Prenatal exposure to sodium valproate alters androgen receptor expression in the developing cerebellum in a region and age specific manner in male and female rats

Valproic acid (VPA) is an anti-epileptic drug with teratogenicity activity that has been related to autism. In rodents, exposure to VPA in utero leads to brain abnormalities similar than those reported in the autistic brain. Particularly, VPA reduces the number of Purkinje neurons in the rat cerebellum parallel to cerebellar abnormalities found in autism. Thus, we injected pregnant females on embryonic day 12 either with VPA (600 mg/kg, i.p.) or 0.9% saline solution and obtained the cerebellum from their offspring at different postnatal time points. Testosterone has been linked to autism and plays an important role during brain development. Therefore, we identified and analyzed the androgen receptor (AR) by immunohistochemistry and densitometry, respectively. We found VPA decreases AR density in the superficial Purkinje layer only in cerebellar lobule 8 at PN7, but increased it at PN14 compared to control in males. In females, VPA decreased AR density in the superficial Purkinje layer in cerebellar lobule 6 at PN14, but increased it in lobule 9 at the same time point. No differences were found in the deep Purkinje layer of any cerebellar lobule in terms of AR density neither in males nor females. We additionally found a particular AR density decreasing in both superficial and deep regions across development in the majority of cerebellar lobules in males, but in all cerebellar lobules in females. Thus, our results indicate that VPA disrupts the AR ontogeny in the developing cerebellum in an age and region specific manner in male and female rats. Future epigenetic studies including the evaluation of histone deacetylases (HDAC’s) might shed light these results as HDAC’s are expressed by Purkinje neurons, interact with the AR and are VPA targets. This work contributes to the understanding of the cerebellar development and it might help to understand the role of the cerebellum in neurodevelopmental disorders such as autism.This research was supported by CONACYT (Consejo Nacional de Ciencia y Tecnologia of Mexico Grant 106531 to Maria Elena Hernandez (MEH) and CONACYT Doctorate scholarship 205779 to Miguel Perez Pouchoulen (MPP). Authors thank M.S. Dulce Mariely Alvarez-Croda for her valuable comments to the manuscript

El cerebelo en el Autismo

Autism is considered as a neurodevelopmental disorder which affects boys more than girls, in a proportion 4:1 respectively. Autism presents neuroanatomical abnormalities located in the frontal cortex, the amygdala and the cerebellum. Autistic cerebellar postmortem studies have revealed a reduced number of Purkinje cells as well as a reduced Purkinje cell size when compared with non-autistic subjects. These anatomical alterations compromise the role of the cerebellum in cognitive, motor, emotional, learning and memory neural processes resulting in a different interpretation of the world, and therefore a different way to respond and behave. There are both biological and environmental insults causing the behavioral and neuroanatomical autistic phenotype. Valproic acid, an antiepileptic drug, has been related to some autistic cases after mothers were under medication with this drug during the first trimester of gestation and given birth autistic children. Therefore, in this brief review we analyzed the most recent advances of autism research in humans, with a primary focus on the use of valproic acid as a teratogen that mimics in rats some of the neuroanatomical alterations seen in autistic humans. In addition to the peculiar cerebellar pathology, all of this to shed light on a better understating of this disorder.El autismo es un trastorno generalizado del desarrollo que afecta más a varones que mujeres, con una proporción de 4 a 1, respectivamente. Dentro de sus características neuropatológicas más sobresalientes se encuentran la alteración anatómica de diversas estructuras del sistema nervioso central como la corteza frontal, la amígdala y el cerebelo. Estudios post mórtem en cerebelos de sujetos autistas han mostrado una notable disminución en el número de neuronas de Purkinje así como en su tamaño, comparado con las de sujetos sanos. Estas alteraciones anatómicas comprometen la participación del cerebelo en los procesos neurales como la cognición, actividad motora, la emoción, el aprendizaje y la memoria, dando como resultado una interpretación diferente del mundo que impacta sobre la respuesta y el comportamiento de los sujetos autistas. Actualmente se desconoce la causa de estas alteraciones anatómicas y aunque se avanza rápido en la ciencia se tiene la limitante de los sujetos experimentales, que en este caso son humanos. Por lo tanto, en esta revisión analizamos los hallazgos más relevantes de la patología cerebelar en el autismo, así como el uso del ácido valproico en ratas como teratógeno para simular alteraciones cerebelares como las observadas en autistas, contribuyendo a un mejor entendimiento de su neuropatología

Novel genetic loci associated with hippocampal volume

The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (rg =-0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness

Novel genetic loci underlying human intracranial volume identified through genome-wide association

Intracranial volume reflects the maximally attained brain size during development, and remains stable with loss of tissue in late life. It is highly heritable, but the underlying genes remain largely undetermined. In a genome-wide association study of 32,438 adults, we discovered five novel loci for intracranial volume and confirmed two known signals. Four of the loci are also associated with adult human stature, but these remained associated with intracranial volume after adjusting for height. We found a high genetic correlation with child head circumference (ρgenetic=0.748), which indicated a similar genetic background and allowed for the identification of four additional loci through meta-analysis (Ncombined = 37,345). Variants for intracranial volume were also related to childhood and adult cognitive function, Parkinson’s disease, and enriched near genes involved in growth pathways including PI3K–AKT signaling. These findings identify biological underpinnings of intracranial volume and provide genetic support for theories on brain reserve and brain overgrowth

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder

The cerebellum in autism

Autism is considered as a neurodevelopmental disorder which affects boys more than girls, in a proportion 4:1 respectively. Autism presents neuroanatomical abnormalities located in the frontal cortex, the amygdala and the cerebellum. Autistic cerebellar postmortem studies have revealed a reduced number of Purkinje cells as well as a reduced Purkinje cell size when compared with non-autistic subjects. These anatomical alterations compromise the role of the cerebellum in cognitive, motor, emotional, learning and memory neural processes resulting in a different interpretation of the world, and therefore a different way to respond and behave. There are both biological and environmental insults causing the behavioral and neuroanatomical autistic phenotype. Valproic acid, an antiepileptic drug, has been related to some autistic cases after mothers were under medication with this drug during the first trimester of gestation and given birth autistic children. Therefore, in this brief review we analyzed the most recent advances of autism research in humans, with a primary focus on the use of valproic acid as a teratogen that mimics in rats some of the neuroanatomical alterations seen in autistic humans. In addition to the peculiar cerebellar pathology, all of this to shed light on a better understating of this disorder.El autismo es un trastorno generalizado del desarrollo que afecta más a varones que mujeres, con una proporción de 4 a 1, respectivamente. Dentro de sus características neuropatológicas más sobresalientes se encuentran la alteración anatómica de diversas estructuras del sistema nervioso central como la corteza frontal, la amígdala y el cerebelo. Estudios post mórtem en cerebelos de sujetos autistas han mostrado una notable disminución en el número de neuronas de Purkinje así como en su tamaño, comparado con las de sujetos sanos. Estas alteraciones anatómicas comprometen la participación del cerebelo en los procesos neurales como la cognición, actividad motora, la emoción, el aprendizaje y la memoria, dando como resultado una interpretación diferente del mundo que impacta sobre la respuesta y el comportamiento de los sujetos autistas. Actualmente se desconoce la causa de estas alteraciones anatómicas y aunque se avanza rápido en la ciencia se tiene la limitante de los sujetos experimentales, que en este caso son humanos. Por lo tanto, en esta revisión analizamos los hallazgos más relevantes de la patología cerebelar en el autismo, así como el uso del ácido valproico en ratas como teratógeno para simular alteraciones cerebelares como las observadas en autistas, contribuyendo a un mejor entendimiento de su neuropatología

Cuidado maternal: madres eficientes e ineficientes

The bond between mother and offspring is a fundamental aspect of individual development. The mother is the one who provides care and seeks infant survival. The quality of such care will depend largely on the state of physical health and an environment with greater opportunity to meet basic needs and a low stress. This topic has been studied from many perspectives, such as psychological, medical and social. Recently described some neurobiological processes motherhood as they are; the impact of motheroffspring relationship both in the nervous system of the infant and mother. In raising this relationship affect all its development from its fetal stage to adulthood. In this paper we explore what today is known in the literature about the mother-infant in the development of a healthy individual and the link between a poor relationship and alterations in the development of progeny or even no offspring survival.El vínculo entre la madre y su descendencia es un aspecto fundamental del desarrollo del individuo. La madre es la que brinda cuidados y procura la supervivencia del infante. La calidad de dicha atención dependerá en gran medida del estado de salud física y de un ambiente propicio con mayor oportunidad de cubrir las necesidades básicas, así como un bajo nivel de estrés. Este tema ha sido estudiado desde muchas perspectivas, como la psicológica, médica y social. Recientemente se han descrito algunos procesos neurobiológicos de la maternidad, como son; el impacto de la relación madre-cría tanto en el sistema nervioso del infante como de la madre. En la cría esta relación afectará todo su desarrollo, desde su etapa fetal, hasta la adultez. En este trabajo exploramos lo que hasta hoy se conoce en la literatura acerca de del vínculo madre-cría en el desarrollo de un individuo sano y la correspondencia de un vínculo deficiente con alteraciones en el desarrollo de la progenie o incluso la no supervivencia

PALVELUTUOTTEEN HINNOITTELUN KEHITTÄMINEN

Tämän opinnäytetyön aiheena on palvelutuotteen hinnoittelun kehittäminen. Tutkimuksen kohteena on Tili- ja isännöitsijätoimisto Ky. Tili- ja isännöitsijätoimisto Ky on Vaasassa toimiva tili- ja isännöintitoimisto, joka tarjoaa taloushallinto- ja isännöintipalveluita yrityksille. Tutkimuksen tavoitteena on kehittää Tili- ja isännöitsijätoimisto Ky:n isännöitsijän palvelutuotteiden hinnoittelua. Hinnoittelumenetelmäksi valittiin toimintoperusteinen hinnoittelu, jonka lähtökohtana on selvittää asiakaskohtaisia välillisiä kustannuksia. Kysymys oli suorite-kohtaisten kustannusten laskemisesta, eli toimintoperusteisesta prosessilaskennasta. Toimintoperusteinen prosessilaskenta tukee hinnoittelun päätöstä. Toiminto-analyysin jälkeen selvitettiin resurssien kohdistumista yrityksen eri toiminnoille. Aluksi selvitettiin yrityksen kustannusajuri, jonka perusteella kustannukset on kohdistettu eri toiminnoille. Seuraavaksi selvitettiin toimintoajurin avulla toimintoihin liittyvät yksikkökustannukset. Tuotteiden hinnoittelussa myyntihinnan on tarkoituksena sisältää kaikkien kustannusten lisäksi voittotavoite. Tutkimuksen teoriaosuuden keskeisiä asioita ovat toimintoperusteisen kustannuslaskennan, sekä hinnoittelun perusteiden esittely. Niiden avulla voidaan perustella hinnoittelupäätöstä tukeva toimintolaskenta. Opinnäytetyössä esitellään lisäksi kustannusperusteista hinnoittelua sekä isännöintiä ja tilitoimistoa yleisesti. Tutkimusmenetelmänä käytettiin kvalitatiivista eli laadullista tutkimusta. Tutkimuksen teoriaosuuteen käytettiin toimintolaskennan, taloushallinnon alan sekä hinnoittelun teoriaan liittyvää kirjallisuutta. Aineistonkeruussa havainnoitiin yrityksen tilinpäätöstä vuodelta 2016 ja yrityksen toimintaa liittyviä ohjelmia sekä tietokantoja. Lisäksi haastateltiin Tili- ja isännöitsijätoimisto Ky:n omistajaa ja työntekijöitä.This research was designed to develop the used pricing method for the case firm Tili- ja isännöitsijätoimisto Ky. The main area of this research focused on the main service products in property management. The case firm offers financial accounting and management services to house companies and other customer companies. Activity based costing was selected as the new pricing method in order to identify the customer-specific indirect costs. The aim of activity-based costing was to support pricing decisions for the case firm. In the implementation steps, activities must be identified first, and then the process continues with an activity analysis. Once the costs of activity and its drivers have been identified and its costs have been determined, then the costs of activity is allocated to the service product. In the allocation process, when the activity driver has been determined, the cost per unit can then be determined. Once the product cost per unit has been determined then the case firm considers the generated value of its service product, so the pricing of all the service product sales cover the fixed expenses with any remaining contribution margin providing profits. The theoretical study of this thesis introduced activity based costing and pricing to support activity based cost implementation and pricing decisions. In addition, it introduced cost based pricing and property management business and accounting firms in general. This research was implemented using the qualitative research method. The research material consists of related activity based costing, financial management, management accounting and pricing literature. The theoretical information was gathered from scientific research, academic books and some material was collect-ed from the Internet. The empirical data in this research was gathered by observing the case company’s financial statement from the year 2016 together with some business activities related programs and databases. In addition, was collected by interviewing the case company owner and the other employers of the company

Sleep characteristics across the lifespan in 1.1 million people from the Netherlands, United Kingdom and United States:a systematic review and meta-analysis

We aimed to obtain reliable reference charts for sleep duration, estimate the prevalence of sleep complaints across the lifespan and identify risk indicators of poor sleep. Studies were identified through systematic literature search in Embase, Medline and Web of Science (9 August 2019) and through personal contacts. Eligible studies had to be published between 2000 and 2017 with data on sleep assessed with questionnaires including ≥100 participants from the general population. We assembled individual participant data from 200,358 people (aged 1-100 years, 55% female) from 36 studies from the Netherlands, 471,759 people (40-69 years, 55.5% female) from the United Kingdom and 409,617 people (≥18 years, 55.8% female) from the United States. One in four people slept less than age-specific recommendations, but only 5.8% slept outside of the 'acceptable' sleep duration. Among teenagers, 51.5% reported total sleep times (TST) of less than the recommended 8-10 h and 18% report daytime sleepiness. In adults (≥18 years), poor sleep quality (13.3%) and insomnia symptoms (9.6-19.4%) were more prevalent than short sleep duration (6.5% with TST < 6 h). Insomnia symptoms were most frequent in people spending ≥9 h in bed, whereas poor sleep quality was more frequent in those spending <6 h in bed. TST was similar across countries, but insomnia symptoms were 1.5-2.9 times higher in the United States. Women (≥41 years) reported sleeping shorter times or slightly less efficiently than men, whereas with actigraphy they were estimated to sleep longer and more efficiently than man. This study provides age- and sex-specific population reference charts for sleep duration and efficiency which can help guide personalized advice on sleep length and preventive practices