBD) in the setting of parkinsonism or dementia often reflects an underlying synucleinopathy. Lewy bodies, intraneuronal aggregates containing abnormal alpha-synuclein, are absent in most cases of parkinsonism with parkin mutations (Park2). We performed clinical history and video-polysomnography in 10 Park2 patients (seven men; age, 51.2 +/- 11.6 years; parkinsonism duration, 18.3 +/- 11.2 years) and found RBD in 6. In all instances, RBD followed the onset of motor symptoms by several years. Our study shows that RBD is frequent in Park2, suggesting that mechanisms other than synuclein deposition can cause RBD in neurodegenerative disorders.     

AACAP 2002 research forum: placebo and alternatives to placebo in randomized controlled trials in pediatric psychopharmacology

OBJECTIVE: The use of placebo in the pediatric age group has come under increasing scrutiny. At the 2002 Annual Meeting of the American Academy of Child and Adolescent Psychiatry, the Academy's Workgroup on Research conducted a research forum. The purpose was to identify challenges and their solutions regarding the use of placebo in randomized controlled trials in pediatric psychopharmacology. METHOD: Workgroups focused on problems and solutions in five areas: ethics and human subjects, research design and statistics, partnering with consumers, U.S. Food and Drug Administration and pharmaceutical industry perspectives, and psychosocial treatments. RESULTS: In many but not all circumstances, inclusion of a placebo control is essential to meet the scientific goals of treatment outcome research. Innovative research designs; involvement of consumers in planning and implementing research; flexibility by industry, academia, the National Institutes of Health, and regulatory agencies acting in partnership; and concomitant use of evidence-based psychosocial services can and should assist in making placebo-controlled trials acceptable. CONCLUSIONS: Properly designed placebo-controlled trials remain necessary, ethical, and feasible.     

Predicting depression, social phobia, and violence in early adulthood from childhood behavior problems

OBJECTIVE: This study examined childhood behavior problems at ages 10 and 11 years as predictors of young adult depression, social phobia, and violence at age 21 years. METHOD: Data were collected as part of the Seattle Social Development Project, a longitudinal study of 808 elementary school students from high-crime neighborhoods of Seattle. Reports of childhood behavior problems were obtained from parents and children in fall 1985 and from teachers in spring 1986. Follow-up reports of violence and DSM-III-R depression and social phobia were collected from 765 respondents using standard survey items and the Diagnostic Interview Schedule in 1996. RESULTS: The past-year prevalences of depressive episode and social phobia were 20% and 17%, respectively. Twenty-one percent of the respondents reported two or more violent acts in the past year at age 21 years. Several available measures of childhood behavior problems as reported by parents, teachers, and children predicted violence (e.g., conduct problems, oppositional defiance); the strongest positive predictor of young adult violence was self-reported conduct problems, whereas self-reported shyness inhibited later violence. Relatively few child behavioral problems predicted social phobia (e.g., shyness). Results showed that children who reported higher, relative to lower, levels of conduct problems were nearly four times more likely to experience a depressive episode in early adulthood. CONCLUSIONS: Findings suggest the potential value of intervening to reduce childhood conduct problems as a prevention strategy for not only violence but also depression.     

Obsessive-compulsive severity spectrum in the community: prevalence,comorbidity, and course

OBJECTIVES: To describe lifetime prevalence rates, course and comorbidity of obsessive-compulsive disorder (OCD), obsessive-compulsive syndromes (OCS) and OC-symptoms (OC-sx) up to age 41. METHODS: In the Zurich community cohort study 591 subjects were selected after screening at the age of 19 and studied prospectively by 6 interviews from 20 to 40; they represent 1599 subjects of the normal population. The diagnoses of OCD met DSM-IV criteria.Course was assessed by graphic illustrations and prospective data. RESULTS: The lifetime prevalence rate was 3.5 % for OCD (males 1.7%, females 5.4 %) and 8.7 % for OCS (males 9.9%, females 7.5 %). The onset of OC-sx was 18 years (median); and in 70% before age 20. OCD was treated in one third of cases, OCS in 6.1%. The course of symptoms was chronic in 60%,but OCD and OCS showed in most cases considerable improvements over time. OCD reduced quality of life mostly in the subject's psychological wellbeing and at work but to a considerable extent also in other social roles. Comorbidity was prominent with bipolar disorder, panic disorder and social phobia and also significant with bulimia, binge eating, generalized anxiety disorder and suicide attempts; there was no association with substance abuse/dependence. CONCLUSION: OCD and OCD are manifestations of a wide spectrum of severity with high prevalence and strong clinical validity. The long-term course is better than generally assumed.     

Is bipolar I disorder heterogeneous?

Abstract.Objectives: The question whether bipolar I disorder should be subdivided into a preponderantly manic group (M) with no depression or only mild depression (Md) and a nuclear manic-depressive group (MD) has been rarely studied although the problem was raised more than 50 years ago. This paper seeks to elucidate this question by contributing further data.Methods: 406 patients with mood disorders hospitalised at some time during the period 1959–1963 were followed-up every five years until 1985; mortality data were collected up to 1997. Data on episodes, outcome, suicides and attempted suicides, alcohol and substance abuse/dependence and long-term medication, as well as on personality (melancholic and manic type) were collected. Major mood disorders were subclassified according to their hospitalisation for depression (D) and/or mania (M).Results: 30 manic patients (M/Md), 130 bipolar I (MD), 60 bipolar II patients (Dm) and 186 major depressive patients (D) were compared. The manic group differed from the bipolar I group in several variables: better school achievement, milder course of the illness (fewer recurrences), significantly less suicidality and a trend to less chronicity and more recovery. Manic patients required less long-term medication than bipolars and they differed in personality types from bipolars, the personality of manic patients being more often of the manic rather than the melancholic type, they were also more aggressive than bipolars. The family history data showed that the overall morbidity risk of first degree relatives of manic patients was significantly lower than that of bipolar patients.Conclusions: In accord with several other studies our data point to the existence of a more manic (M/Md) group of bipolar subjects. The diagnosis predicts a better course, lower suicidality and fewer and different treatment needs than does nuclear bipolar I (MD) disorder. The M/Md groups, as clinically interesting subgroups of the mood spectrum, should become a target of further research.     

S1P and LPA trigger Schwann cell actin changes and migration

The processes by which a Schwann cell (SC) migrates towards, wraps around and, in some cases, myelinates an axon are incompletely understood. The complex morphological rearrangements involved in these events require fundamental changes in the actin cytoskeleton. Sphingosine 1-phosphate (S1P) and lysophosphatidic acid (LPA) are two modulators of the actin cytoskeleton, and receptors for these signalling lipids are expressed on SCs at the time of differentiation. Previous work has revealed a role for LPA in SC survival, morphology and differentiation, but the effects of S1P have received less attention. Here we show that S1P and LPA both cause major rearrangements to the actin cytoskeleton in primary rat SCs and the SCL4.1/F7 rat SC line. S1P and LPA caused formation of lamellipodia and a circular geodesic actin network. We also show that S1P and LPA increased cell migration. The small GTPases RhoA and Rac1 were both activated by S1P/LPA treatment, but the actin rearrangements were dependent on Rac1 and not RhoA. These effects of S1P/LPA could be mimicked by SCL4.1/F7 cell-conditioned medium, which was found to contain S1P. Reduction in cellular synthesis of S1P by adding the sphingosine kinase inhibitor dimethyl sphingosine during medium conditioning reduced the ability of conditioned medium to cause actin rearrangements. These results support a role for S1P as an autocrine signal regulating the actin cytoskeleton during Schwann cell development.     

Magnocellular mediated visual-spatial attention and reading ability

This study explores the relationship between attentional processing mediated by visual magnocellular (MC) processing and reading ability. Reading ability in a group of primary school children was compared to performance on a visual cued coherent motion detection task. The results showed that a brief spatial cue was more effective in drawing attention either away or towards a visual target in the group of readers ranked in the upper 25% of the sample compared to lower ranked readers. Regression analysis showed a significant relationship between attentional processing and reading when the effects of age and intellectual ability were removed. Results suggested a stronger relationship between visual attentional and non-word reading compared to irregular word reading.